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Article ; Online: Evaluation of Barrier Integrity Using a Two-Layered Microfluidic Device Mimicking the Blood-Brain Barrier.

Kadry, Hossam / Cucullo, Luca

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2711, Page(s) 77–88

Abstract: The blood-brain barrier (BBB) plays an essential role in maintaining the homeostasis of the brain microenvironment by controlling the influx and efflux of biological substances that are necessary to sustain the neuronal metabolic activity and functions. ... ...

Abstract	The blood-brain barrier (BBB) plays an essential role in maintaining the homeostasis of the brain microenvironment by controlling the influx and efflux of biological substances that are necessary to sustain the neuronal metabolic activity and functions. This barrier is established at the blood-brain interface of the brain microcapillaries by different cells. These include microvascular endothelial cells, astrocytes, and pericytes besides other components such as microglia, basal membrane, and neuronal cells forming together what is commonly referred to as the neurovascular unit; different in vivo and in vitro platforms are available to study the BBB where each system provides specific benefits and drawbacks. Recently, organ-on-a-chip platforms combine the elegance of microengineering technology with the complexity of biological systems to create near-ideal experimental models for various diseases and organs. These microfluidic devices with micron-sized channels allow the cells to be grown in a more biologically relevant environment, enabling cell to cell communications with continuous bathing in biological fluids in a tissue-like fashion. They also closely represent tissue and organ functionality by recapitulating mechanical forces as well as vascular perfusion. Here, we describe the use of humanized BBB model created with microfluidic organ-on-a-chip technology where human brain microvascular endothelial cells (BMECs) are cocultured with primary human pericytes and astrocytes. We thoroughly described the method to assess BBB integrity using a microfluidic chip and various sizes of labeled dextran as permeability markers. In addition, we provide a detailed protocol on how to microscopically investigate the tight junction proteins expression between hBMECs.
MeSH term(s)	Humans ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; Brain ; Astrocytes/metabolism ; Lab-On-A-Chip Devices
Language	English
Publishing date	2023-09-29
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3429-5_7
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Article ; Online: HIV-1 gp120 and tobacco smoke synergistically disrupt the integrity of the blood-brain barrier.

Bhalerao, Aditya / Cucullo, Luca

European journal of cell biology

2022 Volume 101, Issue 4, Page(s) 151271

Abstract: In the United States, the Centers for Disease Control and Prevention (CDC) terms HIV and tobacco use among the ten most important public health challenges we face today. In the last decade, there has been a remarkable decrease in the number of deaths due ...

Abstract	In the United States, the Centers for Disease Control and Prevention (CDC) terms HIV and tobacco use among the ten most important public health challenges we face today. In the last decade, there has been a remarkable decrease in the number of deaths due to HIV/AIDS, especially after the widespread availability and use of combination antiretroviral therapy (cART). However, people living with HIV/AIDS have a heightened risk of chronic complications and comorbidities, including neurological disorders. Around 40-60 % of HIV-infected individuals progress to NeuroAIDS, a group of disorders caused primarily by HIV-mediated damage to the central and peripheral nervous systems, despite receiving cART. The detrimental effects of chronic smoking on the cerebrovascular system are also well studied and reported. Addictive behavior, such as smoking, is more common in HIV patients compared to the general population. In this context, given the existing immune suppression, smoking can pose a significant risk for the progression of the disease to NeuroAIDS by disrupting the integrity of the blood-brain barrier (BBB). Here we show that co-treatment with Tobacco Smoke Extract (TSE) and HIV-1 gp120 (HIV envelope glycoprotein) in primary cultures of human brain microvascular endothelial cells promoted heightened cellular stress responses compared to control and individual treatments. Our findings suggest that a potential synergistic effect between smoke exposure and gp120 can worsen the loss of BBB viability, possibly exacerbating NeuroAIDS progression.
MeSH term(s)	Humans ; Blood-Brain Barrier ; HIV-1 ; Tobacco Smoke Pollution ; HIV Infections ; Endothelial Cells
Chemical Substances	Tobacco Smoke Pollution
Language	English
Publishing date	2022-08-24
Publishing country	Germany
Document type	Journal Article
ZDB-ID	391967-5
ISSN	1618-1298 ; 0070-2463 ; 0171-9335
ISSN (online)	1618-1298
ISSN	0070-2463 ; 0171-9335
DOI	10.1016/j.ejcb.2022.151271
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Article ; Online: Regenerative Stem Cell Therapy for Neurodegenerative Diseases: An Overview.

Sivandzade, Farzane / Cucullo, Luca

International journal of molecular sciences

2021 Volume 22, Issue 4

Abstract: Neurodegenerative diseases resulting from the progressive loss of structure and/or function of neurons contribute to different paralysis degrees and loss of cognition and sensation. The lack of successful curative therapies for neurodegenerative ... ...

Abstract	Neurodegenerative diseases resulting from the progressive loss of structure and/or function of neurons contribute to different paralysis degrees and loss of cognition and sensation. The lack of successful curative therapies for neurodegenerative disorders leads to a considerable burden on society and a high economic impact. Over the past 20 years, regenerative cell therapy, also known as stem cell therapy, has provided an excellent opportunity to investigate potentially powerful innovative strategies for treating neurodegenerative diseases. This is due to stem cells' capability to repair injured neuronal tissue by replacing the damaged or lost cells with differentiated cells, providing a conducive environment that is in favor of regeneration, or protecting the existing healthy neurons and glial cells from further damage. Thus, in this review, the various types of stem cells, the current knowledge of stem-cell-based therapies in neurodegenerative diseases, and the recent advances in this field are summarized. Indeed, a better understanding and further studies of stem cell technologies cause progress into realistic and efficacious treatments of neurodegenerative disorders.
MeSH term(s)	Animals ; Cell Differentiation ; Humans ; Neurodegenerative Diseases/therapy ; Neurons/pathology ; Neurons/physiology ; Regeneration/physiology ; Regenerative Medicine/methods ; Stem Cell Transplantation/methods ; Stem Cells/classification
Language	English
Publishing date	2021-02-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22042153
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Article ; Online: Use of Conventional Cigarette Smoking and E-Cigarette Vaping for Experimental Stroke Studies in Mice.

Mancuso, Salvatore / Bhalerao, Aditya / Cucullo, Luca

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2616, Page(s) 441–451

Abstract: Cigarette smoking is a major prodromal factor for the onset of many adverse health effects that may occur in the short run and is the leading cause of preventable disease, disability, and death in the United States. Moreover, it is well established that ... ...

Abstract	Cigarette smoking is a major prodromal factor for the onset of many adverse health effects that may occur in the short run and is the leading cause of preventable disease, disability, and death in the United States. Moreover, it is well established that chronic smoking is associated with vascular endothelial dysfunction in a causative and dose-dependent manner primarily related to the release of reactive oxygen species (ROS), nicotine, and the induction of oxidative stress (OS)-driven inflammation. Preclinical studies have also shown that nicotine (the principal e-liquid ingredient used in e-cigarettes) can also cause OS, exacerbating cerebral ischemia and secondary brain injury. Likewise, chronic e-Cig vaping could be prodromal to cerebrovascular impairment and promote cerebrovascular conditions favoring stroke onset and worsening post-ischemic brain injury. Therefore, using mouse models is crucial to understand how xenobiotics such as those released by conventional and/or e-cigs can impact the onset and severity of stroke as well as post-stroke recovery. To appropriately model human-like smoking/vaping behavior in mice, however, the exposure to these xenobiotics must be standardized and undertaken in a controlled environment. This chapter describes a well-validated protocol to reproduce standardized chronic tobacco smoke or e-cigarette vape exposure in mice in the setting of a mouse transient ischemic stroke model.
MeSH term(s)	Mice ; Humans ; Animals ; Electronic Nicotine Delivery Systems ; Nicotine/adverse effects ; Vaping/adverse effects ; Cigarette Smoking/adverse effects ; Xenobiotics ; Stroke/etiology ; Brain Injuries
Chemical Substances	Nicotine (6M3C89ZY6R) ; Xenobiotics
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2926-0_31
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Article ; Online: In Vitro Models of the Blood-Brain Barrier.

Raut, Snehal / Bhalerao, Aditya / Noorani, Behnam / Cucullo, Luca

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2492, Page(s) 25–49

Abstract: Traditional in vitro models can replicate many essential features of drug transport/permeability across the blood-brain barrier (BBB) but are not entirely projecting in vivo central nervous system (CNS) uptake. Species differences fail to translate ... ...

Abstract	Traditional in vitro models can replicate many essential features of drug transport/permeability across the blood-brain barrier (BBB) but are not entirely projecting in vivo central nervous system (CNS) uptake. Species differences fail to translate experimental therapeutics from the research laboratory to the clinic. Improved in vitro modeling of human BBB is vital for both CNS drug discovery and delivery. High-end human BBB models fabricated by microfluidic technologies offer some solutions to this problem. BBB's complex physiological microenvironment has been established by increasing device complexity in terms of multiple cells, dynamic conditions, and 3D designs. It is now possible to predict the therapeutic effects of a candidate drug and identify new druggable targets by studying multicellular interactions using the advanced in vitro BBB models. This chapter reviews the current as well as an ideal in vitro model of the BBB.
MeSH term(s)	Biological Transport ; Blood-Brain Barrier/physiology ; Central Nervous System Agents ; Humans ; Microfluidics ; Permeability
Chemical Substances	Central Nervous System Agents
Language	English
Publishing date	2022-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2289-6_2
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Article ; Online: Impact of Physical Activity and Medication Adherence on the Seizure Frequency and Quality of Life of Epileptic Patients: A Population Study in West Texas.

Lee, YoonJung / Ahn, Yeseul / Cucullo, Luca

BioMed research international

2022 Volume 2022, Page(s) 4193664

Abstract: Epilepsy is a neurological disease that affects 1-3% of the population. People with epilepsy (PWE) have poor physical and psychological health and a lower quality of life (QOL) than people without epilepsy. Moreover, PWE has more comorbid conditions ( ... ...

Abstract	Epilepsy is a neurological disease that affects 1-3% of the population. People with epilepsy (PWE) have poor physical and psychological health and a lower quality of life (QOL) than people without epilepsy. Moreover, PWE has more comorbid conditions (obesity, depression) than general populations. Physical activity (PA) has been reported to have various positive physical and psychological effects in PWE. Meanwhile, poor medication adherence is one of the main precipitating factors for seizure triggers. This study assessed the impact of PA and medication adherence on the seizure frequency and QOL for PWE at the Epilepsy Foundation, West Texas (EFWT). Our results indicate that PA is positively associated with the quality of life and negatively associated with the seizure frequency for PWE at EFWT, which suggests that physically active PWE tend to have fewer seizures and better QOL. Medication adherence did not affect the seizure frequency or QOL in our study. Yet, it is still crucial to encourage medication adherence for PWE since nonadherence is a known seizure promoter. Findings from this study highlight the continuous need to utilize available resources and implement programs to promote physical activity and medication adherence for better seizure control and QOL in PWE at EFWT.
MeSH term(s)	Epilepsy/complications ; Epilepsy/drug therapy ; Epilepsy/epidemiology ; Exercise/psychology ; Humans ; Medication Adherence ; Quality of Life/psychology ; Seizures/drug therapy ; Seizures/epidemiology ; Texas/epidemiology
Language	English
Publishing date	2022-01-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2022/4193664
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Article ; Online: Cerebrovascular and Neurological Dysfunction under the Threat of COVID-19: Is There a Comorbid Role for Smoking and Vaping?

Archie, Sabrina Rahman / Cucullo, Luca

International journal of molecular sciences

2020 Volume 21, Issue 11

Abstract: The recently discovered novel coronavirus, SARS-CoV-2 (COVID-19 virus), has brought the whole world to standstill with critical challenges, affecting both health and economic sectors worldwide. Although initially, this pandemic was associated with ... ...

Abstract	The recently discovered novel coronavirus, SARS-CoV-2 (COVID-19 virus), has brought the whole world to standstill with critical challenges, affecting both health and economic sectors worldwide. Although initially, this pandemic was associated with causing severe pulmonary and respiratory disorders, recent case studies reported the association of cerebrovascular-neurological dysfunction in COVID-19 patients, which is also life-threatening. Several SARS-CoV-2 positive case studies have been reported where there are mild or no symptoms of this virus. However, a selection of patients are suffering from large artery ischemic strokes. Although the pathophysiology of the SARS-CoV-2 virus affecting the cerebrovascular system has not been elucidated yet, researchers have identified several pathogenic mechanisms, including a role for the ACE2 receptor. Therefore, it is extremely crucial to identify the risk factors related to the progression and adverse outcome of cerebrovascular-neurological dysfunction in COVID-19 patients. Since many articles have reported the effect of smoking (tobacco and cannabis) and vaping in cerebrovascular and neurological systems, and considering that smokers are more prone to viral and bacterial infection compared to non-smokers, it is high time to explore the probable correlation of smoking in COVID-19 patients. Herein, we have reviewed the possible role of smoking and vaping on cerebrovascular and neurological dysfunction in COVID-19 patients, along with potential pathogenic mechanisms associated with it.
MeSH term(s)	COVID-19 ; Cerebrovascular Disorders/epidemiology ; Coronavirus Infections/epidemiology ; Humans ; Nervous System Diseases/epidemiology ; Pandemics ; Pneumonia, Viral/epidemiology ; Tobacco Smoking/epidemiology ; Vaping/epidemiology
Keywords	covid19
Language	English
Publishing date	2020-05-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21113916
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Article: Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview.

Archie, Sabrina Rahman / Al Shoyaib, Abdullah / Cucullo, Luca

Pharmaceutics

2021 Volume 13, Issue 11

Abstract: The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and ... ...

Abstract	The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the trafficking of immune cells between the blood and the brain. The BBB is primarily composed of highly specialized microvascular endothelial cells. These cells' special features and physiological properties are acquired and maintained through the concerted effort of hemodynamic and cellular cues from the surrounding environment. This complex multicellular system, comprising endothelial cells, astrocytes, pericytes, and neurons, is known as the neurovascular unit (NVU). The BBB strictly controls the transport of nutrients and metabolites into brain parenchyma through a tightly regulated transport system while limiting the access of potentially harmful substances via efflux transcytosis and metabolic mechanisms. Not surprisingly, a disruption of the BBB has been associated with the onset and/or progression of major neurological disorders. Although the association between disease and BBB disruption is clear, its nature is not always evident, specifically with regard to whether an impaired BBB function results from the pathological condition or whether the BBB damage is the primary pathogenic factor prodromal to the onset of the disease. In either case, repairing the barrier could be a viable option for treating and/or reducing the effects of CNS disorders. In this review, we describe the fundamental structure and function of the BBB in both healthy and altered/diseased conditions. Additionally, we provide an overview of the potential therapeutic targets that could be leveraged to restore the integrity of the BBB concomitant to the treatment of these brain disorders.
Language	English
Publishing date	2021-10-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics13111779
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Article: Harmful Effects of Smoking Cannabis: A Cerebrovascular and Neurological Perspective.

Archie, Sabrina Rahman / Cucullo, Luca

Frontiers in pharmacology

2019 Volume 10, Page(s) 1481

Abstract: Apart from being used as a medicine, cannabis or marijuana is the most widely abused recreational drug all over the world. The legalization and decriminalization of cannabis in Canada and various states of USA may be the underlying reason of the ... ...

Abstract	Apart from being used as a medicine, cannabis or marijuana is the most widely abused recreational drug all over the world. The legalization and decriminalization of cannabis in Canada and various states of USA may be the underlying reason of the widespread popularity of it among young population. Various studies have reported about the relationship between cannabis use and different detrimental effects like cardiovascular, cerebrovascular, and neurological complications among different age groups. Specifically, the young population is getting adversely affected by this, harmful yet, readily accessible recreational drug. Although the mechanism behind cannabis mediated neurological and cerebrovascular complications has not been elucidated yet, the results of these studies have confirmed the association of these diseases with cannabis. Given the lack of comprehensive study relating these harmful complications with cannabis use, the aim of this narrative literature review article is to evaluate and summarize current studies on cannabis consumption and cerebrovascular/neurological diseases along with the leading toxicological mechanisms.
Language	English
Publishing date	2019-12-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2019.01481
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Article ; Online: Anti-Diabetic Countermeasures Against Tobacco Smoke-Dependent Cerebrovascular Toxicity: Use and Effect of Rosiglitazone.

Sivandzade, Farzane / Cucullo, Luca

International journal of molecular sciences

2019 Volume 20, Issue 17

Abstract: Tobacco smoking (TS) is one of the most addictive habit sand a main public health hazards, impacting the vascular endothelium through oxidative stress (OS) stimuli, exposure to nicotine, and smoking-induced inflammation in a dose-dependent manner. ... ...

Abstract	Tobacco smoking (TS) is one of the most addictive habit sand a main public health hazards, impacting the vascular endothelium through oxidative stress (OS) stimuli, exposure to nicotine, and smoking-induced inflammation in a dose-dependent manner. Increasing evidence also suggested that TS increases glucose intolerance and the risk factor of developing type-2 diabetes mellitus (2DM), which, along with TS, is connected to blood-brain barrier (BBB) injuries, and heightens the risk of cerebrovascular disorders. Although the exact mechanism of rosiglitazone (RSG) is unknown, our previous in vitro work showed how RSG, an oral anti-diabetic drug belonging to the family of thiazolidinedione class, can protect BBB integrity through enhancement of nuclear factor erythroid 2-related factor (Nrf2) activity. Herein, we have validated the protective role of rosiglitazone against TS-induced BBB impairment in vivo. Our results revealed that RSG as a peroxisome proliferator-activated receptor gamma (PPARγ), activates counteractive mechanisms primarily associated with the upregulation of Nrf2 and PPARγ pathways which reduce TS-dependent toxicity at the cerebrovascular level. In line with these findings, our results show that RSG reduces inflammation and protects BBB integrity. In conclusion, RSG offers a novel and promising therapeutic application to reduce TS-induced cerebrovascular dysfunction through activation of the PPARγ-dependent and/or PPARγ-independent Nrf2 pathway.
MeSH term(s)	Animals ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/drug effects ; Brain/metabolism ; Cerebrovascular Disorders/etiology ; Cerebrovascular Disorders/prevention & control ; Cotinine/blood ; Cotinine/metabolism ; Diabetes Mellitus/etiology ; Diabetes Mellitus/prevention & control ; Humans ; Hypoglycemic Agents/pharmacology ; Male ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/metabolism ; Nicotine/blood ; Nicotine/metabolism ; PPAR gamma/metabolism ; Rosiglitazone/pharmacology ; Signal Transduction/drug effects ; Tobacco Smoking/adverse effects
Chemical Substances	Hypoglycemic Agents ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; PPAR gamma ; Rosiglitazone (05V02F2KDG) ; Nicotine (6M3C89ZY6R) ; Cotinine (K5161X06LL)
Language	English
Publishing date	2019-08-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20174225
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