Luca Cucullo

Oakland University William Beaumont School of Medicine · Foundational Medical Studies

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 differ...

Introduction: Despite the prevalence of the perception that electronic cigarettes (e-cig) are a safer alternative to tobacco smoke, growing concern about their potential toxic impact warrants adequate investigation focusing on special populations like maternal and pediatric groups. This study evaluated the consequences of maternal e-cig use on neon...

The brain is a highly dynamic organ that requires a constant energy source to function normally. This energy is mostly supplied by glucose, a simple sugar that serves as the brain’s principal fuel source. Glucose transport across the blood–brain barrier (BBB) is primarily controlled via sodium-independent facilitated glucose transport, such as by g...

Mental stress is a risk factor for myocardial infarction in women. The central hypothesis of this study is that restraint stress induces sex-specific changes in gene expression in the heart, which leads to an intensified response to ischemia/reperfusion injury due to the development of a pro-oxidative environment in female hearts. We challenged mal...

Traumatic Brain Injury (TBI) is a primary cause of cerebrovascular and neurological disorders worldwide. The current scientific researchers believe that premorbid conditions such as tobacco smoking (TS) can exacerbate post-TBI brain injury and negatively affect recovery. This is related to vascular endothelial dysfunction resulting from the exposur...

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-depe...

Background The short and long-term health effects of JUUL electronic cigarette (e-Cig) are largely unknown and warrant extensive research. We hypothesized that JUUL exposure could cause cerebrovascular toxicities impacting the progression and outcome of ischemic stroke comparable to tobacco smoke (TS) exposure. Methods We exposed male C57 mice to...

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...

The vascular system plays a critical role in human physiology and diseases. It is a complex subject to study using in vitro models due to its dynamic and three-dimensional microenvironment. Microfluidic technology has recently become a popular technology in various biological fields for its advantages in mimicking complex microenvironments to an ex...

Background The short and long-term health effects of JUUL electronic cigarette (e-Cig) are largely unknown and warrant extensive research. We hypothesized that chronic exposure to JUUL vapor could promote cerebrovascular toxicities impacting the progression and outcome of ischemic stroke to an extent comparable to that resulting from tobacco smoke...

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 var...

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 h...

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 include dry cough, difficult breathing, fever, fatigue, and may lead to pneumonia and respiratory failure. There are significant gaps in the current understanding of whether SAR...

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 compose...

As the number of confirmed cases and deaths occurring from Coronavirus disease 2019 (COVID-19) surges worldwide, health experts are striving hard to fully comprehend the extent of damage caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 primarily manifests itself in the form of severe respiratory distress...

Microfluidics-based organ-on-a-chip technology allows for developing a new class of in-vitro blood-brain barrier (BBB) models that recapitulate many hemodynamic and architectural features of the brain microvasculature not attainable with conventional two-dimensional platforms. Herein, we describe and validate a novel microfluidic BBB model that clo...

Traumatic brain injury (TBI) is a major reason of cerebrovascular and neurological damage. Premorbid conditions such as tobacco smoking (TS) can worsen post‐TBI injuries by promoting vascular endothelial impairments. Indeed, TS‐induced oxidative stress (OS) and inflammation can hamper the blood‐brain barrier (BBB) endothelium. This study evaluated...

Background The blood–brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) from blood-borne agents and potentially harmful xenobiotics. Our group’s previous data has shown that tobacco smoke (TS) and electronic cigarettes (EC) affect the BBB integrity, increase stroke incidence, and are considered a risk factor fo...

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,...

The brain is the most important organ in our body requiring its unique microenvironment. By the virtue of its function, the blood-brain barrier poses a significant hurdle in drug delivery for the treatment of neurological diseases. There are also different theories regarding how molecules are typically effluxed from the brain. In this review, we co...

The blood-brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain's metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures...

Aim The advent of highly active antiretroviral therapy (HAART) and combined antiretroviral therapy (cART) has substantially increased the life expectancy of patients infected with human immunodeficiency virus (HIV). However, this has brought into sharp contrast the incidence of several non-acquired immunodeficiency syndrome (non-AIDS) diseases such...

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 ce...

Chemoprevention of lung cancer is thought to significantly reduce the risk of acquiring these conditions in the subpopulation of patients with underlying health issues, such as chronic obstructive pulmonary disorder and smoking-associated lung problems. Many strategies have been tested in the previous decades, with very few translating to successfu...

Background: Traumatic brain injury (TBI) is among the most prevalent causes of cerebrovascular and neurological damage worldwide. To this end, tobacco smoke (TS) has been shown to promote vascular inflammation, neurovascular impairments, and risk of cerebrovascular and neurological disorders through oxidative stress (OS) stimuli targeting the bloo...

Traumatic brain injury (TBI) is among the most pressing global health issues and prevalent causes of cerebrovascular and neurological disorders all over the world. In addition to the brain injury, TBI may also alter the systemic immune response. Thus, TBI patients become vulnerable to infections, have worse neurological outcomes, and exhibit a high...

Ischemic stroke occurs in 87% of all strokes and is the leading cause of disability in the United States. Smoking has been shown to increase brain edema after ischemic stroke and worsen long‐term clinical outcomes. Electronic nicotine delivery systems or e‐cigarettes (e‐Cigs) are gaining popularity over traditional tobacco smoke cigarettes, and hav...

The blood-brain barrier (BBB) is a fundamental component of the central nervous system. Its functional and structural integrity is vital in maintaining the homeostasis of the brain microenvironment. On the other hand, the BBB is also a major hindering obstacle for the delivery of effective therapies to treat disorders of the Central Nervous System...

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...

Background: Traumatic Brain Injury (TBI) is among the most prevalent causes of cerebrovascular and neurological damage worldwide. To this end, tobacco smoking (TS) has been shown to promote vascular inflammation, neurovascular impairments and risk of cerebrovascular and neurological disorders through oxidative stress (OS) stimuli targeting the bloo...

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 develo...

Tobacco continues to kill about 0.48 million Americans per year and there are currently 34.3 million smokers in the USA. As a consequence of the First Surgeon General’s Report on Tobacco in 1964, tobacco control interventions on part of the government led to a significant decline in conventional tobacco product usage over the last few decades. Howe...

Cellular defense mechanisms, intracellular signaling, and physiological functions are regulated by electrophiles and reactive oxygen species (ROS). Recent works strongly considered imbalanced ROS and electrophile overabundance as the leading cause of cellular and tissue damage, whereas oxidative stress (OS) plays a crucial role for the onset and pr...

Background The use of siRNA-based gene silencing has been recently underscored as a potential therapeutic strategy for the treatment of neurological disorders. However, the stability of siRNA and other small molecule therapeutics is challenged by their intrinsic instability and limited passage across the blood–brain barrier (BBB). Based on these pr...

Background Smoking (TS) and recently e-cigarettes (EC) vaping, have been associated with vascular endothelial dysfunction primarily relevant to oxidative stress, exposure to nicotine, and smoking-induced inflammation. It is accepted that both EC and TS enhance glucose intolerance and the risk of developing type-2 diabetes mellitus which is also one...

Abbreviations ARE antioxidant response element BBB blood-brain barrier COPD chronic obstructive pulmonary disease CS cigarette smoke CSE cigarette smoke extract GSH glutathione MF metformin NQO-1 NAD(P)H quinone reductase I NRF2 nuclear factor erythroid 2-related factor Nrf2 nuclear factor erythroid 2-related factor OS oxidative stress ROS reactive...

“SPC Highlights Emerging Scientists: Biopharmaceutical Safety Assessment” session

In recent years, fluorescent dyes have been frequently used for monitoring mitochondrial membrane potential to evaluate mitochondrial viability and function. However, the reproducibility of the results across laboratories strongly depends upon following well validated and reliable protocols along with the appropriate controls. Herein, we provide a...

To date, many studies aimed at characterizing the multiple pathological paradigms associated with the development and progression of brain diseases are performed in vivo. However, major limitations of this approach, including limited translational significance to human patients, high cost, time, and labor to develop the appropriate model (e.g., tra...

Electrophiles and reactive oxygen species (ROS) play a major role in modulating cellular defense mechanisms as well as physiological functions, and intracellular signaling. However, excessive ROS generation (endogenous and exogenous) can create a state of redox imbalance leading to cellular and tissue damage (Ma and He, 2012) [1]. A growing body of...

Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity...

ischemic injuries and cognitive deficits. Given the robust cerebrovascular protection afforded by SFN, the objective of this study was to profile these effects in vitro using primary mouse brain microvascular endothelial cells and focusing on cellular redox, metabolism and detoxification functions. We used a mouse MitoChip array developed and valid...

Previous studies in our laboratory have shown that nicotine exposure decreases glucose transport across the blood‐brain barrier (BBB) in ischemia‐reperfusion conditions. We hypothesize that nicotine can also dysregulate brain parenchymal glucose utilization by altering glucose transporters with effects on sensitivity to ischemic stroke. In this stu...

The development of realistic in vitro blood–brain barrier (BBB) models that recapitulate the physiological parameters and molecular aspect of the neurovascular unit (NVU) is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the NVU would provide an invaluable tool to aid in dissectin...

It is well established that tobacco smoking is associated with vascular endothelial dysfunction in a causative and dose dependent manner primarily related to the tobacco smoke (TS) content of reactive oxygen species (ROS), nicotine, and oxidative stress (OS) -driven inflammation. Preclinical studies have also shown that nicotine (the principal e-li...

Background A sensitive, rapid and selective UHPLC–MS/MS method has been developed and validated for the quantification of Nicotine (NT) and Cotinine (CN) using Continine-d3 as internal standard (IS) as per FDA guidelines. Sample preparation involved simple protein precipitation of 20 µL mouse plasma or brain homogenate using acetonitrile at 1:8 rat...

Background Globally, tobacco use causes approximately 6 million deaths per year, and predictions report that with current trends; more than 8 million deaths are expected annually by 2030. Cigarette smokings is currently accountable for more than 480,000 deaths each year in United States (US) and is the leading cause of preventable death in the US....

Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer’s disease (AD) in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of a...

Recently published in vitro and in vivo findings strongly suggest that BBB impairment and increased risk for stroke by tobacco smoke (TS) closely resemble that of type-2 diabetes (2DM) and develop largely in response to common key modulators such oxidative stress (OS), inflammation and alterations of the endogenous antioxidative response system (AR...

Blood-brain barrier (BBB) damage is a critical neurovascular complication of diabetes mellitus that adversely affects the CNS health and function. Previously, we showed the protective role of NF-E2 related factor-2 (Nrf2), a redox sensitive transcription factor, in regulation of BBB integrity. Given the pathogenic role of mitochondrial oxidative st...

Background: Use of electronic cigarettes (e-Cig) is a growing health concern in both smoking and nonsmoking populations and rigorous studies are needed to investigate the effects of the nicotine exposure via e-Cig on the neurovascular unit (NVU) and stroke outcome. Previous studies by our group have shown that nicotine and tobacco smoke (TS) exposu...

Cigarette smoking (CS) is associated with vascular endothelial dysfunction in a causative way primarily related to the TS content of reactive oxygen species (ROS), nicotine, and inflammation. TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the...

Introduction: The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal...

Background The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer’s disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis...

It is well known that tobacco consumption is a leading cause of preventable deaths worldwide and has been linked to major diseases ranging from cancer to chronic obstructive pulmonary disease, atherosclerosis, stroke and a host of neurological/neurodegenerative disorders. In the past decade a number of alternative vaping products have hit the marke...

In this study, we sought to investigate how concomitant hyperglycemia influences the impact of combination antiretroviral therapy on blood-brain barrier (BBB) endothelial function. Immortalized human brain microvascular endothelial cell line (hCMEC/D3) was exposed to azidothymidine (AZT; a nucleoside reverse transcriptase inhibitor) and/or indinavi...

Psychostimulants and nicotine are the most widely abused drugs with a detrimental impact on public health globally. While the long-term neurobehavioral deficits and synaptic perturbations are well documented with chronic use of methamphetamine, cocaine, and nicotine, emerging human and experimental studies also suggest an increasing incidence of ne...

Psychostimulants and nicotine are the most widely abused drugs with a detrimental impact on public health globally. While the long-term neurobehavioral deficits and synaptic perturbations are well documented with chronic use of methamphetamine, cocaine, and nicotine, emerging human and experimental studies also suggest an increasing incidence of ne...