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soelitist · 2 years

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Regime Change: Okay [1/6]

Summary: Rand Ridley is officially in charge of Cognito, Inc. None of that danger feels bassive anymore.

Day: 1 | WC: 2.1k | AO3 | Prompt: Adverse Effects

If Brett has learned one thing in his time at Cognito, Inc., it would be that there’s no such thing as an accident anymore. Someone is always scheming and plotting, as much as he would love to think otherwise, and so anything that happens even by chance was carefully planned out. Something like Reagan, practical, uptight, driven Reagan, getting dosed with any sort of drug from inside the company is undoubtedly not an accident. Sure, it looks like one, he thinks. Andre had a chemical spill during his latest experimental drug development for Rand, completely by accident based on his panic at the thought of it getting out anywhere. Accident. His lab and Reagan’s are connected by the ventilation system. Accident. Reagan didn’t smell the vapors because her allergies have been off the charts for days. Accident. It’s just that only so many accidents in a row are excusable, even to him, and this has the potential to be really, really bad for everyone involved.

He gently nudges Reagan into his office chair, which no one complains about despite it being the only chair in the room. She goes easily, much more so than he’s used to when it comes to her, and spins in it a couple of times without any understanding of the gravity of the situation she’s found herself in. Brett stops her only because he doesn’t want to make her dizzy enough to get sick.

“We just have to keep her out of Rand’s sight for the rest of the day,” he says. “It can’t be that hard, right?”

“Except for the cameras, genius.”

Myc punctuates his statement by gesturing to the offending security camera in the corner, red light blinking steadily as if to remind them that it’s watching.

Andre nods and shifts his weight. “Yeah, um, if he wasn’t suspicious before, he definitely is now.”

They all look back to Reagan. Normally, she has some kind of solution for any kind of problem the world throws at them, if not immediately, than within a minute. It’s the whole reason their team, and this company, is so successful. She has nothing to add now besides a vaguely coherent noise and a giggle.

“Right. So, uh, we… take her home?”

“Normally I’d say to the hospital, but who knows what Andre was cooking up. It could make her seriously sick,” Gigi says.

“Wow, I take offense to that, actually.”

“So what were you making?”

“It’s sorta kinda- uh. Well.”

Brett pinches the bridge of his nose. Is this how Reagan feels all the time? "Okay, just- is it dangerous?"

"I don't think so," Andre says, sounding not very convincing at all.

It's simpler to believe him, and Brett is reasonably certain that Reagan would prefer to avoid an unnecessary hospital trip. He leaves Glenn in charge, much to everyone else's chagrin, and nudges Reagan's shoulder lightly.

"Hey, Rea-dog, I think it might be time for us to get going for the day.”

She blinks up at him owlishly with her dark eyes. “Already?”

“Already,” Brett confirms. “Up you go, come on. We can get coffee on the way back, four add-shots, just the way you like it?”

This seems to be enough to convince her, though once Reagan stands up again, Brett has to get a hold on her quickly to prevent her from falling back into the chair, or worse, onto the floor. He tries to just keep one hand on her arm to steady her, not wanting to initiate contact he knows a sober Reagan would not appreciate, but after just a couple of steps, he wraps his arm around her waist to support more of her weight.

He takes them through the side-exit rather than the front, even if there are definitely cameras everywhere, and chirps his car to help him find it in the parking structure. No one else traverses the concrete building while they walk, mostly due to the fact that it’s the middle of the workday, but the privacy is welcome in the face of Reagan bursting into a fit of giggles at a vaguely inappropriate license plate on an old Honda.

“Brett, Brett, look! It’s- it says-”

She breaks off into hysterical laughter before she can finish explaining the joke. Brett gives her a little chuckle of his own to placate her, letting out a soft sigh of relief when he sees his car. He unlocks it and opens the passenger side door for her, more dropping her into the seat than letting her get in herself. When he comes around to his own door, he feels better already. The sooner they’re away from Cognito right now, the better.

With the turn of his key in the ignition, the radio comes on, playing a mindless pop song. If he connects his phone, he could have one of his playlists, but those might be a little intense for Reagan right now; she’s always a little oversensitive to all sorts of sounds and lights and touches, and he can only imagine that’s amplified now with her limited ability to think.

“Seatbelts!” he proclaims, clicking his into place.

Reagan fumbles with her seatbelt briefly, not even getting a solid grip on it, before turning to him. “Your seatbelt is fuckin’ broken, Brett.”

“Okay.”

He leans over her anyways to get ahold of the buckle, bracing his free hand on the door, and tugs it across her body to secure in place. He adjusts it for her, too, making sure that the edge of it doesn’t dig into her neck. She always does that when they ride in the car together.

“Coffee and then home,” he says, almost to himself. “We’re good. We’re fine. We’re not doing anything weird or suspicious right now.”

He flashes his and Reagan’s badges to the camera on their way out of the parking garage. Within minutes, Cognito is just a smudge in the rearview mirror. There’s a Starbucks midway between his place and work, one with a drive-through and everything, so he takes them there for the promised coffee. He gets the same thing every time, and so does Reagan, which makes looking at the menu obsolete when he pulls up to the speaker.

“Thank you for choosing Starbucks, what can I get started for you today?”

“Hi! Um, I’ll take a grande iced skinny vanilla latte, and a venti hot white mocha with almond milk, no whipped cream, and seven shots total, please! Oh, and can I have…” Food is probably a good idea. “Some of those mushroom egg things, and pumpkin bread.”

The speaker crackles out his total and instructs him to pull forward. Reagan is still awake when Brett glances at her, but her eyes are unfocused as she snaps her fingers next to her ears. It’s not the strangest thing he’s seen her do, drugged or not, and she’s not hurting anyone, so he doesn’t say anything about it.

At the window, he hands his card to the barista, who returns it quickly with the addition of two little paper bags. One has the eggs, which he got for Reagan, and one has the pumpkin bread, which is his special treat to himself for not completely freaking out over this entire situation. A moment later, the barista gives him their coffee, which he thanks her for before pulling out of the drive through.

“Why don’t you have some of your coffee, Rea,” he suggests. “It might help you feel a little more yourself?” He gestures to the coffee cup, but when she nearly drops it trying to pick the thing up, he covers it with his own hand and bats hers away. “On second thought, maybe when we get home.”

It’s only fifteen more minutes of driving, but they last an eternity. Reagan keeps it together pretty well, mindlessly tearing chunks off her eggs with the plastic fork and eating them. At least, Brett thinks she’s eating them, because she keeps putting the pieces in her mouth, but she doesn’t seem to be chewing it so much as holding it there for a while before swallowing and then having another piece. The egg bites are soft, from what he remembers of the ham ones he used to get before they were discontinued, so they don’t seem like that much of a choking hazard, and Reagan is still breathing beside him. Maybe he’s blowing this whole issue out of proportion. It’s hard to tell whether or not his emotional reactions are the right magnitude, and none of his business family seem to be good benchmarks to check with.

Finally, he pulls into his driveway, and comes around to Reagan’s side of the car to help her get out. She has her half-eaten bag of egg bites in one hand and the still folded-shut bag with Brett’s food in the other as he unbuckles her seatbelt and pulls her out of the car.

“Think you can walk inside?” he asks.

She swings her feet out of the car and over the pavement. “The floor is lava.”

“Okay.”

So he picks her up, careful to keep a secure but respectful grip around her body as he carries her toward the front door, barely managing to unlock it. Home at last. Brett carries Reagan through the threshold and toward the couch, which welcomes her in its soft embrace when he settles her on the cushions.

“This isn’t home,” she complains. “You said we were goin’ home, dude. Messed up.”

He blinks. “Oh. Yeah, huh, I did say- sorry. I’m sorry, that’s totally my fault. I brought you to my place. But we can still hang out here!”

She grumbles unintelligibly and stuffs more egg into her mouth.

“Great! Great. Um, I’m gonna go get our coffee out of the car, I’ll be right back. Don’t move!”

Brett nearly trips over his own feet in his haste to get their drinks and come back as quickly as possible, but he feels better once he shuts, locks, and deadbolts the front door behind him. Nothing can get to them here. It’ll be safe to let whatever drug got into Reagan run its course.

“Here’s that latte,” he says, extending it out to her. He takes his pumpkin bread in exchange, sitting on the coffee table in front of her. Some of the ice has melted in his drink, and the pumpkin bread isn’t really warm anymore, but he doesn’t mind the inconvenience. It’s better than nothing, he reminds himself, crunching down on one of the seeds from the top of the bread. “How’re you feeling, Reagan?”

She blows a raspberry and sips at her coffee. “This doesn’t taste right.”

“What’s wrong with it?”

“There’s no whipped cream!”

He smiles at her without meaning to. “You don’t like whipped cream.”

“Oh.” She squints at her cup. “Yeah. I forgot. Sometimes I forget to tell them not to put it on there, but even when I remember, they still do it sometimes. It’s so fucked up, dude, you have no idea. Whipped cream is evil.”

“Okay.”

They finish their coffee without further words. Reagan seems to be too intently focused on drinking her coffee and humming something to herself, and Brett is busy just watching her. Part of it is to make sure she’s alright; if she’s in any kind of distress, physical or emotional, he’s determined to make it better. But part of him just likes to look at her sometimes. All the little details of her visage, from the bags under her eyes to the slope of her nose to the indent of her cheek when she bites on it in concentration, are unique to her and filed away under the metaphorical box in his brain labeled “Reagan” with little hearts doodled around her name.

“Hey, Brett?” she drawls, lazily waving her empty cup back and forth.

“Yeah, what’s up?”

She sets the cup on the ground and slouches further into the couch. “No one ever holds me.”

“Okay.”

He joins her on the couch, leaving a few inches of space between them and keeps his arms wide, making room for her to let him hold her without forcing too much contact she may not want. Almost immediately, Reagan leans up against him, burying her face in his shoulder. He tentatively embraces her, more mindful than he’s ever been about keeping the pressure light to avoid any sort of discomfort on her part, only to find the weight of his arms causes Reagan to relax further into him.

“Okay?” he asks softly.

“Okay,” Reagan mumbles, and drifts off to sleep.

#whumptober2022 #no.1 #adverse effects #inside job #inside job netflix #fic #drugs #brett hand #reagan ridley #breagan #emwrite #emwt22 #whumptober

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juniperpublishers-sciences · 5 years

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Nanotechnology, A Promising Tool to Combat the Pitfalls of The Phenolic Transport across Blood- Brain Barrier-Juniper Publishers

Abstract

The growing interest in natural polyphenols during the last years is aimed to identify new applications to these natural compounds of biological interest, as well as to design new uses in the field of health care. In this regard, to date, it has been demonstrated a wide range of positive health effects for phenolic compounds, being most research studies focused on the anti-oxidant, anti- inflammatory, anti-microbial, and anti-aging effects, while the biological potential demonstrated for these compounds have led to search for specific applications in the field of neurodegenerative diseases. Indeed, brain related diseases factors like antioxidant and anti-inflammatory capacities, as well as proteins defibrillation and mitochondrial regulation have been pointed as the advantages of the use of all kind of phenolics. However, the transport of these molecules to can be prevented by specific biological barriers developed to protect these sensible structures. In this short review, the effects of phenolic compounds described in nervous tissues and cells, has been studied, as well as the downsides of their use, and how nanotechnology can help to provide new valuable alternatives to get enhanced biological impacts despite de constraint represented by the blood-brain barrier.

Keywords: Phenolic compounds; Nervous system; Blood-brain barriers; Bioavailability; Bassive transport; Bioactivity

Introduction

For several decades, it has been experienced a growing interest in natural phenolic compounds as bioactive molecules present in edible and non-edible plant material with potential effects on human health. The main goal of this trend is to find new applications to these natural compounds of biological interest and design new uses for them in the field of medical treatments [1-3]. Indeed, to date it has been demonstrated a wide range of positive health effects for phenolic compounds, being most research studies focused on the anti-oxidant, antiinflammatory, anti-microbial, and anti-aging effects. In the last years, the biological potential demonstrated for phenolic compounds have led to the interest in assessing their effects in the treatment of neurodegenerative diseases [2-6].

Discussion

Proved facts on the neuroprotective effects of phenolic compounds

Several studies have contributed to establish a link between phenolic compounds and neuroprotection, revealing their potential against aging and neurodegenerative diseases [4,5]. In this regard, it is required to notice that there are innumerous possible patho physiological mechanisms related with neurodegeneration, even though the major pathways already identified are neuro- inflammation, oxidative stress, mitochondrial dysfunction, and protein misfolding, all of them susceptible to be affected by the presence of polyphenol [4,7,8]. However, despite the plethora of mechanisms responsible for neurodegeneration, oxidative damage to neuron molecules, and decreased cellular antioxidant species, such as glutathione in the brain, are major aspects of most common neurological diseases [4,8,9]. For instance, dopaminergic neurons of the central nervous system are susceptible to oxidative stress, turning oxidative stress into a risk factor for nigral substance degeneration. In this frame, polyphenols are recognized on their antioxidant particularities, while their presence in neurons has been related with lower levels of reactive oxygen species (ROS) [8]. However, radical scavenging is not the only biological activity of phenolics, which besides working as antioxidants, are also competent to increase the activity and expression of enzymes with antioxidant power. Hence, the endogenous glutathione system, one of the most important antioxidant defense of the organism, can also be boosted by polyphenols, according to previous works in vitro and in vivo [8-10]. In addition, polyphenols also contribute to diminish the level of pro-inflammatory cytokines in brain therapeutic models, such as IL-1β, TNF-α, 1L-4, 1L-6, and 1L-10 [10-12]. Resveratrol has been shown capable to decrease the level of nitrite and the expression of myeloperoxidase, an enzyme that, during microglial respiration, produces hypochlorous acid and tyrosyl radical that are cytotoxic to pathogens, but also to cells [13] Some polyphenols have shown the ability to prevent protein fibrillization, by promoting the clearance of aggregates and oligomers, thus stimulating the cell autophagic pathways [8] which proves once more their neuroprotective actions. Regarding this, for instance, phenolic compounds from green tea have been characterized on their fibril-destabilizing properties in neurological diseases. Hence, resorting to several in vitro studies, it has been demonstrated that epigallocatechin gallate and quercetin can prevent growth and aggregation of amyloidogenic a-synuclein and reduce their levels in the hippocampus and the striatum [14-16]. Mitochondrial disturbances can also be responsible for the damage observed in neurological diseases. Indeed, the loss of the mitochondrial transmembrane potential triggers mechanisms of apoptosis in dopaminergic neurons. In this sense, polyphenols have been noticed as competent to enhance mitochondrial function by increasing the ATP production, while lower ROS and lactate production [17,18].

Constraints to the biological action of polyphenols in the nervous tissues

Despite all the studies aimed at characterizing in vitro and in vivo the benefits of phenolic compounds, there are several biological limits that interfere with the beneficial properties of these compounds, preventing the direct extrapolation of the results retrieved, so far, on biological activity to the pathophysiology of the nervous system [19]. One of the main obstacle for the biological action of phenolics in cells is their bioavailability. In this regard, the amount of phenolic compounds that reaches the cells is conditioned by the physiochemical properties of the compounds, their interaction with food matrix, and the response to the gastrointestinal tract conditions, which means that in most cases, the concentration available is significantly lower to that administrated and, even, to that tested upon in vitro characterizations [8,12,20]. Moreover, a high proportion of phenolic compounds are esterified in glycoside or polymeric forms. This entails that they are poorly absorbed in the gastrointestinal tract, rapidly metabolized upon phase I and II metabolism, and excreted by both urine and bile [4,12,21,22]. This implies that, since the phenolic compounds bioactivity is mostly executed by their metabolites, as a result of the modifications triggered upon the gastrointestinal digestion, it could appear metabolites less effective as antioxidants than the original compounds [23,24]. Despite the evident effect of the factors discussed above, the main obstacle to take advantage of the biological potential of polyphenolic compounds in the nervous system is the final concentrations reached in the cells that for most compounds is not sufficient to trigger operative reactions capable to restore physiological condition of the nervous cells [4]. This is mainly due to the barriers existent between the central nervous system and the environments surrounding it [25]. In this concern, the most selective barrier is represented by the blood- brain barrier that constitutes a dynamic interface between the peripheral tissues and the central nervous system. Blood- brain barrier maintains normal brain function, preserving the homeostatic conditions for nervous cells, required to work appropriately and also shield them against invading organisms and damaging elements [26-28]. This barrier is primarily constituted of endothelial cells connected by adherent tight junctions and functions as a physical, metabolic/enzymatic, transport, and immunological barriers [25,27].

The main difficulties that the phenolic compounds find to cross to the blood-brain barrier are the endothelium of brain microvessles and multidrug resistance-associated proteins. Despite this, some phenolic compounds, such as anthocyanins and curcumin, are able to pass through in a lipophilicity- dependent way, while others cross the blood-brain barrier by a mechanism of phosphorylation/dephosphorylation that regulate their passage (quercetin), but the mechanisms of transport into the blood-brain barrier are still relatively unknown [4,29] and the administration of compounds of interest to develop their biological action in these cells deserve to be explored towards the description of new alternatives.

Nanotechnology contribution to bioavailability of phenolic compounds in brain cells

The drawbacks drawn related to polyphenols bioavailability in cells of the central nervous system led to an interesting field of studies to find new ways to overcome those pitfalls and thus, to take advantage of the biological properties of phenolic compounds. Nanotechnology seems to be a valuable contributor to give response to these constraints, and more specifically nanoparticles. These are promising and versatile delivery systems to transport compounds into remote areas of the body, like the brain [25-27]. Usually nanoparticles size range between 1 and 100nm and can have a natural or synthetic origin [25] Synthetic nanoparticles are manufactured using two basic methods: top-down and bottom-up. The first consists in size- reduction by mechanical processes to shrunk big materials to nano-scale, while the second one consists in the aggregation of diverse nanoparticles [18]. Among the different materials used to obtain nanoparticles it can be stressed poly (ethylenimine), poly (alkylcanonaacrylates) poly (amidoamine) dendrimers, poly (s-caprolactone), poly (lactic-co- glycolic acid), polyesters (poly(lactic acid), and inorganic materials like gold and silica [18,25-29].

The commodities and the nanoparticles obtained from them must be nontoxic, biodegradable, and biocompatible, be featured by a prolonged blood circulation time, and be stable, avoiding aggregation and dissociation [18]. These carriers can transport compounds by adsorbing, entrapping or bounding covalently to them [30,31]. The properties of nanoparticles make them a promising system to deliver biologically active compounds into brain, due to the possibility of modifying size, shape, hydrophobicity, surface charge, chemistry, and coating. In this connection, addressing appropriately these features, according to the characteristics of the bioactive molecule and the target tissue were their activity is desired can contribute to enhance the transport of phenolic compounds to the brain and thus, to improve their stability, while circulating, controlling the release of the compound through the blood-brain barrier [25,33].

Nanoparticles improve the solubility of phenolics by encapsulating them, and also protect the compounds from degradation in he gastrointestinal tract. Besides that, and maybe the most important feature of including polyphenols in nanoparticles is that they are able to enhance the absorption of the phenolic compound in brain cells either by disrupting the tight junction of the blood-brain barrier or promote the direct intake by endocytosis [18,25]. Regardless of all that some factors still need to be further studied to make nanoparticles even more helpful in the transport of bioactive compounds to brain cells. Factors like pH, ions, and enzymes, among others, can negatively modulate the properties of the nanoparticles and their delivery as well.

Conclusion

Phenolic compounds from all sorts of plants have been long studied regarding their potential use as bioactive agents. In brain related diseases there are a large amount of evidence that points towards the several potential uses of phenolic compounds as treatments for those diseases. Factors like antioxidant and anti-inflammatory capacities, as well as proteins defibrillation and mitochondrial regulation, have been pointed as the advantages of the use of all kind of phenolics. Otherwise, the transport of those molecules to cells and tissues, where they can be helpful, can be very complicated or even impossible and, in most cases, this situation is responsible for the loss of important properties of metabolites from phenolic compounds. Nano carriers present themselves as an innovating solution that can help to diminish in a great extent the pitfall of phenolic compounds bioavailability, specially concerning the central nervous system. Thus, although nanotechnology seems to contribute to promising solutions, additional studies should be made in order to make nano carriers even more resistant and suitable for the transport of a growing number of phenolic compounds, which might be helpful to combat neurodegenerative disabling illness.

Acknowledgement

This work was partisally supported by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) through Research Projects AGL2016-75332-C2-1-R and RTC-201658362. RDP was sponsored by a Postdoctoral Contract (Juan de la Cierva de Incorporation ICJI2015- 25373) from the Ministry of Economy, Industry, and Competitiveness of Spain. The authors declare no competing financial interests.

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