scholarly journals Enhanced Transport Capabilities via Nanotechnologies: Impacting Bioefficacy, Controlled Release Strategies, and Novel Chaperones

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Thomai Panagiotou ◽  
Robert J. Fisher
Keyword(s):  
Controlled Release ◽  
Process Analytical Technology ◽  
Critical Role ◽  
Process Intensification ◽  
Therapeutic Interventions ◽  
Continuous Manufacturing ◽  
Transfer Energy ◽  
Analytical Technology ◽  
The Brain

Emerging nanotechnologies have, and will continue to have, a major impact on the pharmaceutical industry. Their influence on a drug's life cycle, inception to delivery, is rapidly expanding. As the industry moves more aggressively toward continuous manufacturing modes, utilizing Process Analytical Technology (PAT) and Process Intensification (PI) concepts, the critical role of transport phenomena becomes elucidated. The ability to transfer energy, mass, and momentum with directed purposeful outcomes is a worthwhile endeavor in establishing higher production rates more economically. Furthermore, the ability to obtain desired drug properties, such as size, habit, and morphology, through novel manufacturing strategies permits unique formulation control for optimum delivery methodologies. Bottom-up processing to obtain nano-sized crystals is an excellent example. Formulation and delivery are intimately coupled in improving bio-efficacy at reduced loading and/or better controlled release capabilities, minimizing side affects and providing improved therapeutic interventions. Innovative nanotechnology applications, such as simultaneous targeting, imaging and delivery to tumors, are now possible through use of novel chaperones. Other examples include nanoparticles attachment to T-cells, release from novel hydrogel implants, and functionalized encapsulants. Difficult tasks such as drug delivery to the brain via the blood brain barrier and/or the cerebrospinal fluid are now easier to accomplish.

A critical role for central vasopressin in regulation of fever during bacterial infection

1992 ◽  
Vol 263 (6) ◽  
pp. R1235-R1240
Author(s):  
R. A. Cridland ◽  
N. W. Kasting
Keyword(s):  
Body Temperature ◽  
Arginine Vasopressin ◽  
Continuous Measurement ◽  
Critical Role ◽  
Experimental Models ◽  
Bacterial Endotoxins ◽  
Chronic Infusion ◽  
Live Bacteria ◽  
The Brain

Previous investigations on the antipyretic properties of arginine vasopressin have used bacterial endotoxins or pyrogens to induce fever. Because these experimental models of fever fail to mimic all aspects of the responses to infection, we felt it was important to examine the role of endogenously released vasopressin as a neuromodulator in febrile thermoregulation during infection. Therefore the present study examines the effects of chronic infusion of a V1-receptor antagonist or saline (via osmotic minipumps into the ventral septal area of the brain) on a fever induced by injection of live bacteria. Telemetry was used for continuous measurement of body temperature in the awake unhandled rat. Animals infused with the V1-antagonist exhibited fevers that were greater in duration compared with those of saline-infused animals. These results support the hypothesis that vasopressin functions as an antipyretic agent or fever-reducing agent in brain. Importantly, they suggest that endogenously released vasopressin may play a role as a neuromodulator in natural fever.

scholarly journals Syk and Hrs Regulate TLR3-Mediated Antiviral Response in Murine Astrocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-21 ◽  
Author(s):  
Matylda B. Mielcarska ◽  
Magdalena Bossowska-Nowicka ◽  
Karolina P. Gregorczyk-Zboroch ◽  
Zbigniew Wyżewski ◽  
Lidia Szulc-Dąbrowska ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathway ◽  
Critical Role ◽  
Antiviral Response ◽  
Proteolytic Processing ◽  
Viral Dsrna ◽  
Kinase Substrate ◽  
Tlr3 Signaling ◽  
The Brain

Toll-like receptors (TLRs) sense the presence of pathogen-associated molecular patterns. Nevertheless, the mechanisms modulating TLR-triggered innate immune responses are not yet fully understood. Complex regulatory systems exist to appropriately direct immune responses against foreign or self-nucleic acids, and a critical role of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), endosomal sorting complex required for transportation-0 (ESCRT-0) subunit, has recently been implicated in the endolysosomal transportation of TLR7 and TLR9. We investigated the involvement of Syk, Hrs, and STAM in the regulation of the TLR3 signaling pathway in a murine astrocyte cell line C8-D1A following cell stimulation with a viral dsRNA mimetic. Our data uncover a relationship between TLR3 and ESCRT-0, point out Syk as dsRNA-activated kinase, and suggest the role for Syk in mediating TLR3 signaling in murine astrocytes. We show molecular events that occur shortly after dsRNA stimulation of astrocytes and result in Syk Tyr-342 phosphorylation. Further, TLR3 undergoes proteolytic processing; the resulting TLR3 N-terminal form interacts with Hrs. The knockdown of Syk and Hrs enhances TLR3-mediated antiviral response in the form of IFN-β, IL-6, and CXCL8 secretion. Understanding the role of Syk and Hrs in TLR3 immune responses is of high importance since activation and precise execution of the TLR3 signaling pathway in the brain seem to be particularly significant in mounting an effective antiviral defense. Infection of the brain with herpes simplex type 1 virus may increase the secretion of amyloid-β by neurons and astrocytes and be a causal factor in degenerative diseases such as Alzheimer’s disease. Errors in TLR3 signaling, especially related to the precise regulation of the receptor transportation and degradation, need careful observation as they may disclose foundations to identify novel or sustain known therapeutic targets.

scholarly journals Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits

2020 ◽  
Vol 29 (18) ◽  
pp. 3054-3063
Author(s):  
Congyao Zha ◽  
Carole A Farah ◽  
Richard J Holt ◽  
Fabiola Ceroni ◽  
Lama Al-Abdi ◽  
...  
Keyword(s):  
Optic Lobe ◽  
Critical Role ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Clinical Genetic ◽  
Eye Disorders ◽  
Neurodevelopmental Deficits ◽  
Independent Families ◽  
The Brain

Abstract Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.

scholarly journals Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1018
Author(s):  
Caitlyn A. Mullins ◽  
Ritchel B. Gannaban ◽  
Md Shahjalal Khan ◽  
Harsh Shah ◽  
Md Abu B. Siddik ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Energy Homeostasis ◽  
Dorsal Striatum ◽  
Brain Regions ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Obesity Prevalence ◽  
Beneficial Effects ◽  
The Brain

Obesity prevalence is increasing at an unprecedented rate throughout the world, and is a strong risk factor for metabolic, cardiovascular, and neurological/neurodegenerative disorders. While low-grade systemic inflammation triggered primarily by adipose tissue dysfunction is closely linked to obesity, inflammation is also observed in the brain or the central nervous system (CNS). Considering that the hypothalamus, a classical homeostatic center, and other higher cortical areas (e.g. prefrontal cortex, dorsal striatum, hippocampus, etc.) also actively participate in regulating energy homeostasis by engaging in inhibitory control, reward calculation, and memory retrieval, understanding the role of CNS oxidative stress and inflammation in obesity and their underlying mechanisms would greatly help develop novel therapeutic interventions to correct obesity and related comorbidities. Here we review accumulating evidence for the association between ER stress and mitochondrial dysfunction, the main culprits responsible for oxidative stress and inflammation in various brain regions, and energy imbalance that leads to the development of obesity. Potential beneficial effects of natural antioxidant and anti-inflammatory compounds on CNS health and obesity are also discussed.

scholarly journals Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations

2021 ◽  
Author(s):  
Niklas Schwarz ◽  
Simone Seiffert ◽  
Manuela Pendziwiat ◽  
Annika Rademacher ◽  
Tobias Bruenger ◽  
...  
Keyword(s):  
Functional Analysis ◽  
De Novo ◽  
Critical Role ◽  
Specific Response ◽  
Loss Of Function ◽  
Causative Gene ◽  
Characteristic Functional ◽  
Research Collaborations ◽  
The Brain

Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes. Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid. Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

scholarly journals Fast and Flexible mRNA Vaccine Manufacturing as a Solution to Pandemic Situations by Adopting Chemical Engineering Good Practice—Continuous Autonomous Operation in Stainless Steel Equipment Concepts

Processes ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1874
Author(s):  
Axel Schmidt ◽  
Heribert Helgers ◽  
Florian Lukas Vetter ◽  
Alex Juckers ◽  
Jochen Strube
Keyword(s):  
Stainless Steel ◽  
Chemical Engineering ◽  
Process Analytical Technology ◽  
Good Practice ◽  
Operation Mode ◽  
Continuous Manufacturing ◽  
Efficient Operation ◽  
Messenger Ribonucleic Acid ◽  
Autonomous Operation ◽  
Analytical Technology

SARS-COVID-19 vaccine supply for the total worldwide population has a bottleneck in manufacturing capacity. Assessment of existing messenger ribonucleic acid (mRNA) vaccine processing shows a need for digital twins enabled by process analytical technology approaches in order to improve process transfer for manufacturing capacity multiplication, a reduction in out-of-specification batch failures, qualified personal training for faster validation and efficient operation, optimal utilization of scarce buffers and chemicals and speed-up of product release by continuous manufacturing. In this work, three manufacturing concepts for mRNA-based vaccines are evaluated: Batch, full-continuous and semi-continuous. Technical transfer from batch single-use to semi-continuous stainless-steel, i.e., plasmid deoxyribonucleic acid (pDNA) in batch and mRNA in continuous operation mode, is recommended, in order to gain: faster plant commissioning and start-up times of about 8–12 months and a rise in dose number by a factor of about 30 per year, with almost identical efforts in capital expenditures (CAPEX) and personnel resources, which are the dominant bottlenecks at the moment, at about 25% lower operating expenses (OPEX). Consumables are also reduceable by a factor of 6 as outcome of this study. Further optimization potential is seen at consequent digital twin and PAT (Process Analytical Technology) concept integration as key-enabling technologies towards autonomous operation including real-time release-testing.

scholarly journals Electro-acupuncture Alleviates METH Withdrawal-induced Spatial Memory Deficits by Restoring Astrocyte-drived Glutamate Uptake in dCA1

2020 ◽  
Author(s):  
Pengbo Shi ◽  
Zhaosu Li ◽  
Xing Xu ◽  
Jiaxun Nie ◽  
Dekang Liu ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Cognitive Deficits ◽  
Glutamate Uptake ◽  
Cognitive Disorders ◽  
Memory Deficits ◽  
Therapeutic Interventions ◽  
Therapeutic Effects ◽  
Non Invasive ◽  
The Brain

ABSTRACTMethamphetamine (METH) is frequently abused drug and produces cognitive deficits. METH could induce hyper-glutamatergic state in the brain, which could partially explain METH-related cognitive deficits, but the synaptic etiology remains incompletely understood. To address this issue, we explored the role of dCA1 tripartite synapses and the potential therapeutic effects of electro-acupuncture (EA) in the development of METH withdrawal-induced spatial memory deficits in mice. We found that METH withdrawal weakened astrocytic capacity of glutamate (Glu) uptake, but failed to change Glu release from dCA3, which lead to hyper-glutamatergic excitotoxicity at dCA1 tripartite synapses. By restoring the astrocytic capacity of Glu uptake, EA treatments suppressed the hyper-glutamatergic state and normalized the excitability of postsynaptic neuron in dCA1, finally alleviated spatial memory deficits in METH withdrawal mice. These findings indicate that astrocyte at tripartite synapses might be a key target for developing therapeutic interventions against METH-associated cognitive disorders, and EA represent a promising non-invasive therapeutic strategy for the management of drugs-caused neurotoxicity.

scholarly journals Role of astroglial Connexin 43 in pneumolysin cytotoxicity and during pneumococcal meningitis

2020 ◽  
Vol 16 (12) ◽  
pp. e1009152
Author(s):  
Chakir Bello ◽  
Yasmine Smail ◽  
Vincent Sainte-Rose ◽  
Isabelle Podglajen ◽  
Alice Gilbert ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Connexin 43 ◽  
Critical Role ◽  
Neurovascular Unit ◽  
Brain Slices ◽  
Host Cells ◽  
Intermediate Filament Protein ◽  
Young Infants ◽  
The Brain

Streptococcus pneumoniae or pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people worldwide. The mechanism underlying PN crossing of the blood brain barrier (BBB) and specifically, the role of non-endothelial cells of the neurovascular unit that control the BBB function, remains poorly understood. Here, we show that the astroglial connexin 43 (aCx43), a major gap junctional component expressed in astrocytes, plays a predominant role during PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. Immunofluorescence analysis of brain slices indicated that PN induces the aCx43–dependent destruction of the network of glial fibrillary acid protein (GFAP), an intermediate filament protein specifically expressed in astrocytes and up-regulated in response to brain injury. PN also induced nuclear shrinkage in astrocytes associated with the loss of BBB integrity, bacterial translocation across endothelial vessels and replication in the brain cortex. We found that aCx4-dependent astrocyte damages could be recapitulated using in vitro cultured cells upon challenge with wild-type PN but not with a ply mutant deficient for the pore-forming toxin pneumolysin (Ply). Consistently, we showed that purified Ply requires Cx43 to promote host cell plasma membrane permeabilization in a process involving the Cx43-dependent release of extracellular ATP and prolonged increase of cytosolic Ca2+ in host cells. These results point to a critical role for astrocytes during PN meningitis and suggest that the cytolytic activity of the major virulence factor Ply at concentrations relevant to bacterial infection requires co-opting of connexin plasma membrane channels.

scholarly journals Glymphatics: A Transformative Development in Medical Neuroscience Relevant to Injuries in Military Central Nervous System

2021 ◽  
Author(s):  
James Meyerhoff ◽  
Nabarun Chakraborty ◽  
Rasha Hammamieh
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Sleep Deprivation ◽  
Brain Edema ◽  
Critical Role ◽  
Spatial Relationship ◽  
Military Operations ◽  
Glymphatic System ◽  
The Brain

ABSTRACT Introduction The glia-operated glymphatic system, analogous to but separate from the lymphatics in the periphery, is unique to brain and retina, where it is very closely aligned with the arteriolar system. This intimate relationship leads to a “blood vessel like” distribution pattern of glymphatic vessels in the brain. The spatial relationship of glymphatics, including their essential component aquaporin-4 with vascular pericytes of brain arterioles is critical to functionality and is termed “polarization”. Materials and Methods We review the available literature on the factors affecting the resting state of glymphatics under normal conditions, including the important role of sleep in supporting normal glymphatic function (including waste removal) as well as the critical role of “polarization” under normal conditions. We then examine the effects of traumatic brain injury (TBI) or seizures on the glymphatic system and its state of “polarization”. Results Injury, such as TBI, can disrupt polarization resulting in “depolarization” leading to brain edema. Conclusion Damage to the glymphatic system might explain the brain edema so often seen following TBI or other insult. Moreover, similar damage should be expected in response to seizures, which can often be associated with chemical exposures as well as with TBI. Military operations, whether night operations or continuous operations, quite often impose limitations on sleep. As glymphatic function is sleep-dependent, sleep deprivation alone could compromise glymphatic function, as well, and might in addition, explain some of the well-known performance deficits associated with sleep deprivation. Possible effects of submarine and diving operations, chemical agents (including seizures), as well as high altitude exposure and other threats should be considered. In addition to the brain, the retina is also served and protected by the glymphatic system. Accordingly, the effect of military-related risks (e.g., exposure to laser or other threats) to retinal glymphatic function should also be considered. An intact glymphatic system is absolutely essential to support normal central nervous system functionality, including cognition. This effects a broad range of military threats on brain and retinal glymphatics should be explored. Possible preventive and therapeutic measures should be proposed and evaluated, as well.

scholarly journals Cathelicidin Protects the Brain from Mitochondrial DNA Damage in Health, but not Following Septic Shock

2021 ◽  
Author(s):  
Denise Frediani barbeiro ◽  
Suely Kubo Ariga ◽  
Hermes Vieira Barbeiro ◽  
Nadja C Souza-Pinto ◽  
Fabiano Pinheiro da Silva
Keyword(s):  
Septic Shock ◽  
Dna Damage ◽  
Mitochondrial Dna ◽  
Critical Role ◽  
Innate Immune ◽  
Experimental Sepsis ◽  
Mitochondrial Dna Damage ◽  
Innate Immune Signaling ◽  
The Brain

Abstract Recent discoveries have demonstrated that mitochondria play a critical role in innate immune signaling. By the other hand, immune responses may lead to mitochondrial deregulation. Cathelicidins play a critical role in innate immunity, promoting poorly understood cellular responses that may enhance or inhibit several signaling pathways, depending on the health conditions and subjacent microenvironment.Here, we investigated the role of CRAMP, the murine cathelicidin, in healthy mice and following experimental sepsis. We found that sepsis induces significant mitochondrial DNA damage in the prefrontal cortex and that cathelicidin protects the brain from this kind of damage in healthy animals, but not following septic shock.

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