Search Results (19)

This study reports an improved diastereoselective synthesis of substituted spiro[chromane-2,4′-pyrimidin]-2′(3′H)-ones via the acid-catalyzed condensation of 6-styryl-4-aryldihydropyrimidin-2-ones with resorcinol, 2-methylresorcinol, and pyrogallol. The optimized method allows for the isolation of diastereomerically pure products, with stereoselectivity controlled by varying acid catalysts (e.g., methanesulfonic acid vs. toluenesulfonic acid) and solvent conditions. The synthesized compounds were evaluated for antimicrobial and antioxidant activities. Notably, the (2S*,4R*,6′R*)-diastereomers exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacterial strains with minimal inhibition concentration down to 2 µg/mL, while derivatives containing vicinal bisphenol moieties demonstrated potent antioxidant activity, with IC₅₀ values (12.5 µg/mL) comparable to ascorbic acid. Pharmacokinetic analysis of selected hit compounds revealed favorable drug-like properties, including high gastrointestinal absorption and blood-brain barrier permeability. These findings highlight the potential of spirochromane-pyrimidine hybrids as promising candidates for further development in the treatment of infectious diseases and oxidative stress-related pathologies. Full article

The state of well-being and health of our body is regulated by the fine osmotic and biochemical balance established between the cells of the different tissues, organs, and systems. Specific districts of the human body are defined, kept in the correct state of functioning, and, therefore, protected from exogenous or endogenous insults of both mechanical, physical, and biological nature by the presence of different barrier systems. In addition to the placental barrier, which even acts as a linker between two different organisms, the mother and the fetus, all human body barriers, including the blood–brain barrier (BBB), blood–retinal barrier, blood–nerve barrier, blood–lymph barrier, and blood–cerebrospinal fluid barrier, operate to maintain the physiological homeostasis within tissues and organs. From a pharmaceutical point of view, the most challenging is undoubtedly the BBB, since its presence notably complicates the treatment of brain disorders. BBB action can impair the delivery of chemical drugs and biopharmaceuticals into the brain, reducing their therapeutic efficacy and/or increasing their unwanted bioaccumulation in the surrounding healthy tissues. Recent nanotechnological innovation provides advanced biomaterials and ad hoc customized engineering and functionalization methods able to assist in brain-targeted drug delivery. In this context, lipid nanocarriers, including both synthetic (liposomes, solid lipid nanoparticles, nanoemulsions, nanostructured lipid carriers, niosomes, proniosomes, and cubosomes) and cell-derived ones (extracellular vesicles and cell membrane-derived nanocarriers), are considered one of the most successful brain delivery systems due to their reasonable biocompatibility and ability to cross the BBB. This review aims to provide a complete and up-to-date point of view on the efficacy of the most varied lipid carriers, whether FDA-approved, involved in clinical trials, or used in in vitro or in vivo studies, for the treatment of inflammatory, cancerous, or infectious brain diseases. Full article

Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt–Jakob Disease, pose unique challenges to the scientific and medical communities due to their infectious nature, neurodegenerative effects, and the absence of a cure. Central to the progression of TSEs is the conversion of the normal cellular prion protein (PrPC) into its infectious scrapie form (PrPSc), leading to neurodegeneration through a complex interplay involving the immune system. This review elucidates the current understanding of the immune response in prion diseases, emphasizing the dual role of the immune system in both propagating and mitigating the disease through mechanisms such as glial activation, cytokine release, and blood–brain barrier dynamics. We highlight the differential cytokine profiles associated with various prion strains and stages of disease, pointing towards the potential for cytokines as biomarkers and therapeutic targets. Immunomodulatory strategies are discussed as promising avenues for mitigating neuroinflammation and delaying disease progression. This comprehensive examination of the immune response in TSEs not only advances our understanding of these enigmatic diseases but also sheds light on broader neuroinflammatory processes, offering hope for future therapeutic interventions. Full article

Nanotechnology has played a pioneering role in advancing medical applications, aiming to enhance healthcare through innovation and collaboration. Nanomedicine can be seen expanding into many fields from cancer therapies, cosmetics, tissue regeneration, biosensing, and infectious diseases, and now, it is seen venturing into the realm of research geared toward autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by restrictive, monotonous activities or fixed interests as well as difficulties with social communication. As of now, there are no validated quantitative metrics for diagnosing autism, nor is there a drug that is specifically designed to treat the condition. As identifiers of ASD have improved, the diagnosis of individuals who meet established criteria have dramatically increased over the years. Although there is still no recognized nanomedicine treatment specifically intended for ASD, research is looking into how nanotechnology might be used in a number of ASD-related areas. This comprehensive review examines prior research efforts aimed at preventing, treating, and diagnosing individuals with ASD. It particularly focuses on the significance of prenatal care and investigates advancements in drug delivery methods through the blood–brain barrier concerning ASD treatment and management. Full article

Explosive developments in mRNA vaccine technology in the last decade have made it possible to achieve great success in clinical trials of mRNA vaccines to prevent infectious diseases and develop cancer treatments and mRNA-based gene therapy products. The approval of the mRNA-1273 and BNT162b2 mRNA vaccines against SARS-CoV-2 by the U.S. Food and Drug Administration has led to mass vaccination (with mRNA vaccines) of several hundred million people around the world, including children. Despite its effectiveness in the fight against COVID-19, rare adverse effects of the vaccination have been shown in some studies, including vascular microcirculation disorders and autoimmune and allergic reactions. The biodistribution of mRNA vaccines remains one of the most poorly investigated topics. This mini-review discussed the results of recent experimental studies on humans and rodents regarding the biodistribution of mRNA vaccines, their constituents (mRNA and lipid nanoparticles), and their encoded antigens. We focused on the dynamics of the biodistribution of mRNA vaccine products and on the possibility of crossing the blood–brain and blood–placental barriers as well as transmission to infants through breast milk. In addition, we critically assessed the strengths and weaknesses of the detection methods that have been applied in these articles, whose results’ reliability is becoming a subject of debate. Full article

Central nervous system (CNS) diseases are currently a major challenge in medicine. One reason is the presence of the blood–brain barrier, which is a significant limitation for currently used medicinal substances that are characterized by a high molecular weight and a short half-life. Despite the application of nanotechnology, there is still the problem of targeting and the occurrence of systemic toxicity. Viral vectors and virus-like particles (VLPs) may provide a promising solution to these challenges. Their small size, biocompatibility, ability to carry medicinal substances, and specific targeting of neural cells make them useful in research when formulating a new generation of biological carriers. Additionally, the possibility of genetic modification has the potential for gene therapy. Among the most promising viral vectors are adeno-associated viruses, adenoviruses, and retroviruses. This is due to their natural tropism to neural cells, as well as the possibility of genetic and surface modification. Moreover, VLPs that are devoid of infectious genetic material in favor of increasing capacity are also leading the way for research on new drug delivery systems. The aim of this study is to review the most recent reports on the use of viral vectors and VLPs in the treatment of selected CNS diseases. Full article

The blood brain barrier (BBB) is a multicellular microenvironment that plays an important role in regulating bidirectional transport to and from the central nervous system (CNS). Infections by many acutely infectious viruses such as alphaviruses and flaviviruses are known to impact the integrity of the endothelial lining of the BBB. Infection by Venezuelan Equine Encephalitis Virus (VEEV) through the aerosol route causes significant damage to the integrity of the BBB, which contributes to long-term neurological sequelae. An effective therapeutic intervention strategy should ideally not only control viral load in the host, but also prevent and/or reverse deleterious events at the BBB. Two dimensional monocultures, including trans-well models that use endothelial cells, do not recapitulate the intricate multicellular environment of the BBB. Complex in vitro organ-on-a-chip models (OOC) provide a great opportunity to introduce human-like experimental models to understand the mechanistic underpinnings of the disease state and evaluate the effectiveness of therapeutic candidates in a highly relevant manner. Here we demonstrate the utility of a neurovascular unit (NVU) in analyzing the dynamics of infection and proinflammatory response following VEEV infection and therapeutic effectiveness of omaveloxolone to preserve BBB integrity and decrease viral and inflammatory load. Full article

Drug transporters play an important role in the maintenance of chemical balance and homeostasis in different tissues. In addition to their physiological functions, they are crucial for the absorption, distribution, and elimination of many clinically important drugs, thereby impacting therapeutic efficacy and toxicity. Increasing evidence has demonstrated that infectious, metabolic, inflammatory, and neurodegenerative diseases alter the expression and function of drug transporters. However, the current knowledge on transporter regulation in critical protective barriers, such as the brain and placenta, is still limited and requires more research. For instance, while many studies have examined P-glycoprotein, it is evident that research on the regulation of highly expressed transporters in the blood–brain barrier and blood–placental barrier are lacking. The aim of this review is to summarize the currently available literature in order to better understand transporter regulation in these critical barriers. Full article

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people’s lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood–brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain. Full article

The anatomical structure of the brain at the blood–brain barrier (BBB) creates a limitation for the movement of drugs into the central nervous system (CNS). Drug delivery facilitated by magneto-electric nanoparticles (MENs) is a relatively new non-invasive approach for the delivery of drugs into the CNS. These nanoparticles (NPs) can create localized transient changes in the permeability of the cells of the BBB by inducing electroporation. MENs can be applied to deliver antiretrovirals and antibiotics towards the treatment of human immunodeficiency virus (HIV) and tuberculosis (TB) infections in the CNS. This review focuses on the drug permeation challenges and reviews the application of MENs for drug delivery for these diseases. We conclude that MENs are promising systems for effective CNS drug delivery and treatment for these diseases, however, further pre-clinical and clinical studies are required to achieve translation of this approach to the clinic. Full article

The coronavirus disease of 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). In addition to pneumonia, individuals affected by the disease have neurological symptoms. Indeed, SARS-CoV-2 has a neuroinvasive capacity. It is known that the infection caused by SARS-CoV-2 leads to a cytokine storm. An exacerbated inflammatory state can lead to the blood–brain barrier (BBB) damage as well as to intestinal dysbiosis. These changes, in turn, are associated with microglial activation and reactivity of astrocytes that can promote the degeneration of neurons and be associated with the development of psychiatric disorders and neurodegenerative diseases. Studies also have been shown that SARS-CoV-2 alters the composition and functional activity of the gut microbiota. The microbiota-gut-brain axis provides a bidirectional homeostatic communication pathway. Thus, this review focuses on studies that show the relationship between inflammation and the gut microbiota–brain axis in SARS-CoV-2 infection. Full article

Bacterial meningitis (BM) is an acute infectious central nervous system (CNS) disease worldwide, occurring with 50% of the survivors left with a long-term serious sequela. Acute bacterial meningitis is more prevalent in resource-poor than resource-rich areas. The pathogenesis of BM involves complex mechanisms that are related to bacterial survival and multiplication in the bloodstream, increased permeability of blood–brain barrier (BBB), oxidative stress, and excessive inflammatory response in CNS. Considering drug-resistant bacteria increases the difficulty of meningitis treatment and the vaccine also has been limited to several serotypes, and the morbidity rate of BM still is very high. With recent development in neurology, there is promising progress for drug supplements of effectively preventing and treating BM. Several in vivo and in vitro studies have elaborated on understanding the significant mechanism of melatonin on BM. Melatonin is mainly secreted in the pineal gland and can cross the BBB. Melatonin and its metabolite have been reported as effective antioxidants and anti-inflammation, which are potentially useful as prevention and treatment therapy of BM. In bacterial meningitis, melatonin can play multiple protection effects in BM through various mechanisms, including immune response, antibacterial ability, the protection of BBB integrity, free radical scavenging, anti-inflammation, signaling pathways, and gut microbiome. This manuscript summarizes the major neuroprotective mechanisms of melatonin and explores the potential prevention and treatment approaches aimed at reducing morbidity and alleviating nerve injury of BM. Full article

Cryptococcus neoformans is an opportunistic fungal pathogen and a leading cause of death in immunocompromised individuals. The interactions of this yeast with host phagocytes are critical to disease outcome, and C. neoformans is equipped with an array of factors to modulate these processes. Cryptococcal infection begins with the deposition of infectious particles into the lungs, where the fungal cells deploy various antiphagocytic factors to resist internalization by host cells. If the cryptococci are still engulfed, they can survive and proliferate within host cells by modulating the phagolysosome environment in which they reside. Lastly, cryptococcal cells may escape from phagocytes by host cell lysis, nonlytic exocytosis, or lateral cell-to-cell transfer. The interactions between C. neoformans and host phagocytes also influence the dissemination of this pathogen to the brain, where it may cross the blood-brain barrier and cause an often-fatal meningoencephalitis. In this review, we highlight key cryptococcal factors involved in various stages of cryptococcal-host interaction and pathogenesis. Full article

Recent studies provide evidence to support that cluster of differentiation 38 (CD38) and CD157 meaningfully act in the brain as neuroregulators. They primarily affect social behaviors. Social behaviors are impaired in Cd38 and Cd157 knockout mice. Single-nucleotide polymorphisms of the CD38 and CD157/BST1 genes are associated with multiple neurological and psychiatric conditions, including autism spectrum disorder, Parkinson’s disease, and schizophrenia. In addition, both antigens are related to infectious and immunoregulational processes. The most important clues to demonstrate how these molecules play a role in the brain are oxytocin (OT) and the OT system. OT is axo-dendritically secreted into the brain from OT-containing neurons and causes activation of OT receptors mainly on hypothalamic neurons. Here, we overview the CD38/CD157-dependent OT release mechanism as the initiation step for social behavior. The receptor for advanced glycation end-products (RAGE) is a newly identified molecule as an OT binding protein and serves as a transporter of OT to the brain, crossing over the blood–brain barrier, resulting in the regulation of brain OT levels. We point out new roles of CD38 and CD157 during neuronal development and aging in relation to nicotinamide adenine dinucleotide⁺ levels in embryonic and adult nervous systems. Finally, we discuss how CD38, CD157, and RAGE are crucial for social recognition and behavior in daily life. Full article