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Background: Maintaining the structural and functional integrity of the blood–brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. Main body: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. Conclusions: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches. [ABSTRACT FROM AUTHOR]

In ischaemic stroke, a large reduction in blood supply can lead to the breakdown of the blood-brain barrier and to cerebral oedema after reperfusion therapy. The resulting fluid accumulation in the brain may contribute to a significant rise in intracranial pressure (ICP) and tissue deformation. Changes in the level of ICP are essential for clinical decision-making and therapeutic strategies. However, the measurement of ICP is constrained by clinical techniques and obtaining the exact values of the ICP has proven challenging. In this study, we propose the first computational model for the simulation of cerebral oedema following acute ischaemic stroke for the investigation of ICP and midline shift (MLS) relationship. The model consists of three components for the simulation of healthy blood flow, occluded blood flow and oedema, respectively. The healthy and occluded blood flow components are utilized to obtain oedema core geometry and then imported into the oedema model for the simulation of oedema growth. The simulation results of the model are compared with clinical data from 97 traumatic brain injury patients for the validation of major model parameters. Midline shift has been widely used for the diagnosis, clinical decision-making, and prognosis of oedema patients. Therefore, we focus on quantifying the relationship between ICP and midline shift (MLS) and identify the factors that can affect the ICP-MLS relationship. Three major factors are investigated, including the brain geometry, blood-brain barrier damage severity and the types of oedema (including rare types of oedema). Meanwhile, the two major types (stress and tension/compression) of mechanical brain damage are also presented and the differences in the stress, tension, and compression between the intraparenchymal and periventricular regions are discussed. This work helps to predict ICP precisely and therefore provides improved clinical guidance for the treatment of brain oedema. Author summary: Midline shift has been widely employed in clinical settings to estimate the severity of post-stroke brain oedema. However, the midline shift is affected by many factors and its relationship with intracranial pressure has been proven to vary among patients. In this paper, we utilise a computational tool to investigate the midline shift under large brain deformation from a mechanical perspective. The Augmented Lagrange Method is for the first time employed to solve the large deformation of oedema brains with midline shifts over 5 mm. In the model validation, a reasonable agreement between clinical data and simulation results are obtained. This paper models three different factors that can affect midline shift during oedema development, including brain geometry, blood-brain barrier damage severity and type of oedema. Meanwhile, we discuss the scenarios that can lead to unexpectedly small midline shifts and present quantitative results for a better understanding of brain mechanics during oedema. [ABSTRACT FROM AUTHOR]

Objective A bibliometric analysis of the literature related to stroke and the blood-brain barrier was conducted to obtain a research map, explore hotspots and trends, and provide references for clinical treatment and research. Methods The literature related to stroke and blood-brain barrier from 1 January 2001 to 28 February 2023 was explored in the Web of Science core database. Using bibliometrics, CiteSpace V6.1.R6 was used to analyze the distribution of years, countries/regions, research institutions/system, authors, publications, cited literature, keywords and research trends. Results A total of 5028 papers were included after screening, with an overall upward trend in the number of published papers. The United States had the most research on this topic, followed by China’s mainland and Germany. Most of the top 10 research institutions/system were from the United States, France and China, with strong collaboration between countries/regions and research institutions/system. Among the authors, Chopp Michael from the United States ranked first with 49 papers. Among the research trends, ischemic stroke, miR-126 in non-coding RNA, blood-brain barrier dysfunction and drug delivery were the hot spots in the last three years. Conclusions Blood-brain barrier and stroke are inextricably linked. The dysfunction and repair mechanism of blood-brain barrier during stroke, the circulation biomarkers released by blood brain barrier and the use of blood-brain barrier opening time to increase drug absorption are worthy of further study [ABSTRACT FROM AUTHOR]

Background: Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain. Methods: The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than 6 months before administration of study medication. Patients are treated for 3 months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper–pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests in a cognitive sub-study. Discussion: The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in the year 2024. Trial registration: Clinicaltrials.gov, NCT05173896. Registered on 30 December 2021. [ABSTRACT FROM AUTHOR]

The human polyomavirus JCPyV is an opportunistic pathogen that infects greater than 60% of the world's population. The virus establishes a persistent and asymptomatic infection in the urogenital system but can cause a fatal demyelinating disease in immunosuppressed or immunomodulated patients following invasion of the CNS. The mechanisms responsible for JCPyV invasion into CNS tissues are not known but direct invasion from the blood to the cerebral spinal fluid via the choroid plexus has been hypothesized. To study the potential of the choroid plexus as a site of neuroinvasion, we used an adult human choroid plexus epithelial cell line to model the blood-cerebrospinal fluid (B-CSF) barrier in a transwell system. We found that these cells formed a highly restrictive barrier to virus penetration either as free virus or as virus associated with extracellular vesicles (EVJC+). The restriction was not absolute and small amounts of virus or EVJC+ penetrated and were able to establish foci of infection in primary astrocytes. Disruption of the barrier with capsaicin did not increase virus or EVJC+ penetration leading us to hypothesize that virus and EVJC+ were highly cell-associated and crossed the barrier by an active process. An inhibitor of macropinocytosis increased virus penetration from the basolateral (blood side) to the apical side (CSF side). In contrast, inhibitors of clathrin and raft dependent transcytosis reduced virus transport from the basolateral to the apical side of the barrier. None of the drugs inhibited apical to basolateral transport suggesting directionality. Pretreatment with cyclosporin A, an inhibitor of P-gp, MRP2 and BCRP multidrug resistance transporters, restored viral penetration in cells treated with raft and clathrin dependent transcytosis inhibitors. Because choroid plexus epithelial cells are known to be susceptible to JCPyV infection both in vitro and in vivo we also examined the release of infectious virus from the barrier. We found that virus was preferentially released from the cells into the apical (CSF) chamber. These data show clearly that there are two mechanisms of penetration, direct transcytosis which is capable of seeding the CSF with small amounts of virus, and infection followed by directional release of infectious virions into the CSF compartment. Author summary: In patients with compromised immune systems due to underlying immunosuppressive diseases or due to treatment with immunomodulatory drugs, JC virus (JCPyV) invades the brain and causes a rapidly progressing and often fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). The brain is protected from invading pathogens by two major barriers, the blood-brain barrier (BBB), and the blood-cerebrospinal fluid barrier (BCSFB). The BCSFB is composed of choroid plexus epithelial cells that are directly exposed to the blood. The epithelial cells in the choroid plexus are held together by tight junctions that limit and regulate the movement of molecules and cells from the blood to the cerebral spinal fluid. In this paper we used an established adult choroid plexus epithelial cell line to model the blood-cerebrospinal fluid barrier and found that it was highly restrictive of virus penetration. The restriction was not absolute and small amounts of virus penetrated and established infection in underlying human glial cells. We also show a second mechanism of virus invasion involving direct infection of choroid plexus epithelial cells by JCPyV and directional release of infectious virions across the barrier. Both mechanisms likely contribute to the neuroinvasiveness of JCPyV. [ABSTRACT FROM AUTHOR]

Generally, Cryptococcus initially infects the respiratory tract, but can spread, eventually crossing the blood-brain barrier (BBB) and causing meningitis or meningoencephalitis. Specifically, Cryptococcus invades the vascular endothelial cells of the BBB, from which it enters the brain. The main mechanisms through which Cryptococcus crosses the BBB are transcellular traversal, the paracellular pathway, and via Trojan horse. In this paper, the mechanisms by which Cryptococcus crosses the BBB were explained in detail. In addition to pathways of entry to the brain, this paper presents a discussion on some rare cryptococcal infections and provides some insights for future research directions. [ABSTRACT FROM AUTHOR]

A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression. [ABSTRACT FROM AUTHOR]

A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression. [ABSTRACT FROM AUTHOR]

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's. [ABSTRACT FROM AUTHOR]

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood–brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND. [ABSTRACT FROM AUTHOR]

In recent years, the frequency of strokes has been on the rise year by year and has become the second leading cause of death around the world, which is characterized by a high mortality rate, high recurrence rate, and high disability rate. Ischemic strokes account for a large percentage of strokes. A reperfusion injury in ischemic strokes is a complex cascade of oxidative stress, neuroinflammation, immune infiltration, and mitochondrial damage. Conventional treatments are ineffective, and the presence of the blood–brain barrier (BBB) leads to inefficient drug delivery utilization, so researchers are turning their attention to nano-drug delivery systems. Functionalized nano-drug delivery systems have been widely studied and applied to the study of cerebral ischemic diseases due to their favorable biocompatibility, high efficiency, strong specificity, and specific targeting ability. In this paper, we briefly describe the pathological process of reperfusion injuries in strokes and focus on the therapeutic research progress of nano-drug delivery systems in ischemic strokes, aiming to provide certain references to understand the progress of research on nano-drug delivery systems (NDDSs). [ABSTRACT FROM AUTHOR]

The accumulation of harmful substances has long been recognized as a likely cause of many neurodegenerative diseases. The two classic brain clearance pathways are cerebrospinal fluid (CSF) and vascular circulation systems. Since the discovery of the glymphatic system, research on the CSF pathway has gained momentum, and impaired CSF clearance has been implicated in virtually all neurodegenerative animal models. However, the contribution of the direct participation of vascular transport across the blood-brain barrier in clearing substances is often ignored in glymphatic papers. Supportive evidence for the direct involvement of parenchymal vasculature in substance clearance is accumulated. First, multiple mechanisms have been proposed for the vascular drainage of exogenous and endogenous substances across the blood-brain barriers. Second, the "traditional" role of arachnoid villi and granulations as the main site for CSF draining into the vasculature system has been questioned. Third, MRI studies using different CSF tracers indicate that parenchymal vasculature directly participates in tracer efflux, consistent with immunohistochemical findings. Here we will review evidence in the literature that supports the direct participation of the parenchymal vascular system in substance clearance, in addition to the CSF clearance pathways. [ABSTRACT FROM AUTHOR]

Due to their biocompatibility, non-toxicity, and surface-conjugation capabilities, liposomes are effective nanocarriers that can encapsulate chemotherapeutic drugs and facilitate targeted delivery across the blood–brain barrier (BBB). Additionally, strategies have been explored to synthesize liposomes that respond to internal and/or external stimuli to release their payload controllably. Although research into liposomes for brain cancer treatment is still in its infancy, these systems have great potential to fundamentally change the drug delivery landscape. This review paper attempts to consolidate relevant literature regarding the delivery to the brain using nanocarriers, particularly liposomes. The paper first briefly explains conventional treatment modalities for cancer, followed by describing the blood–brain barrier and ways, challenges, and techniques involved in transporting drugs across the BBB. Various nanocarrier systems are introduced, with attention to liposomes, due to their ability to circumvent the challenges imposed by the BBB. Relevant studies involving liposomal systems researched to treat brain tumors are reviewed in vitro, in vivo, and clinical studies. Finally, the challenges associated with the use of liposomes to treat brain tumors and how they can be addressed are presented. [ABSTRACT FROM AUTHOR]

An important cellular barrier to maintain the stability of the brain's internal and external environment is the blood-brain barrier (BBB). It also prevents harmful substances from entering brain tissue through blood circulation while providing protection for the central nervous system. It should be noted, however, that the intact BBB can be a barrier to the transport of most drugs into the brain via the conventional route of administration, which can prevent them from reaching effective concentrations for the treatment of disorders affecting the central nervous system. Electroacupuncture stimulation has been shown to be effective at opening the BBB in a series of experimental studies. This study systematically analyzes the possibility and mechanism by which electroacupuncture opens the BBB. In PubMed, Web of Science, VIP Database, Wanfang Database, and the Chinese National Knowledge Infrastructure, papers have been published for nearly 22 years aimed at opening the BBB and its associated structures. A comparison of EB content between electroacupuncture and control was selected as the primary outcome. There were also results on vascular endothelial growth factor (VEGF), nerve growth factor (NGF), P-Glycoprotein (P-gp), Matrix Metalloproteinase 9 (MMP-9), and glial fibrillary acidic protein (GFAP). We utilized Review Manager software analysis to analyze correlations between studies with a view to exploring the mechanisms of similarity. Evans Blue infiltration forest plot: pooled effect size of 2.04, 95% CI: 1.21 to 2.87, P < 0.01. These results indicate that electroacupuncture significantly increases EB penetration across the BBB. Most studies have reported that GFAP, MMP-9, and VEGF were upregulated after treatment. P-gp expression decreased as well. Electroacupuncture can open the BBB, and the sparse-dense wave is currently the most effective electroacupuncture frequency for opening the BBB. VEGF plays an important role in opening the BBB. It is also important to regulate the expression of MMP-9 and GFAP and inhibit the expression of P-gp. [ABSTRACT FROM AUTHOR]

Background: The blood–brain barrier (BBB) regulates brain substance entry, posing challenges for treating brain diseases. Traditional methods face limitations, leading to the exploration of non-invasive intranasal drug delivery. This approach exploits the direct nose-to-brain connection, overcoming BBB restrictions. Intranasal delivery enhances drug bioavailability, reduces dosage, and minimizes systemic side effects. Notably, lipid nanoparticles, such as solid lipid nanoparticles and nanostructured lipid carriers, offer advantages like improved stability and controlled release. Their nanoscale size facilitates efficient drug loading, enhancing solubility and bioavailability. Tailored lipid compositions enable optimal drug release, which is crucial for chronic brain diseases. This review assesses lipid nanoparticles in treating neuro-oncological and neurodegenerative conditions, providing insights for effective nose-to-brain drug delivery. Methods: A systematic search was conducted across major medical databases (PubMed, Ovid MEDLINE, and Scopus) up to 6 January 2024. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "lipid nanoparticles", "intranasal administration", "neuro-oncological diseases", and "neurodegenerative disorders". This review consists of studies in vitro, in vivo, or ex vivo on the intranasal administration of lipid-based nanocarriers for the treatment of brain diseases. Results: Out of the initial 891 papers identified, 26 articles met the eligibility criteria after a rigorous analysis. The exclusion of 360 articles was due to reasons such as irrelevance, non-reporting selected outcomes, the article being a systematic literature review or meta-analysis, and lack of method/results details. This systematic literature review, focusing on nose-to-brain drug delivery via lipid-based nanocarriers for neuro-oncological, neurodegenerative, and other brain diseases, encompassed 60 studies. A temporal distribution analysis indicated a peak in research interest between 2018 and 2020 (28.3%), with a steady increase over time. Regarding drug categories, Alzheimer's disease was prominent (26.7%), followed by antiblastic drugs (25.0%). Among the 65 drugs investigated, Rivastigmine, Doxorubicin, and Carmustine were the most studied (5.0%), showcasing a diverse approach to neurological disorders. Notably, solid lipid nanoparticles (SLNs) were predominant (65.0%), followed by nanostructured lipid carriers (NLCs) (28.3%), highlighting their efficacy in intranasal drug delivery. Various lipids were employed, with glyceryl monostearate being prominent (20.0%), indicating preferences in formulation. Performance assessment assays were balanced, with in vivo studies taking precedence (43.3%), emphasizing the translation of findings to complex biological systems for potential clinical applications. Conclusions: This systematic review reveals the transformative potential of intranasal lipid nanoparticles in treating brain diseases, overcoming the BBB. Positive outcomes highlight the effectiveness of SLNs and NLCs, which are promising new approaches for ailments from AD to stroke and gliomas. While celebrating progress, addressing challenges like nanoparticle toxicity is also crucial. [ABSTRACT FROM AUTHOR]

Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC50 = 23 µM), human leukaemia cell line CCRF-CEM (IC50 = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by parallel artificial membrane permeability—gastrointestinal tract (PAMPA—GIT) and low permeation by parallel artificial membrane permeability—blood–brain barrier (BBB) (PAMPA—BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells. [ABSTRACT FROM AUTHOR]

Ischemic stroke, accounting for the majority of stroke events, significantly contributes to global morbidity and mortality. Vascular recanalization therapies, namely intravenous thrombolysis and mechanical thrombectomy, have emerged as critical interventions, yet their success hinges on timely application and patient‐specific factors. This review focuses on the early phase pathophysiological mechanisms of ischemic stroke and the nuances of recanalization. It highlights the dual role of neutrophils in tissue damage and repair, and the critical involvement of the blood–brain barrier (BBB) in stroke outcomes. Special emphasis is placed on ischemia–reperfusion injury, characterized by oxidative stress, inflammation, and endothelial dysfunction, which paradoxically exacerbates cerebral damage post‐revascularization. The review also explores the potential of targeting molecular pathways involved in BBB integrity and inflammation to enhance the efficacy of recanalization therapies. By synthesizing current research, this paper aims to provide insights into optimizing treatment protocols and developing adjuvant neuroprotective strategies, thereby advancing stroke therapy and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Evernia prunastri is a lichen widely distributed in the Northern Hemisphere. Its biological properties still need to be discovered. Therefore, our paper focuses on studies of E. prunastri extracts, including its main metabolites evernic acid (EA) or atranorin (ATR). Phytochemical profiles using chromatographic analysis were confirmed. The antioxidant activity was evaluated using in vitro chemical tests and in vitro enzymatic cells-free tests, namely superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT). The anti-inflammatory potential using cyclooxygenase-2 (COX-2) and hyaluronidase were determined. The neuroprotective potential using acetylcholinesterase, (AChE), butyrylcholinesterase (BChE), and tyrosinase (Tyr) was estimated. The hypoglycemic activity was also confirmed (α-glucosidase). Principal component analysis was performed to determine the relationship between the biological activity of extracts. The inhibitory effect of EA and ATR on COX-2 AChE, BChE, Tyr, and α-glucosidase was evaluated using molecular docking techniques and confirmed for EA and ATR (besides α-glucosidase). The penetration of EA and ATR from extracts through the blood–brain barrier was confirmed using the parallel artificial membrane permeability assay blood–brain barrier test. In conclusion, depending on chemical surroundings and the concentration, the E. prunastri extracts, EA or ATR, showed attractive pleiotropic properties, which should be further investigated. [ABSTRACT FROM AUTHOR]

Following the results of the CROWN phase III trial, the third-generation macrocyclic ALK inhibitor lorlatinib has been introduced as a salvage option after the failure of a first-line TKI in ALK-rearranged NSCLC, while its precise role in the therapeutic algorithm of ROS1 positive disease is still to be completely defined. The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood–brain barrier penetration are the reasons for the growing popularity and interest in this molecule. Nevertheless, the major vulnerability of this drug resides in a peculiar profile of related collateral events, with neurological impairment being the most conflicting and debated clinical issue. The cognitive safety concern, the susceptibility to heterogeneous resistance pathways, and the absence of a valid alternative in the second line are strongly jeopardizing a potential paradigm shift in this oncogene-addicted disease. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses. [ABSTRACT FROM AUTHOR]

This journal article provides information about the upcoming 96th National Congress of the Italian Society for Experimental Biology, which will take place in L'Aquila, Italy from April 25-28, 2024. The article includes a table of contents for the journal issue, featuring various topics such as anthropology, aging, environment and health, aquatic environments, biology of reproduction and infertility, regenerative medicine, micro- and nanovesicles, neuroscience, nutrition, oncology, cell stress, and miscellaneous subjects. Additionally, the article includes summaries of three research papers: one on the relationship between comparative anthropology and urban biodiversity in forensic practice, another on the use of infrared spectroscopy in analyzing the preservation state of archaeological remains, and a third on dental morphology and its impact on periodontal disease in primates. The article also discusses two studies on the potential benefits of using probiotic Streptococcus thermophilus and Artemisia absinthium extract as skincare and mouthwash ingredients, respectively. These studies provide insights into the potential applications of probiotics and herbal extracts in improving skin health and oral hygiene. [Extracted from the article]

The physiological mechanisms for releasing and resolving gravitational ischemia in the brain, and their susceptibility to malfunction, may play an important role in a variety of neurological illnesses. An astronaut on a space walk in a micro-gravity environment may be susceptible to neuro-ocular symptoms associated with unopposed gravity-resistance mechanisms for partially preventing gravitational ischemia in the brain, and for attenuating its impact—mechanisms which may be required for normal brain physiology on Earth. Astronauts on the International Space Station typically breathe a mixture of gasses similar in composition to what they breathed on Earth, following the 1967 death of three astronauts, including Ed White, by fire on the Apollo 1 spacecraft, which was carrying 100% oxygen. For the last decade, astronauts have been studied extensively by flight physicians regarding the commonly experienced symptoms of VIIP, or 'visual impairment and intracranial pressure' syndrome. In this paper, we compare VIIP syndrome to the neuro-ocular and Parkinson's-like symptoms which occurred during and after the 1918–1919 influenza pandemic. The common denominator may be gravitational ischemia in the brain, and the mirror-imaging failed mechanisms for its release (in influenza) versus unopposed gravity-resistance mechanisms (in astronauts). Some research has suggested that astronauts may benefit from breathing oxygen concentrations somewhat higher than 20%, and under slightly elevated pressure. These may possibly prevent maladaptive mechanisms leading to Alzheimer's- or Parkinson's-like illness by compensating for impaired mechanisms for releasing and resolving gravitational ischemia in the brain. [ABSTRACT FROM AUTHOR]

Background: Pediatric brain tumors (PBT) stand as the leading cause of cancer‐related deaths in children. Chemoradiation protocols have improved survival rates, even for non‐resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long‐lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti‐tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood–brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti‐cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical agents with the BBB remain limited and do not provide a comprehensive explanation for the ineffectiveness of established anti‐cancer drugs in PBT. Methods: We conducted our search for chemotherapeutic agents associated with the blood–brain barrier (BBB) using the following keywords: Chemotherapy in Cancer, Chemotherapy in Brain Cancer, Chemotherapy in PBT, BBB Inhibition of Drugs into CNS, Suboptimal Concentration of CNS Drugs, PBT Drugs and BBB, and Potential PBT Drugs. We reviewed each relevant article before compiling the information in our manuscript. For the generation of figures, we utilized BioRender software. Focus: We focused our article search on chemical agents for PBT and subsequently investigated the role of the BBB in this context. Our search criteria included clinical trials, both randomized and non‐randomized studies, preclinical research, review articles, and research papers. Finding: Our research suggests that, despite the availability of potent chemotherapeutic agents for several types of cancer, the effectiveness of these chemical agents in treating PBT has not been comprehensively explored. Additionally, there is a scarcity of studies examining the role of the BBB in the suboptimal outcomes of PBT treatment, despite the effectiveness of these drugs for other types of tumors. [ABSTRACT FROM AUTHOR]

Non-invasive drug delivery across the blood–brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive procedures and devices have been developed or are currently being investigated to enhance drug delivery across the BBB. This paper presents a review and a prospective analysis of the art and science that address pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) ε4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood–brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE ε4 in AD, information about the effect of peripheral ApoE ε4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE ε4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE ε4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE ε4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives. [ABSTRACT FROM AUTHOR]

Blood-brain barrier penetrating peptides (BBBPs) are short peptide sequences that possess the ability to traverse the selective blood-brain interface, making them valuable drug candidates or carriers for various payloads. However, the in vivo or in vitro validation of BBBPs is resource-intensive and time-consuming, driving the need for accurate in silico prediction methods. Unfortunately, the scarcity of experimentally validated BBBPs hinders the efficacy of current machine-learning approaches in generating reliable predictions. In this paper, we present DeepB3P3, a novel framework for BBBPs prediction. Our contribution encompasses four key aspects. Firstly, we propose a novel deep learning model consisting of a transformer encoder layer, a convolutional network backbone, and a capsule network classification head. This integrated architecture effectively learns representative features from peptide sequences. Secondly, we introduce masked peptides as a powerful data augmentation technique to compensate for small training set sizes in BBBP prediction. Thirdly, we develop a novel threshold-tuning method to handle imbalanced data by approximating the optimal decision threshold using the training set. Lastly, DeepB3P3 provides an accurate estimation of the uncertainty level associated with each prediction. Through extensive experiments, we demonstrate that DeepB3P3 achieves state-of-the-art accuracy of up to 98.31% on a benchmarking dataset, solidifying its potential as a promising computational tool for the prediction and discovery of BBBPs. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor, and the most prevalent primary malignant tumor affecting the brain and central nervous system. Recent research indicates that the genetic profile of GBM makes it resistant to drugs and radiation. However, the main obstacle in treating GBM is transporting drugs through the blood–brain barrier (BBB). Albumin is a versatile biomaterial for the synthesis of nanoparticles. The efficiency of albumin-based delivery systems is determined by their ability to improve tumor targeting and accumulation. In this review, we will discuss the prevalence of human glioblastoma and the currently adopted treatment, as well as the structure and some essential functions of the BBB, to transport drugs through this barrier. We will also mention some aspects related to the blood–tumor brain barrier (BTBB) that lead to poor treatment efficacy. The properties and structure of serum albumin were highlighted, such as its role in targeting brain tumors, as well as the progress made until now regarding the techniques for obtaining albumin nanoparticles and their functionalization, in order to overcome the BBB and treat cancer, especially human glioblastoma. The albumin drug delivery nanosystems mentioned in this paper have improved properties and can overcome the BBB to target brain tumors. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDs) are a major cause of disability and are related to brain development. The neurological signs of brain lesions can vary from mild clinical shortfalls to more delicate and severe neurological/behavioral symptoms and learning disabilities, which are progressive. In this paper, we have tried to summarize a collective view of various NDs and their possible therapeutic outcomes. These diseases often occur as a consequence of the misfolding of proteins post-translation, as well as the dysfunctional trafficking of proteins. In the treatment of neurological disorders, a challenging hurdle to cross regarding drug delivery is the blood–brain barrier (BBB). The BBB plays a unique role in maintaining the homeostasis of the central nervous system (CNS) by exchanging components between the circulations and shielding the brain from neurotoxic pathogens and detrimental compounds. Here, we outline the current knowledge about BBB deterioration in the evolving brain, its origin, and therapeutic interventions. Additionally, we summarize the physiological scenarios of the BBB and its role in various cerebrovascular diseases. Overall, this information provides a detailed account of BBB functioning and the development of relevant treatments for neurological disorders. This paper will definitely help readers working in the field of neurological scientific communities. [ABSTRACT FROM AUTHOR]

The presence of the blood–brain barrier (BBB) limits the delivery of therapies into the brain. There has been significant interest in overcoming the BBB for the effective delivery of therapies to the brain. Inorganic nanomaterials, especially silica nanoparticles with varying surface chemistry and surface topology, have been recently used as permeation enhancers for oral protein delivery. In this context, nanoparticles with varying sizes and surface chemistries have been employed to overcome this barrier; however, there is no report examining the effect of nanoscale roughness on BBB permeability. This paper reports the influence of nanoscale surface roughness on the integrity and permeability of the BBB in vitro, using smooth surface Stöber silica nanoparticles (60 nm) compared to rough surface virus-like silica nanoparticles (VSNP, 60 nm). Our findings reveal that VSNP (1 mg/mL) with virus-mimicking-topology spiky surface have a greater effect on transiently opening endothelial tight junctions of the BBB than the same dose of Stöber silica nanoparticles (1 mg/mL) by increasing the FITC-Dextran (70 kDa) permeability 1.9-fold and by decreasing the trans-endothelial electrical resistance (TEER) by 2.7-fold. This proof-of-concept research paves the way for future studies to develop next-generation tailored surface-modified silica nanoparticles, enabling safe and efficient macromolecule transport across the BBB. [ABSTRACT FROM AUTHOR]

The systemic treatments are not able to assure adequate drug concentration in the brain tissues in many neurological disorders due to the biological barriers such as the blood-brain barrier. Therefore, drug delivery systems can directly target the brain cells in a noninvasive means and bring about adequate drug in the brain is the focus in many of central nervous system (CNS) diseases. Perhaps the intranasal route and the direct anatomical connection between the nasal cavity and the brain can be supportive in the direct entry of therapeutic agents into the brain. This review paper is an insight into various considerations involved in the nose to brain drug delivery, such as the pros and cons of intranasal delivery, the anatomical and physiological features of the nose, various pathways, mechanisms of drug transport, disease perspectives, approaches to enhance the drug absorption with brief emphasis on types, and examples of agents used and advents in the nose to brain drug delivery. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) is a highly sophisticated system with the ability to regulate compounds transporting through the barrier and reaching the central nervous system (CNS). The BBB protects the CNS from toxins and pathogens but can cause major issues when developing novel therapeutics to treat neurological disorders. PLGA nanoparticles have been developed to successfully encapsulate large hydrophilic compounds for drug delivery. Within this paper, we discuss the encapsulation of a model compound Fitc-dextran, a large molecular weight (70 kDa), hydrophilic compound, with over 60% encapsulation efficiency (EE) within a PLGA nanoparticle (NP). The NP surface was chemically modified with DAS peptide, a ligand that we designed which has an affinity for nicotinic receptors, specifically alpha 7 nicotinic receptors, found on the surface of brain endothelial cells. The attachment of DAS transports the NP across the BBB by receptor-mediated transcytosis (RMT). Assessment of the delivery efficacy of the DAS-conjugated Fitc-dextran-loaded PLGA NP was studied in vitro using our optimal triculture in vitro BBB model, which successfully replicates the in vivo BBB environment, producing high TEER (≥230 Ω/cm2) and high expression of ZO1 protein. Utilising our optimal BBB model, we successfully transported fourteen times the concentration of DAS-Fitc-dextran-PLGA NP compared to non-conjugated Fitc-dextran-PLGA NP. Our novel in vitro model is a viable method of high-throughput screening of potential therapeutic delivery systems to the CNS, such as our receptor-targeted DAS ligand-conjugated NP, whereby only lead therapeutic compounds will progress to in vivo studies. [ABSTRACT FROM AUTHOR]

The purpose of this paper was to discuss the achievements of in vitro modeling in terms of the blood–brain barrier [BBB] and to create a clear overview of this research area, which is useful in research planning. The text was divided into three main parts. The first part describes the BBB as a functional structure, its constitution, cellular and noncellular components, mechanisms of functioning and importance for the central nervous system, in terms of both protection and nourishment. The second part is an overview of parameters important in terms of establishing and maintaining a barrier phenotype that allows for formulating criteria of evaluation of the BBB in vitro models. The third and last part discusses certain techniques for developing the BBB in vitro models. It describes subsequent research approaches and models, as they underwent change alongside technological advancement. On the one hand, we discuss possibilities and limitations of different research approaches: primary cultures vs. cell lines and monocultures vs. multicultures. On the other hand, we review advantages and disadvantages of specific models, such as models-on-a-chip, 3D models or microfluidic models. We not only attempt to state the usefulness of specific models in different kinds of research on the BBB but also emphasize the significance of this area of research for advancement of neuroscience and the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Senkyunolide I (SI) is a natural phthalide that has drawn increasing interest for its potential as a cardio-cerebral vascular drug candidate. In this paper, the botanical sources, phytochemical characteristics, chemical and biological transformations, pharmacological and pharmacokinetic properties, and drug-likeness of SI are reviewed through a comprehensive literature survey, in order to provide support for its further research and applications. In general, SI is mainly distributed in Umbelliferae plants, and it is relatively stable to heat, acid, and oxygen, with good blood–brain barrier (BBB) permeability. Substantial studies have established reliable methods for the isolation, purification, and content determination of SI. Its pharmacological effects include analgesic, anti-inflammatory, antioxidant, anti-thrombotic, anti-tumor effects, alleviating ischemia–reperfusion injury, etc. Pharmacokinetic parameters indicate that its metabolic pathway is mainly phase Ⅱ metabolism, and it is rapidly absorbed in vivo and widely distributed in the kidneys, liver, and lungs. [ABSTRACT FROM AUTHOR]

Several obstacles limit the efficacy of brain tumour treatment, most notably the blood‐brain barrier (BBB), which prevents the brain uptake of the majority of accessible medicines due to tight junctions. The presence of glutathione (GSH) receptors on the BBB surface has been demonstrated in numerous papers; consequently, products containing glutathione as a targeting ligand coupled with nanoliposomes are used to enhance drug delivery across the BBB. Here, the 5% pre‐inserted PEG2000‐GSH PEGylated liposomal doxorubicin was conducted according to 2B3‐101 being tested in clinical trials. In addition, PEGylated nanoliposomal doxorubicin connected to the spacer‐GSH targeting ligand (GSGGCE) and the PEG3400 was conducted using post‐insertion method. Next, in vivo biodistribution of the produced formulations was tested on healthy mice to see if GSGGCE, as the targeted ligand, could cross the BBB compared to 5% pre‐inserted PEG2000‐GSH and Caelyx®. Compared to the pre‐inserted formulation and Caelyx®, the post‐inserted formulations' concentration was lower in the heart and higher in brain tissues, resulting in boosting the brain concentration of accumulated doxorubicin with fewer possible side effects, including cardiotoxicity. In comparison to the pre‐insertion procedure, the post‐insertion method is easier, faster, and more cost‐effective. Moreover, employing PEG3400 and the post‐insertion approach in the PEG3400‐GSGGCE liposomal formulations was found to be effective in crossing the BBB. [ABSTRACT FROM AUTHOR]

This review is presenting the design and performance of some electrochemical sensors used for the determination of L-dopa in real samples as reported in a series of relevant scientific papers published in the past 5 years. L-dopa was intensively studied using electrochemical sensors with applications in the biomedical field, pharmaceutical field and food industry. The determination of L-dopa is of great importance, due to the fact that it can cross the blood brain barrier (which dopamine can’t) and then can be converted to dopamine. Thus, it can be used in treating some disease, such as Parkinson’s. Because fast detective methods for L-dopa determination are required, this paper focused on four types of electrochemical sensors, such as modified carbon paste electrodes, modified glassy carbon electrodes, modified screen-printed electrodes and modified indium tin oxide electrodes. Each has its advantages and disadvantages and the appropriate sensor should be used depending on the type of application. [ABSTRACT FROM AUTHOR]

Background: Over the last decade, since clinical trials examining targeted therapeutics for gliomas have failed to demonstrate a meaningful increase in survival, the emphasis has recently been switched toward innovative techniques for modulating the immune response against tumors and their microenvironments (TME). Cancerous cells have eleven hallmarks which make it distinct from normal ones, among which is immune evasion. Immune evasion in glioblastoma helps it evade various treatment modalities. Summary: Glioblastoma's TME is composed of various array of cellular actors, ranging from peripherally derived immune cells to a variety of organ-resident specialized cell types. For example, the blood–brain barrier (BBB) serves as a selective barrier between the systemic circulation and the brain, which effectively separates it from other tissues. It is capable of blocking around 98% of molecules that transport different medications to the target tumor. Objectives: The purpose of this paper is to offer a concise overview of fundamental immunology and how 'clever' gliomas avoid the immune system despite the discovery of immunotherapy for glioma. Conclusions: Herein, we highlight the complex interplay of the tumor, the TME, and the nearby normal structures makes it difficult to grasp how to approach the tumor itself. Numerous researchers have found that the brain TME is a critical regulator of glioma growth and treatment efficacy. [ABSTRACT FROM AUTHOR]

The low bioaccessibility of hesperetin and piperine hampers their application as therapeutic agents. Piperine has the ability to improve the bioavailability of many compounds when co-administered. The aim of this paper was to prepare and characterize the amorphous dispersions of hesperetin and piperine, which could help to improve solubility and boost the bioavailability of both plant-origin active compounds. The amorphous systems were successfully obtained by means of ball milling, as confirmed by XRPD and DSC studies. What's more, the FT-IR-ATR study was used to investigate the presence of intermolecular interactions between the systems' components. Amorphization enhanced the dissolution rate as a supersaturation state was reached, as well as improving the apparent solubility of both compounds by 245-fold and 183-fold, respectively, for hesperetin and piperine. In the in vitro permeability studies simulating gastrointestinal tract and blood-brain barrier permeabilities, these increased by 775-fold and 257-fold for hesperetin, whereas they were 68-fold and 66-fold for piperine in the GIT and BBB PAMPA models, respectively. Enhanced solubility had an advantageous impact on antioxidant as well as anti-butyrylcholinesterase activities—the best system inhibited 90.62 ± 0.58% of DPPH radicals and 87.57 ± 1.02% butyrylcholinesterase activity. To sum up, amorphization considerably improved the dissolution rate, apparent solubility, permeability, and biological activities of hesperetin and piperine. [ABSTRACT FROM AUTHOR]

Intranasal (IN) drug delivery is a non-invasive and effective route for the administration of drugs to the brain at pharmacologically relevant concentrations, bypassing the blood–brain barrier (BBB) and minimizing adverse side effects. IN drug delivery can be particularly promising for the treatment of neurodegenerative diseases. The drug delivery mechanism involves the initial drug penetration through the nasal epithelial barrier, followed by drug diffusion in the perivascular or perineural spaces along the olfactory or trigeminal nerves, and final extracellular diffusion throughout the brain. A part of the drug may be lost by drainage through the lymphatic system, while a part may even enter the systemic circulation and reach the brain by crossing the BBB. Alternatively, drugs can be directly transported to the brain by axons of the olfactory nerve. To improve the effectiveness of drug delivery to the brain by the IN route, various types of nanocarriers and hydrogels and their combinations have been proposed. This review paper analyzes the main biomaterials-based strategies to enhance IN drug delivery to the brain, outlining unsolved challenges and proposing ways to address them. [ABSTRACT FROM AUTHOR]

The aim of the present study is to develop Doxorubicin–Erlotinib nanoparticles (Dox–Erlo NPs) and folate-armored Dox–Erlo-NP conjugates for targeting glioma cancer. Glioma is one of the most common progressive cancerous growths originating from brain glial cells. However, the blood–brain barrier (BBB) is only semi-permeable and is highly selective as to which compounds are let through; designing compounds that overcome this constraint is therefore a major challenge in the development of pharmaceutical agents. We demonstrate that the NP conjugates studied in this paper may ameliorate the BBB penetration and enrich the drug concentration in the target bypassing the BBB. NPs were prepared using a biopolymer with a double-emulsion solvent evaporation technique and functionalized with folic acid for site-specific targeting. Dox–Erlo NPs and Dox–Erlo-NP conjugates were extensively characterized in vitro for various parameters. Dox–Erlo NPs and Dox–Erlo-NP conjugates incurred a z-average of 95.35 ± 10.25 nm and 110.12 ± 9.2 nm, respectively. The zeta potentials of the Dox–Erlo NPs and Dox–Erlo-NP conjugates were observed at −18.1 mV and −25.1 mV, respectively. A TEM image has shown that the NPs were well-dispersed, uniform, de-aggregated, and consistent. A hemolytic assay confirmed hemocompatibility with the developed formulation and that it can be safely administered. Dox–Erlo-NP conjugates significantly reduced the number of viable cells to 24.66 ± 2.08% and 32.33 ± 2.51% in U87 and C6 cells, respectively, and IC50 values of 3.064 µM and 3.350 µM in U87 and C6 cells were reported after 24 h, respectively. A biodistribution study revealed that a significant concentration of Dox and Erlo were estimated in the brain relative to drug suspension. Dox–Erlo-NP conjugates were also stable for three months. The findings suggest that the developed Dox–Erlo-NP conjugates may be a promising agent for administration in glioma therapy. [ABSTRACT FROM AUTHOR]

Paeoniflorin is a glycoside compound found in Paeonia lactiflora Pall that is used in traditional herbal medicine and shows various protective effects on the cardio-cerebral vascular system. It has been reported that the pharmacological effects of paeoniflorin might be generated by its metabolites. However, the bioavailability of paeoniflorin by oral administration is low, which greatly limits its clinical application. In this paper, a paeoniflorin-converting enzyme gene (G6046, GenBank accession numbers: OP856858) from Cunninghamella blakesleeana (AS 3.970) was identified by comparative analysis between MS analysis and transcriptomics. The expression, purification, enzyme activity, and structure of the conversion products produced by this paeoniflorin-converting enzyme were studied. The optimal conditions for the enzymatic activity were found to be pH 9, 45 °C, resulting in a specific enzyme activity of 14.56 U/mg. The products were separated and purified by high-performance counter-current chromatography (HPCCC). Two main components were isolated and identified, 2-amino-2-p-hydroxymethyl-methyl alcohol-benzoate (tirs-benzoate) and 1-benzoyloxy-2,3-propanediol (1-benzoyloxypropane-2,3-diol), via UPLC-Q-TOF-MS and NMR. Additionally, paeoniflorin demonstrated the ability to metabolize into benzoic acid via G6046 enzyme, which might exert antidepressant effects through the blood–brain barrier into the brain. [ABSTRACT FROM AUTHOR]

Brain tumor glioblastoma is one of the worst types of cancer. The blood–brain barrier prevents drugs from reaching brain cells and shields glioblastoma from treatment. The creation of nanocarriers to improve drug delivery and internalization effectiveness may be the solution to this issue. In this paper, we report on a new nanocarrier that was developed to deliver the anticancer drug doxorubicin to glioblastoma cells. The nanocarrier was obtained by nanoemulsion polymerization of diallyl disulfide with 1-allylthymine. Diallyl disulfide is a redox-sensitive molecule involved in redox cell activities, and thymine is a uracil derivative and one of the well-known bioactive compounds that can enhance the pharmacological activity of doxorubicin. Doxorubicin was successfully introduced into the nanocarrier with a load capacity of about 4.6%. Biological studies showed that the doxorubicin nanocarrier composition is far more cytotoxic to glioblastoma cells (T98G) than it is to cancer cells (M-HeLa) and healthy cells (Chang liver). The nanocarrier improves the penetration of doxorubicin into T98G cells and accelerates the cells' demise, as is evident from flow cytometry and fluorescence microscopy data. The obtained nanocarrier, in our opinion, is a promising candidate for further research in glioblastoma therapy. [ABSTRACT FROM AUTHOR]

Both astrocytic and microglial functions have been extensively investigated in healthy subjects and neurodegenerative diseases. For astrocytes, not only various sub-types were identified but phagocytic activity was also clarified recently and is making dramatic progress. In this review paper, we mostly focus on the functional role of astrocytes in the extracellular matrix and on interactions between reactive astrocytes and reactive microglia in normal states and in neurodegenerative diseases, because the authors feel it is necessary to elucidate the mechanisms among activated glial cells in the pathology of neurological diseases in order to pave the way for drug discovery. Finally, we will review cyclic phosphatidic acid (cPA), a naturally occurring phospholipid mediator that induces a variety of biological activities in the brain both in vivo and in vitro. We propose that cPA may serve as a novel therapeutic molecule for the treatment of brain injury and neuroinflammation. [ABSTRACT FROM AUTHOR]

The purpose of this review is to attempt to outline the potential role of fluoride in the pathogenesis of brain tumours, including glioblastoma (GBM). In this paper, we show for the first time that fluoride can potentially affect the generally accepted signalling pathways implicated in the formation and clinical course of GBM. Fluorine compounds easily cross the blood–brain barrier. Enhanced oxidative stress, disruption of multiple cellular pathways, and microglial activation are just a few examples of recent reports on the role of fluoride in the central nervous system (CNS). We sought to present the key mechanisms underlying the development and invasiveness of GBM, as well as evidence on the current state of knowledge about the pleiotropic, direct, or indirect involvement of fluoride in the regulation of these mechanisms in various tissues, including neural and tumour tissue. The effects of fluoride on the human body are still a matter of controversy. However, given the growing incidence of brain tumours, especially in children, and numerous reports on the effects of fluoride on the CNS, it is worth taking a closer look at these mechanisms in the context of brain tumours, including gliomas. [ABSTRACT FROM AUTHOR]

Although the clinical application of nanoparticles is still limited by biological barriers and distribution, with the deepening of our understanding of nanoparticles over the past decades, people are gradually breaking through the previous limitations in the diagnosis and treatment of tumors, providing novel strategies for clinical decision makers. The transition of nanoparticles from passive targeting to active tumor-targeting by abundant surface-modified nanoparticles is also a development process of precision cancer treatment. Different particles can be used as targeted delivery tools of antitumor drugs. The mechanism of gold nanoparticles inducing apoptosis and cycle arrest of tumor cells has been discovered. Moreover, the unique photothermal effect of gold nanoparticles may be widely used in tumor therapy in the future, with less side effects on surrounding tissues. Lipid-based nanoparticles are expected to overcome the blood–brain barrier due to their special characteristics, while polymer-based nanoparticles show better biocompatibility and lower toxicity. In this paper, we discuss the development of nanoparticles in tumor therapy and the challenges that need to be addressed. [ABSTRACT FROM AUTHOR]

Astrocytes play critical roles in regulating neuronal synaptogenesis, maintaining blood–brain barrier integrity, and recycling neurotransmitters. Increasing numbers of studies have suggested astrocyte heterogeneity in morphology, gene profile, and function. However, metabolic phenotype of astrocytes in different brain regions have not been explored. In this paper, we investigated the metabolic signature of cortical and cerebellar astrocytes using primary astrocyte cultures. We observed that cortical astrocytes were larger than cerebellar astrocytes, whereas cerebellar astrocytes had more and longer processes than cortical astrocytes. Using a Seahorse extracellular flux analyzer, we demonstrated that cortical astrocytes had higher mitochondrial respiration and glycolysis than cerebellar astrocytes. Cerebellar astrocytes have lower spare capacity of mitochondrial respiration and glycolysis as compared with cortical astrocytes. Consistently, cortical astrocytes have higher mitochondrial oxidation and glycolysis-derived ATP content than cerebellar astrocytes. In addition, cerebellar astrocytes have a fuel preference for glutamine and fatty acid, whereas cortical astrocytes were more dependent on glucose to meet energy demands. Our study indicated that cortical and cerebellar astrocytes display distinct metabolic phenotypes. Future studies on astrocyte metabolic heterogeneity and brain function in aging and neurodegeneration may lead to better understanding of the role of astrocyte in brain aging and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Phosphorylation of beta-amyloid peptide (Aβ) at the Ser8 residue affects its neurotoxicity, metal-dependent oligomerisation, amyloidogenicity, and other pathogenic properties. Phosphorylated Aβ (pS8-Aβ) was detected in vivo in AD model mice and in the brains of patients with AD. However, the pS8-Aβ production and the regulation of its levels have not been previously studied in detail. In this paper, immunochemical methods together with radioactive labelling were used to study the Aβ phosphorylation by intracellular and surface protein kinases of HEK293 cells and brain endothelial cells (bEnd.3). It was found that HEK293 robustly phosphorylated Aβ, likely with contribution from casein kinase 2 (CK2), whereas in bEnd.3, the activity of Aβ phosphorylation was relatively low. Further, the study showed that both HEK293 and bEnd.3 could dephosphorylate pS8-Aβ, mainly due to the activity of protein phosphatases PP1 and PP2A. The Aβ dephosphorylation efficiency in bEnd.3 was three times higher than in HEK293, which correlated with the reduced abundance of pS8-Aβ in vascular amyloid deposits of patients with AD compared to senile plaques. These data suggest an important role of CK2, PP1, and PP2A as regulators of Aβ phosphorylation, and point to the involvement of the blood–brain barrier in the control of Aβ modification levels. [ABSTRACT FROM AUTHOR]

The method of iron-dependent cell death known as ferroptosis is distinct from apoptosis. The suppression of ferroptosis after intracerebral hemorrhage (ICH) will effectively treat ICH and improve prognosis. This paper primarily summarizes the mechanism of ferroptosis after ICH, with an emphasis on lipid peroxidation, the antioxidant system, iron metabolism, and other pathways. In addition, regulatory targets and drug molecules were described. Although there has been some progress in the field of study, there are still numerous gaps. The mechanism by which non-heme iron enters neurons through the blood–brain barrier (BBB), the mitochondrial role in ferroptosis, and the specific mechanism by which lipid peroxidation induces ferroptosis remain unclear and require further study. In addition, the inhibitory effect of many drugs on ferroptosis after ICH has only been demonstrated in basic experiments and must be translated into clinical trials. In summary, research on ferroptosis following ICH will play an important role in the treatment of ICH. [ABSTRACT FROM AUTHOR]

Simple Summary: Aggressive types of breast cancer spread to the brain and can form a new tumor there. The treatment of such a tumor is more difficult because there is a membrane around the brain that limits the entrance of drugs. Currently, chemotherapy is the most well-known treatment for these patients, but it cannot pass through that membrane and such patients often die within two years. Here, we looked at some of the drug candidates that are extracted from plants and traditional herbal medicines and these candidates can activate the immune system to kill cancer. We reviewed whether these molecules could pass the brain membrane to activate the immune system inside the brain to kill cancer there. The limited treatment options for triple-negative breast cancer with brain metastasis (TNBC-BM) have left the door of further drug development for these patients wide open. Although immunotherapy via monoclonal antibodies has shown some promising results in several cancers including TNBC, it cannot be considered the most effective treatment for brain metastasis. This is due to the protective role of the blood–brain barrier (BBB) which limits the entrance of most drugs, especially the bulky ones such as antibodies, to the brain. For a drug to traverse the BBB via passive diffusion, various physicochemical properties should be considered. Since natural medicine has been a key inspiration for the development of the majority of current medicines, in this paper, we review several naturally-derived molecules which have the potential for immunotherapy via blocking the interaction of programmed cell death protein-1 (PD-1) and its ligand, PD-L1. The mechanism of action, physicochemical properties and pharmacokinetics of these molecules and their theoretical potential to be used for the treatment of TNBC-BM are discussed. [ABSTRACT FROM AUTHOR]

This study systematically reviews and characterizes the existing literature on transferrin/transferrin receptor-mediated drug delivery. Transferrin is an iron-binding protein. It can be used as a ligand to deliver various proteins, genes, ions, and drugs to the target site via transferrin receptors for therapeutic or diagnostic purposes via transferrin receptors. This study is based on a cross-sectional bibliometric analysis of 583 papers limited to the subject areas of pharmacology, toxicology, and pharmaceutics as extracted from the Scopus database in mid-September 2022. The data were analyzed, and we carried out a performance analysis and science mapping. There was a significant increase in research from 2018 onward. The countries that contributed the most were the USA and China, and most of the existing research was found to be from single-country publications. Research studies on transferrin/transferrin receptor-mediated drug delivery focus on drug delivery across the blood–brain barrier in the form of nanoparticles. The thematic analysis revealed four themes: transferrin/transferrin receptor-mediated drug delivery to the brain, cancer cells, gene therapy, nanoparticles, and liposomes as drug delivery systems. This study is relevant to academics, practitioners, and decision makers interested in targeted and site-specific drug delivery. [ABSTRACT FROM AUTHOR]

The number of papers that have investigated the interaction between microglia and pericytes is still relatively low, but recent evidence has demonstrated the importance of the association of pericytes with microglia [[83]]. Keywords: blood-brain barrier; blood vessel; brain development; cortex; endothelial cell; microglia; neurovascular unit; pericyte; vascular structure EN blood-brain barrier blood vessel brain development cortex endothelial cell microglia neurovascular unit pericyte vascular structure 1835 14 11/17/22 20221101 NES 221101 1. Glp1r SP + sp mural cells are largely SMCs, while the majority of Gipr SP + sp mural cells are pericytes, indicating that Gipr may be a useful marker of pericytes [[14]]. A previous study reported that FACS-isolated cells expressing Tbx18, a transcription factor that is selectively expressed in pericytes and vascular SMCs in multiple organs of adult mice, behaved similarly to mesenchymal stem cells in vitro, but lineage tracing experiments using an inducible Tbx18-CreERT2 line revealed that pericytes and vascular SMCs maintained their identity with age and in diverse pathological settings, suggesting that these cell types did not significantly contribute to other cell lineages [[104]]. An in vitro cell culture experiment of microglia and pericytes, which were isolated as NG2 SP + sp PDGFR SP - sp cells, demonstrated that the density of microglia was increased in microglia cultured together with pericytes as compared to microglia cultured alone, suggesting that pericytes promote microglial proliferation. [Extracted from the article]

This paper reviews the predictive capabilities of blood-based biomarkers to quantify traumatic brain injury (TBI). Biomarkers for concussive conditions also known as mild, to moderate and severe TBI identified along with post-traumatic stress disorder (PTSD) and chronic traumatic encephalopathy (CTE) that occur due to repeated blows to the head during one's lifetime. Since the pathways of these biomarkers into the blood are not fully understood whether there is disruption in the blood–brain barrier (BBB) and the time it takes after injury for the expression of the biomarkers to be able to predict the injury effectively, there is a need to understand the protein biomarker structure and other physical properties. The injury events in terms of brain and mechanics are a result of external force with or without the shrapnel, in the wake of a wave result in local tissue damage. Thus, these mechanisms express specific biomarkers kinetics of which reaches half-life within a few hours after injury to few days. Therefore, there is a need to determine the concentration levels that follow injury. Even though current diagnostics linking biomarkers with TBI severity are not fully developed, there is a need to quantify protein structures and their viability after injury. This research was conducted to fully understand the structures of 12 biomarkers by performing molecular dynamics simulations involving atomic movement and energies of forming hydrogen bonds. Molecular dynamics software, NAMD and VMD were used to determine and compare the approximate thermodynamic stabilities of the biomarkers and their bonding energies. Five biomarkers used clinically were S100B, GFAP, UCHL1, NF-L and tau, the kinetics obtained from literature show that the concentration values abruptly change with time after injury. For a given protein length, associated number of hydrogen bonds and bond energy describe a lower bound region where proteins self-dissolve and do not have long enough half-life to be detected in the fluids. However, above this lower bound, involving higher number of bonds and energy, we hypothesize that biomarkers will be viable to disrupt the BBB and stay longer to be modeled for kinetics for diagnosis and therefore may help in the discoveries of new biomarkers. [ABSTRACT FROM AUTHOR]