Effects of Hypertension on Alzheimer's Disease: Updates in Pathophysiological and Neuroimaging Findings.

Alzheimer's disease (AD) is recognized as the leading cause of dementia, imposing a significant economic toll on society. Despite the emergence of novel therapeutic approaches for AD, their efficacy and safety mandates further validation through rigorous clinical trials. In this context, hypertension (HTN) has garnered considerable attention as an amendable risk factor for AD. Research indicates that hypertension during midlife is associated with an elevated risk of AD in later years, influencing both the onset and progression of the disease. Nevertheless, the relationship between AD and hypertension in the later stages of life remains a subject of debate. Moreover, the consequences of blood pressure reduction on cognitive function, along with the optimal pharmacological interventions and therapeutic thresholds for hypertension, have emerged as pivotal areas of inquiry. This review synthesizes findings on epidemiology, neuroimaging, and biomarkers, and the effects of antihypertensive medications to elucidate the link between hypertension and cognitive performance. We particularly investigate how hypertension and AD are related by plasma sulfide dysregulation, offering possible indicators for future diagnosis and therapy.

Stroke-like onset of calcified brain metastases with Wallerian degeneration: a case report and review of the literature.

INTRODUCTION: Metastatic brain tumors are a common complication of systemic cancer. They tend to have a chronic onset and are located at the gray-white junction of the cerebral hemispheres, those larger than 9.4 mm in diameter are often accompanied by substantial vasogenic edema. Herein, we report a rare case of calcified metastatic adenocarcinoma with Wallerian degeneration. In addition, we discuss the atypical manifestations of brain metastases. CASE REPORT: A 71-year-old man who went through stroke-like onset twice during 8 months with a history of resection of the left pulmonary adenocarcinoma 5 years prior was examined. Diffusion weighted magnetic resonance imaging of the brain showed an enlarged open-ring-shaped hyperintensity on the left periventricular white matter and basal ganglia, with Wallerian degeneration on the left cerebral peduncle. Brain computed tomography revealed nodular calcification of the lesion. The pathology of stereotactic biopsy indicated metastatic adenocarcinoma. CONCLUSION: When patients present with acute nervous system symptoms and a previous history of cancer, the possibility of metastases should be considered, even if neuroimaging is atypical.

Fucoxanthin has potential for therapeutic efficacy in neurodegenerative disorders by acting on multiple targets.

Fucoxanthin, one of the most abundant carotenoids from edible brown seaweeds, for years has been used as a bioactive dietary supplement and functional food ingredient. Recently, fucoxanthin was reported to penetrate the blood-brain barrier, and was superior to other carotenoids to exert anti-neurodegenerative disorder effects via acting on multiple targets, including amyloid protein aggregation, oxidative stress, neuroinflammation, neuronal loss, neurotransmission dysregulation and gut microbiota disorder. However, the concentration of fucoxanthin required for in vivo neuroprotective effects is somewhat high, and the poor bioavailability of this molecule might prevent its clinical use. As such, new strategies have been introduced to overcome these obstacles, and may help to develop fucoxanthin as a novel lead for neurodegenerative disorders. Moreover, it has been shown that some metabolites of fucoxanthin may produce potent in vivo neuroprotective effects. Altogether, these studies suggest the possibility for future development of fucoxanthin as a one-compound-multiple-target or pro-drug type pharmaceutical or nutraceutical treatment for neurodegenerative disorders.Trial registration: ClinicalTrials.gov identifier: NCT03625284.Trial registration: ClinicalTrials.gov identifier: NCT02875392.Trial registration: ClinicalTrials.gov identifier: NCT03613740.Trial registration: ClinicalTrials.gov identifier: NCT04761406.

Evans Blue Might Produce Pathologically Activated Neuroprotective Effects via the Inhibition of the P2X4R/p38 Signaling Pathway.

The main pathological features of ischemic stroke include neuronal damage and blood-brain barrier (BBB) dysfunction. Previous studies have shown that Evans Blue, a dye used to probe BBB integrity, could enter the brain only during the pathological status of ischemic stroke, indicating the potential pathologically activated therapeutic use of this chemical to treat ischemic stroke. In this study, we have reported that Evans Blue could produce in vitro neuroprotective effects against iodoacetic acid (IAA)-induced hypoxia neuronal death in HT22 cells. We further found that P2X purinoreceptor 4 (P2X4R), a subtype of ATP-gated cation channel, was expressed in HT22 cells. Evans Blue could prevent IAA-induced increase of P2X4R mRNA and protein expression. Interestingly, shRNA of P2X4R could protect against IAA-induced activation of p38, and SB203580, a specific inhibitor of p38, could reverse IAA-induced neurotoxicity, indicating that p38 is a downstream signaling molecule of P2X4R. Molecular docking analysis further demonstrated the possible interaction between Evans Blue and the ATP binding site of P2X4R. Most importantly, pre-treatment of Evans Blue could largely reduce neurological and behavioral abnormity, and decrease brain infarct volume in middle cerebral artery occlusion/reperfusion (MCAO) rats. All these results strongly suggested that Evans Blue could exert neuroprotective effects via inhibiting the P2X4R/p38 pathway, possibly by acting on the ATP binding site of P2X4R, indicating that Evans Blue might be further developed as a pathologically activated therapeutic drug against ischemic stroke.

9-Methylfascaplysin Is a More Potent Aß Aggregation Inhibitor than the Marine-Derived Alkaloid, Fascaplysin, and Produces Nanomolar Neuroprotective Effects in SH-SY5Y Cells.

ß-Amyloid (Aß) is regarded as an important pathogenic target for Alzheimer's disease (AD), the most prevalent neurodegenerative disease. Aß can assemble into oligomers and fibrils, and produce neurotoxicity. Therefore, Aß aggregation inhibitors may have anti-AD therapeutic efficacies. It was found, here, that the marine-derived alkaloid, fascaplysin, inhibits Aß fibrillization in vitro. Moreover, the new analogue, 9-methylfascaplysin, was designed and synthesized from 5-methyltryptamine. Interestingly, 9-methylfascaplysin is a more potent inhibitor of Aß fibril formation than fascaplysin. Incubation of 9-methylfascaplysin with Aß directly reduced Aß oligomer formation. Molecular dynamics simulations revealed that 9-methylfascaplysin might interact with negatively charged residues of Aß42 with polar binding energy. Hydrogen bonds and π⁻π interactions between the key amino acid residues of Aß42 and 9-methylfascaplysin were also suggested. Most importantly, compared with the typical Aß oligomer, Aß modified by nanomolar 9-methylfascaplysin produced less neuronal toxicity in SH-SY5Y cells. 9-Methylfascaplysin appears to be one of the most potent marine-derived compounds that produces anti-Aß neuroprotective effects. Given previous reports that fascaplysin inhibits acetylcholinesterase and induces P-glycoprotein, the current study results suggest that fascaplysin derivatives can be developed as novel anti-AD drugs that possibly act via inhibition of Aß aggregation along with other target mechanisms.

5-Hydroxycyclopenicillone Inhibits ß-Amyloid Oligomerization and Produces Anti-ß-Amyloid Neuroprotective Effects In Vitro.

The oligomer of ß-amyloid (Aß) is considered the main neurotoxin in Alzheimer's disease (AD). Therefore, the inhibition of the formation of Aß oligomer could be a target for AD therapy. In this study, with the help of the dot blotting assay and transmission electronic microscopy, it was have discovered that 5-hydroxycyclopenicillone, a cyclopentenone recently isolated from a sponge-associated fungus, effectively reduced the formation of Aß oligomer from Aß peptide in vitro. Molecular dynamics simulations suggested hydrophobic interactions between 5-hydroxycyclopenicillone and Aß peptide, which might prevent the conformational transition and oligomerization of Aß peptide. Moreover, Aß oligomer pre-incubated with 5-hydroxycyclopenicillone was less toxic when added to neuronal SH-SY5Y cells compared to the normal Aß oligomer. Although 5-hydroxycyclopenicillone is not bioavailable in the brain in its current form, further modification or encapsulation of this chemical might improve the penetration of 5-hydroxycyclopenicillone into the brain. Based on the current findings and the anti-oxidative stress properties of 5-hydroxycyclopenicillone, it is suggested that 5-hydroxycyclopenicillone may have potential therapeutic efficacy in treating AD.

Advances in retinal imaging biomarkers for the diagnosis of cerebrovascular disease.

The increasing incidence and mortality rates of cerebrovascular disease impose a heavy burden on both patients and society. Retinal imaging techniques, such as fundus photography, optical coherence tomography, and optical coherence tomography angiography, can be used for rapid, non-invasive evaluation of cerebral microcirculation and brain function since the retina and the central nervous system share similar embryonic origin characteristics and physiological features. This article aimed to review retinal imaging biomarkers related to cerebrovascular diseases and their applications in cerebrovascular diseases (stroke, cerebral small vessel disease [CSVD], and vascular cognitive impairment [VCI]), thus providing reference for early diagnosis and prevention of cerebrovascular diseases.

Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research.

Gastrointestinal cancers account for approximately one-third of the total global cancer incidence and mortality with a poor prognosis. It is one of the leading causes of cancer-related deaths worldwide. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. As a novel preclinical model, tumor patient-derived organoids (PDOs), can be established from patients' tumor tissue and cultured in the laboratory in 3D architectures. This 3D model can not only highly simulate and preserve key biological characteristics of the source tumor tissue in vitro but also reproduce the in vivo tumor microenvironment through co-culture. Our review provided an overview of the different in vitro models in current tumor research, the derivation of cells in PDO models, and the application of PDO model technology in gastrointestinal cancers, particularly the applications in combination with CRISPR/Cas9 gene editing technology, tumor microenvironment simulation, drug screening, drug development, and personalized medicine. It also elucidates the ethical status quo of organoid research and the current challenges encountered in clinical research, and offers a forward-looking assessment of the potential paths for clinical organoid research advancement.

Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and ß-amyloid (Aß) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aß production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aß oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aß oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aß aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

9-Methylfascaplysin exerts anti-ischemic stroke neuroprotective effects via the inhibition of neuroinflammation and oxidative stress in rats.

OBJECTIVES: This study was aimed to investigate the neuroprotective effects of 9-methylfascaplysin, a novel marine derivative derived from sponge, against middle cerebral artery occlusion/reperfusion (MCAO)-induced motor impairments, neuroinflammation and oxidative stress in rats. METHODS: Neurological and behavioral tests were used to evaluate behavioral changes. The 2, 3, 5-triphenyltetrazolium chloride staining was used to determine infarct size and edema extent. Activated microglia/macrophage was analyzed by immunohistochemical staining of Iba-1. RT-PCR and ELISA were used to measure the expression of inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1ß, CD16 and CD206. Western blotting analysis was performed to explore the activation of nuclear factor-κB (NF-κB) and NLRP3. The levels of oxidative stress were studied by evaluating the activities of superoxide dismutase, catalase and glutathione peroxidase. RESULTS: Post-occlusion intracerebroventricular injection of 9-methylfascaplysin significantly attenuated motor impairments and infarct size in MCAO rats. Moreover, 9-methylfascaplysin reduced the activation of microglia/macrophage in ischemic penumbra as evidenced by the decreased Iba-1-positive area and the reduced expression of pro-inflammatory factors. Furthermore, 9-methylfascaplysin inhibited MCAO-induced oxidative stress and activation of NF-κB and NLRP3 inflammasome. CONCLUSION: All the results suggested that 9-methylfascaplysin might produce neuroprotective effects against MCAO via the reduction of oxidative stress and neuroinflammation, simultaneously, possibly via the inhibition of NF-κB and NLRP3 inflammasome.

PLGA-PEG Nanoparticles Facilitate In Vivo Anti-Alzheimer's Effects of Fucoxanthin, a Marine Carotenoid Derived from Edible Brown Algae.

The marine natural product fucoxanthin has been reported previously to produce anti-Alzheimer's disease (AD) neuroprotective effects in vitro and in vivo. Fucoxanthin was also demonstrated to be safe in preclinical and small population clinical studies, but the low bioavailability of fucoxanthin in the central nervous system (CNS) has limited its clinical applications. To overcome this, poly lactic-co-glycolic acid-block-polyethylene glycol loaded fucoxanthin (PLGA-PEG-Fuc) nanoparticles with diameter at around 200 nm and negative charge were synthesized and suggested to penetrate into the CNS. Loaded fucoxanthin could be liberated from PLGA-PEG nanoparticles by sustained released in the physiological environment. PLGA-PEG-Fuc nanoparticles were shown to significantly inhibit the formation of Aß fibrils and oligomers. Moreover, these nanoparticles were taken up by both neurons and microglia, leading to the reduction of Aß oligomers-induced neurotoxicity in vitro. Most importantly, intravenous injection of PLGA-PEG-Fuc nanoparticles prevented cognitive impairments in Aß oligomers-induced AD mice with greater efficacy than free fucoxanthin, possibly via acting on Nrf2 and NF-κB signaling pathways. These results altogether suggest that PLGA-PEG nanoparticles can enhance the bioavailability of fucoxanthin and potentiate its efficacy for the treatment of AD, thus potentially enabling its future use for AD therapy.

CSB6B prevents ß-amyloid-associated neuroinflammation and cognitive impairments via inhibiting NF-κB and NLRP3 in microglia cells.

Pathological ß-amyloid (Aß)-induced microglial activation could cause chronic neuroinflammation in the brain of Alzheimer's disease (AD) patients, and has been considered as one of the main pathological events of this disease. Chicago sky blue 6B (CSB6B), a pigment used in biochemical staining, has been reported to produce analgesic effects in neuroinflammatory-associated pain models. We have previously found that CSB6B could directly inhibit Aß aggregation and prevent Aß toxicity in neurons. However, it remains unclear whether this compound could prevent Aß-induced neuroinflammation and impairments of learning and memory in the AD models. In this study, CSB6B was found to effectively inhibit the production of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, without affecting cell viability in BV2 microglia cells stimulated by Aß oligomer and lipopolysaccharide. Moreover, CSB6B significantly reduced mRNA expression of inducible nitric oxide synthase and increased mRNA expression of arginase-1, suggesting that CSB6B might promote the polarization of BV2 cells into M2 phenotype. In Aß oligomer-treated mice, hippocampal injection of CSB6B prevented cognitive impairments, and attenuated pro-inflammatory cytokines production. In addition, CSB6B inhibited nuclear transcription factor-κB (NF-κB), and restrainedthe activation of NOD-like receptor pyrin domain containing-3 (NLRP3) both in vitro and in vivo. According to our results, CSB6B may counteract Aß-induced cognitive impairments and neuroinflammation by inhibiting NF-κB and NLRP3. Combined with previous studies, we anticipated that CSB6B may further develop into a potential anti-AD drug with multiple functions on neurons and microglia cells, concurrently.

25C-NBOMe, a Novel Designer Psychedelic, Induces Neurotoxicity 50 Times More Potent Than Methamphetamine In Vitro.

25C-NBOMe is a designer substituted phenethylamine and a high-potency psychedelic that acts on the 5-HT2A receptor. Although 25C-NBOMe overdoses have been related to several deaths in the USA and Europe, very limited data exists on the in vitro neurotoxicity of 25C-NBOMe. In this study, we found that 25C-NBOMe potently reduced cell viability of SH-SY5Y, PC12, and SN4741 cells, with IC50 values of 89, 78, and 62 µM, respectively. Methamphetamine decreased the cell viability of these cells with IC50 values at millimolar range in the same tests, indicating that 25C-NBOMe is > 50 times more potent than methamphetamine in its ability to reduce viability of SH-SY5Y cells. The neurotoxicity of 25C-NBOMe on SH-SY5Y cells was further confirmed by using fluorescein diacetate/propidium iodide double staining. 25C-NBOMe elevated the expression of phosphorylated extracellular signal-regulated kinase (pERK), but decreased the expression of phosphorylated Akt and phosphorylated Ser9- glycogen synthase kinase 3ß (GSK3ß) in time- and concentration-dependent manners. Interestingly, either specific GSK3ß inhibitors or specific mitogen-activated protein kinase kinase (MEK) inhibitors significantly prevented 25C-NBOMe-induced neurotoxicity in SH-SY5Y cells. These results suggest that 25C-NBOMe unexpectedly produced more potent neurotoxicity than methamphetamine and that the inhibition of the Akt pathway and activation of the ERK cascade might be involved in 25C-NBOMe-induced neurotoxicity. Most importantly, these findings further inform the toxicity of 25C-NBOMe abuse to the central nervous system for public health.

Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aß Oligomer-Induced Cognitive Impairments in Mice.

Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3ß (GSK3ß), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3-23.3 µg/kg 7Bio effectively prevented ß-amyloid (Aß) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aß oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aß oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aß oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aß oligomer-decreased expression of pSer9-GSK3ß. Those results suggested that 7Bio could potently inhibit Aß oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound.