The blood–brain barrier (BBB) plays a vital role in the protection and maintenance of homeostasis in the brain. In this way, it is an interesting target as an interface for various types of drug delivery, specifically in the context of the treatment of several neuropathological conditions where the therapeutic agents cannot cross the BBB. Drug toxicity and on-target specificity are among some of the limitations associated with current neurotherapeutics. In recent years, advances in nanodrug delivery have enabled the carrier system containing the active therapeutic drug to target the signaling pathways and pathophysiology that are closely linked to central nervous system (CNS) disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), brain tumor, epilepsy, ischemic stroke, and neurodegeneration. At present, among the nano formulations, solid lipid nanoparticles (SLNs) have emerged as a putative drug carrier system that can deliver the active therapeutics (drug-loaded SLNs) across the BBB at the target site of the brain, offering a novel approach with controlled drug delivery, longer circulation time, target specificity, and higher efficacy, and more importantly, reducing toxicity in a biomimetic way. This paper highlights the synthesis and application of SLNs as a novel nontoxic formulation strategy to carry CNS drugs across the BBB to improve the use of therapeutics agents in treating major neurological disorders in future clinics.

Psychiatric disorders pose a significant global health challenge, exacerbated by the COVID-19 pandemic and insufficiently addressed by the current treatments. This review explores the emerging role of bile acids and the TGR5 receptor in the pathophysiology of psychiatric conditions, emphasizing their signaling within the gut-brain axis. We detail the synthesis and systemic functions of bile acids, their transformation by gut microbiota, and their impact across various neuropsychiatric disorders, including major depressive disorder, general anxiety disorder, schizophrenia, autism spectrum disorder, and bipolar disorder. The review highlights how dysbiosis and altered bile acid metabolism contribute to the development and exacerbation of these neuropsychiatric disorders through mechanisms involving inflammation, oxidative stress, and neurotransmitter dysregulation. Importantly, we detail both pharmacological and non-pharmacological interventions that modulate TGR5 signaling, offering potential breakthroughs in treatment strategies. These include dietary adjustments to enhance beneficial bile acids production and the use of specific TGR5 agonists that have shown promise in preclinical and clinical settings for their regulatory effects on critical pathways such as cAMP-PKA, NRF2-mediated antioxidant responses, and neuroinflammation. By integrating findings from the dynamics of gut microbiota, bile acids metabolism, and TGR5 receptor related signaling events, this review underscores cutting-edge therapeutic approaches poised to revolutionize the management and treatment of psychiatric disorders.

Dysregulated human monocytes/macrophages can synthesize and secrete matrix metalloproteinases (MMPs), which play important roles in the progression of sepsis. In this study, we investigated the effects and mechanism of a novel histone deacetylase (HDAC8) inhibitor, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (WK2-16), on MMP-9 production and activation in stimulated human monocytic THP-1 cells. Our results demonstrated that the acetylation level of structural maintenance of chromosomes 3 (SMC3) was up-regulated by WK2-16 in THP-1 cells. Consistently, an in vitro enzyme study demonstrated that WK2-16 selectively inhibited HDAC8 activity. Moreover, the WK2-16 concentration dependently suppressed MMP-9-mediated gelatinolysis induced by tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS). Additionally, WK2-16 significantly inhibited both MMP-9 protein and mRNA expression without cellular toxicity. Nevertheless, WK2-16 suppressed the extracellular levels of interleukin (IL)-6 from LPS-stimulated THP-1 cells. For the signaling studies, WK2-16 had no effect on LPS/TLR4 downstream signaling pathways, such as the NF-κB and ERK/JNK/P38 MAPK pathways. On the other hand, WK2-16 enhanced the recruitment of acetylated Yin Yang 1 (YY1) with HDAC1. Finally, in vivo studies indicated that WK2-16 could reduce the serum levels of TNF-α and IL-6 in endotoxemic mice. These results suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis.

Activated human monocytes/macrophages, which increase the levels of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines, are the essential mechanisms for the progression of sepsis. In the present study, we determined the functions and mechanisms of hirsutanolA (HA), which is isolated from the red alga-derived marine fungus Chondrostereum sp. NTOU4196, on the production of pro-inflammatory mediators produced from lipopolysaccharide (LPS)-treated THP-1 cells. Our results showed that HA suppressed LPS-triggered MMP-9-mediated gelatinolysis and expression of protein and mRNA in a concentration-dependent manner without effects on TIMP-1 activity. Also, HA significantly attenuated the levels of TNF-α, IL-6, and IL-1β from LPS-treated THP-1 cells. Moreover, HA significantly inhibited LPS-mediated STAT3 (Tyr705) phosphorylation, IκBα degradation and ERK1/2 activation in THP-1 cells. In an LPS-induced endotoxemia mouse model, studies indicated that HA pretreatment improved endotoxemia-induced acute sickness behavior, including acute motor deficits and anxiety-like behavior. HA also attenuated LPS-induced phospho-STAT3 and pro-MMP-9 activity in the hippocampus. Notably, HA reduced pathologic lung injury features, including interstitial tissue edema, infiltration of inflammatory cells and alveolar collapse. Likewise, HA suppressed the induction of phospho-STAT3 and pro-MMP-9 in lung tissues. In conclusion, our results provide pharmacological evidence that HA could be a useful agent for treating inflammatory diseases, including sepsis.

Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are activated, comprising necrosis, apoptosis, and autophagy as well as glial activation and white matter injury, which leads to neuronal cell death. Current treatments for strokes include challenging mechanical thrombectomy or tissue plasminogen activator, which increase the danger of cerebral bleeding, brain edema, and cerebral damage, limiting their usage in clinical settings. Monoclonal antibody therapy has proven to be effective and safe in the treatment of a variety of neurological disorders. In contrast, the evidence for stroke therapy is minimal. Recently, Clone MTS510 antibody targeting toll-like receptor-4 (TLR4) protein, ASC06-IgG1 antibody targeting acid sensing ion channel-1a (ASIC1a) protein, Anti-GluN1 antibodies targeting N-methyl-D-aspartate (NMDA) receptor associated calcium influx, GSK249320 antibody targeting myelin-associated glycoprotein (MAG), anti-High Mobility Group Box-1 antibody targeting high mobility group box-1 (HMGB1) are currently under clinical trials for cerebral ischemia treatment. In this article, we review the current antibody-based pharmaceuticals for neurological diseases, the use of antibody drugs in stroke, strategies to improve the efficacy of antibody therapeutics in cerebral ischemia, and the recent advancement of antibody drugs in clinical practice. Overall, we highlight the need of enhancing blood–brain barrier (BBB) penetration for the improvement of antibody-based therapeutics in the brain, which could greatly enhance the antibody medications for cerebral ischemia in clinical practice.