Caspase-8 has been classified as an apoptotic caspase, and its initial definition was an initiator of extrinsic cell death. During the past decade, the concept of caspase-8 functioning has been changed by findings of its additional roles in diverse biological processes. Although caspase-8 was not originally thought to be involved in the inflammation process, many recent works have determined that caspase-8 plays an important role in the regulatory functions of inflammatory processes. In this review, we describe the recent advances in knowledge regarding the manner in which caspase-8 modulates the inflammatory responses concerning inflammasome activation, cell death, and cytokine induction.

The most common neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are the seventh leading cause of mortality and morbidity in developed countries. Clinical observations of NDD patients are characterized by a progressive loss of neurons in the brain along with memory decline. The common pathological hallmarks of NDDs include oxidative stress, the dysregulation of calcium, protein aggregation, a defective protein clearance system, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, and damage to cholinergic neurons. Therefore, managing this pathology requires screening drugs with different pathological targets, and suitable drugs for slowing the progression or prevention of NDDs remain to be discovered. Among the pharmacological strategies used to manage NDDs, natural drugs represent a promising therapeutic strategy. This review discusses the neuroprotective potential of seaweed and its bioactive compounds, and safety issues, which may provide several beneficial insights that warrant further investigation.

Necroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none of them are currently in clinical use. In the present study, we identified a new compound, 4-({[5-(4-aminophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-N-(1,3-thiazol-2-yl) benzamide (NTB451), with significant inhibitory activity on the necroptosis induced by various triggers, such as tumor necrosis factor-α (TNF-α) and toll-like receptor (TLR) agonists. Mechanistic studies revealed that NTB451 inhibited phosphorylation and oligomerization of mixed lineage kinase domain like (MLKL), and this activity was linked to its inhibitory effect on the formation of the receptor interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3 complex. Small interfering RNA (siRNA)-mediated RIPK1 knockdown, drug affinity responsive target stability assay, and molecular dynamics (MD) simulation study illustrated that RIPK1 is a specific target of NTB451. Moreover, MD simulation showed a direct interaction of NTB451 and RIPK1. Further experiments to ensure that the inhibitory effect of NTB451 was restricted to necroptosis and NTB451 had no effect on nuclear factor-κB (NF-κB) activation or apoptotic cell death upon triggering with TNF-α were also performed. Considering the data obtained, our study confirmed the potential of NTB451 as a new necroptosis inhibitor, suggesting its therapeutic implications for pathological conditions induced by necroptotic cell death.

Background/Objectives: Neuroinflammatory mechanisms, primarily mediated by activated microglia, play a key role in the progression of conditions such as mild cognitive impairment associated with Alzheimer’s disease. Rubus occidentalis (R. occidentalis), a black-fruited raspberry native to North America, is reported to possess antimicrobial, antidiabetic, and anticancer properties. This study investigated the neuroprotective and anti-neuroinflammatory effects of a 100% ethanol extract from premature R. occidentalis fruits (ROE) in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced amnesic mouse model. Methods: C57BL/6N mice were orally administered ROE (100 or 200 mg/kg/b.w.) and donepezil (DNZ, 5 mg/kg) for 9 days and intraperitoneally injected with scopolamine (2 mg/kg/b.w.) for two days. Spatial learning and cognitive function were assessed using the Y-maze and Morris water maze tests. Protein and mRNA levels were examined both in vitro and in vivo through Western blotting and RT-PCR analysis. Results: In vitro, ROE improved cell viability and reduced nitric oxide overproduction in LPS-stimulated BV-2 cells, attenuated LPS-induced phosphorylation and degradation of IκB-α (thereby limiting NF-κB p65 nuclear translocation), and suppressed phosphorylation of MAPK signaling components. In vivo, ROE administration enhanced spatial learning and memory in scopolamine-treated C57BL/6N mice, increased hippocampal levels of brain-derived neurotrophic factor (BDNF) and phosphorylated CREB, and reduced the expression of iNOS and COX-2. Conclusions: Collectively, these results suggest that ROE possesses neuroprotective properties mediated by inhibition of NF-κB and MAPK signaling, promotion of CREB/BDNF pathways, and amelioration of neuroinflammation and cognitive deficits. Thus, ROE may represent a promising therapeutic candidate for neuroinflammatory disorders.