Apoptosis is the crucial pathological mechanism following cerebral ischemic injury. Our previous studies demonstrated that clonidine, one agonist of alpha2-adrenergic receptor (α2-AR), could attenuate cerebral ischemic injury in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). However, it's unclear whether clonidine exerts neuroprotective effects by regulating neuronal apoptosis. In this study, we elucidated whether clonidine can exert anti-apoptotic effects in cerebral ischemic injury, and further explored the possible mechanisms. Neurological deficit score was measured to evaluate the neurological function. TTC staining was used for the measurement of brain infarct size. Hematoxylin-Eosin (HE) staining was applied to examine the cell morphology. TUNEL and DAPI fluorescent staining methods were used to analyze the cell apoptosis in brain tissue. Fluorescence quantitative real-time PCR was performed to assess the gene expression of Caspase-3 and P53. Western blotting assay was applied to detect the protein expression of Caspase-3 and P53. The results showed that clonidine improved neurological function, reduced brain infarct size, alleviated neuronal damage, and reduced the ratio of cell apoptosis in the brain with MCAO/R injury. moreover, clonidine down-regulated the gene and protein expression of Caspase-3 and P53 which were over-expressed after MCAO/R injury. Whereas, yohimbine (one selective α2-AR antagonist) mitigated the anti-apoptosis effects of clonidine, accompanied by reversed gene and protein expression changes. The results indicated that clonidine attenuated cerebral MCAO/R injury via suppressing neuronal apoptosis, which may be mediated, at least in part, by activating α2-AR.

Dexmedetomidine and propofol are two sedatives used for long-term sedation. It remains unclear whether dexmedetomidine provides superior cerebral protection for patients undergoing long-term mechanical ventilation.

To compare the neuroprotective effects of dexmedetomidine and propofol for sedation during prolonged mechanical ventilation in patients without brain injury.

Patients who underwent mechanical ventilation for > 72 h were randomly assigned to receive sedation with dexmedetomidine or propofol. The Richmond Agitation and Sedation Scale (RASS) was used to evaluate sedation effects, with a target range of -3 to 0. The primary outcomes were serum levels of S100-β and neuron-specific enolase (NSE) every 24 h. The secondary outcomes were remifentanil dosage, the proportion of patients requiring rescue sedation, and the time and frequency of RASS scores within the target range.

A total of 52 and 63 patients were allocated to the dexmedetomidine group and propofol group, respectively. Baseline data were comparable between groups. No significant differences were identified between groups within the median duration of study drug infusion [52.0 (IQR: 36.0-73.5) h vs 53.0 (IQR: 37.0-72.0) h, P = 0.958], the median dose of remifentanil [4.5 (IQR: 4.0-5.0) μg/kg/h vs 4.6 (IQR: 4.0-5.0) μg/kg/h, P = 0.395], the median percentage of time in the target RASS range without rescue sedation [85.6% (IQR: 65.8%-96.6%) vs 86.7% (IQR: 72.3%-95.3), P = 0.592], and the median frequency within the target RASS range without rescue sedation [72.2% (60.8%-91.7%) vs 73.3% (60.0%-100.0%), P = 0.880]. The proportion of patients in the dexmedetomidine group who required rescue sedation was higher than in the propofol group with statistical significance (69.2% vs 50.8%, P = 0.045). Serum S100-β and NSE levels in the propofol group were higher than in the dexmedetomidine group with statistical significance during the first six and five days of mechanical ventilation, respectively (all P < 0.05).

Dexmedetomidine demonstrated stronger protective effects on the brain compared to propofol for long-term mechanical ventilation in patients without brain injury.

Dexmedetomidine is a commonly used sedative in perioperative and intensive care settings with purported immunomodulatory properties. Since its effects on immune functions against infections have not been extensively studied, we tested the effects of dexmedetomidine on Gram-positive [Staphylococcus aureus and Enterococcus faecalis] and Gram-negative bacteria [Escherichia coli], and on effector functions of human monocytes THP-1 cells against them. We evaluated phagocytosis, reactive oxygen species (ROS) formation, and CD11b activation, and performed RNA sequencing analyses. Our study revealed that dexmedetomidine improved Gram-positive but mitigated Gram-negative bacterial phagocytosis and killing in THP-1 cells. The attenuation of Toll-like receptor 4 (TLR4) signaling by dexmedetomidine was previously reported. Thus, we tested TLR4 inhibitor TAK242. Similar to dexmedetomidine, TAK242 reduced E. coli phagocytosis but enhanced CD11b activation. The reduced TLR4 response potentially increases CD11b activation and ROS generation and subsequently enhances Gram-positive bacterial killing. Conversely, dexmedetomidine may inhibit the TLR4-signaling pathway and mitigate the alternative phagocytosis pathway induced by TLR4 activation through LPS-mediated Gram-negative bacteria, resulting in worsened bacterial loads. We also examined another α2 adrenergic agonist, xylazine. Because xylazine did not affect bacterial clearance, we proposed that dexmedetomidine may have an off-target effect on bacterial killing process, potentially involving crosstalk between CD11b and TLR4. Despite its potential to attenuate inflammation, we provide a novel insight into potential risks of dexmedetomidine use during Gram-negative infections, highlighting the differential effect of dexmedetomidine on Gram-positive and Gram-negative bacteria.

Alzheimer's disease (AD) is the most common type of dementia and seriously affects human life and health. Kaempferol (KMP) is a common flavonoid, that is mainly derived from the rhizomes of Kaempferol galanga L. and is widely found in various fruits and vegetables. Previous studies have suggested that KMP has multiple pharmacological activities. However, the anti-AD mechanism of KMP has not been elucidated.

This systematic review aims to summarize the existing preclinical experiments on KMP, further confirm the therapeutic effect of KMP in an AD model, and summarize the possible mechanism by which KMP exerts anti-AD effects. Electronic databases, including PubMed, China National Knowledge Infrastructure (CNKI), Baidu Academic, and Wanfang, were searched using the keywords of 'Kaempferol,' 'KMP,' 'pharmacology,' and 'Alzheimer's disease'.

We evaluated the reliability of the 12 included studies, and the results showed that the anti-AD mechanism of KMP was reliable and that the prospect of KMP in the treatment of cognitive impairment was promising. We comprehensively assessed the neuroprotective effects of KMP in in vivo and in vitro models of AD. These studies shown that KMP ameliorated AD through several mechanisms, including its antioxidant, anti-inflammatory, anti-apoptotic, and anti-acetylcholinesterase effects.

KMP may exert anti-AD effects through various mechanisms and is a potential drug with broad prospects for the treatment of AD.

Vascular smooth muscle cell (VSMC) phenotypic modulation regulates the initiation and progression of intracranial aneurysm (IA). Dexmedetomidine (DEX) is suggested to play neuroprotective roles in patients with craniocerebral injury. Therefore, we investigated the biological functions of DEX and its mechanisms against IA formation and progression in the current study. The rat primary VSMCs were isolated from Sprague-Dawley rats. IA and superficial temporal artery (STA) tissue samples were obtained from patients with IA. Flow cytometry was conducted to identify the characteristics of isolated VSMCs. Hydrogen peroxide (H₂O₂) was used to mimic IA-like conditions in vitro. Cell viability was detected using CCK-8 assays. Wound healing and Transwell assays were performed to detect cell motility. ROS production was determined by immunofluorescence using DCFH-DA probes. Western blotting and RT-qPCR were carried out to measure gene expression levels. Inflammation responses were determined by measuring inflammatory cytokines. Immunohistochemistry staining was conducted to measure α₂-adrenergic receptor levels in tissue samples. DEX alleviated the H₂O₂-induced cytotoxicity, attenuated the promoting effects of H₂O₂ on cell malignancy, and protected VSMCs against H₂O₂-induced oxidative damage and inflammation response. DEX regulated the GSK-3β/MKP-1/NRF2 pathway via the α2AR. DEX alleviates the inflammatory responses and oxidative damage of VSMCs by regulating the GSK-3β/MKP-1/NRF2 pathway via the α2AR in IA.

Vascular leakage plays a vital role in sepsis-induced multi-organ dysfunction. Currently, no specific measures are available for vascular leakage. Ferroptosis, as a recently recognized form of cell death, plays a crucial role in cell dysfunction. It is still unknown whether ferroptosis participates in the occurrence of organ dysfunction following sepsis. Our previous study showed that dexmedetomidine (Dex) could alleviate sepsis-induced organ dysfunction. However, whether the mechanism is related to ferroptosis is not clear.

The publicly available datasets of septic patients were reanalyzed, and septic models in vivo and vitro by cecal ligation and puncture and lipopolysaccharide-stimulated vascular endothelial cells (VECs) were applied. The occurrence of ferroptosis in septic patients and rats was observed, and the protective effects of Dex on ferroptosis, and related mechanisms on regulating metabolic reprogramming and mitochondrial fission were further studied.

The transcriptomics data of patients from the GEO database showed that ferroptosis was closely related to sepsis. Sepsis induced significant ferroptosis in VECs by metabolomics analysis. The level of lipid peroxidation was increased in VECs, and the mitochondrial cristae was decreased after sepsis. Metabolomics analysis showed that Dex activated the pentose phosphate pathway and increased glutathione in VECs via up-regulation of G6PD expression. Dex could antagonize sepsis-induced the decrease in the level of Nrf2. The Nrf2 inhibitor reversed the protective effect of Dex on ferroptosis. Further study showed that Dex significantly alleviated sepsis-induced mitochondrial over-division, improved mitochondrial function, and decreased ROS, further inhibiting the ferroptosis of VECs. Dex alleviated the permeability of vessels by reducing ferroptosis and enhanced the intercellular junction of VECs.

Dex protects vascular leakage following sepsis by inhibiting ferroptosis. The mechanism is mainly related to metabolic reprogramming via Nrf2 up-regulation and inhibition of mitochondrial fission.