Absence in CX3CR1 receptor signaling promotes post-ischemic stroke cognitive function recovery through suppressed microglial pyroptosis in mice.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a major source of morbidity and mortality after stroke, but the pathological mechanisms remain unclear. Previous studies have demonstrated that the CX3CR1 receptor plays a crucial role in maintaining an early protective microenvironment after stroke, but whether it persistently influences cognitive dysfunction in the chronic phase requires further investigation. METHODS: Mouse was used to establish a middle cerebral artery occlusion (MCAO)/reperfusion model to study PSCI. Cognitive function was assessed by the Morris water maze (MWM) and the novel object recognition test. Neurogenesis was assessed by immunofluorescence staining with Nestin+ /Ki67+ and DCX+ /BrdU+ double-positive cells. The cerebral damage was monitored by [18 F]-DPA-714 positron emission tomography, Nissel, and TTC staining. The pyroptosis was histologically, biochemically, and electron microscopically examined. RESULTS: Upon MCAO, at 28 to 35 days, CX3CR1 knockout (CX3CR1-/- ) mice had better cognitive behavioral performance both in MWM and novel object recognition test than their CX3CR1+/- counterparts. Upon MCAO, at 7 days, CX3CR1-/- mice increased the numbers of Nestin+ /Ki67+ and DCX+ /BrdU+ cells, and meanwhile it decreased the protein expression of GSDMD, NLRP3 inflammasome subunit, caspase-1, mature IL-1ß/IL-18, and p-P65 in the hippocampus as compared with CX3CR1+/- mice. In addition, CX3CR1-/- mice could reverse infarct volume in the hippocampus region post-stroke. CONCLUSION: Our study demonstrated that CX3CR1 gene deletion was beneficial to PSCI recovery. The mechanism might lie in inhibited pyroptosis and enhanced neurogenesis. CX3CR1 receptor may serve as a therapeutic target for improving the PSCI.

Strong opioids-induced cardiac, neurologic, and respiratory disorders: a real-world study from 2004 to 2023 based on FAERS.

Opioids are mainly used as adjuncts to the induction and maintenance of general anesthesia, postoperative analgesia, and treating moderate to severe cancer pain and chronic pain. However, the hazards of these drugs to various organ organs still need to be further explored. This study used the US FDA Adverse Event Reporting System (FAERS) database to determine whether commonly receiving opioids was higher than the baseline risk for all other medications. FAERS was asked about adverse events (AEs) for the opioids "morphine," "fentanyl," "oxycodone," "hydromorphone," "sufentanil," and "remifentanil" from the first quarter of 2004 (2004Q1) through the second quarter of 2023 (2023Q2). Disproportionality signaling analysis was performed by calculating reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). AEs with system organ classes (SOCs) of "cardiac disease," "neurologic disease," and "respiratory, thoracic, and mediastinal disease" were then screened. The statistical analysis included 12,819,518 reports in the FAERS database from 2004Q1 to 2023Q2, of which 236,619 AEs were reported as "primary suspect" for the six drugs mentioned above, which were selected as "cardiac disorders," "nervous system disorders," and "respiratory, thoracic and mediastinal disorders." Some AEs identified in this study are consistent with the drug labeling, such as bradycardia, respiratory depression, and somnolence. In addition, some unexpected and significant acute adverse drug reactions (ADRs), such as toxic leukoencephalopathy and coma, may occur. This study identified potential new and unexpected ADRs for opioids, providing valuable evidence for safety studies of opioids.

Spatial and temporal mapping of neuron-microglia interaction modes in acute ischemic stroke.

Ischemic stroke (IS) is a major cause of morbidity and mortality worldwide, accounting for 75-80% of all strokes. Under conditions of ischemia and hypoxia, neurons suffer damage or death, leading to a series of secondary immune reactions. Microglia, the earliest activated immune cells, can exert neurotoxic or neuroprotective effects on neurons through secretion of factors. There exists a complex interaction between neurons and microglia during this process. Moreover, the interaction between them becomes even more complex due to differences in the infarct area and reperfusion time. This review first elaborates on the differences in neuronal death modes between the ischemic core and penumbra, and then introduces the differences in microglial markers across different infarct areas with varying reperfusion time, indicating distinct functions. Finally, we focus on exploring the interaction modes between neurons and microglia in order to precisely target beneficial interactions and inhibit harmful ones, thus providing new therapeutic strategies for the treatment of IS.

The potential role of T-cell metabolism-related molecules in chronic neuropathic pain after nerve injury: a narrative review.

Neuropathic pain is a common type of chronic pain, primarily caused by peripheral nerve injury. Different T-cell subtypes play various roles in neuropathic pain caused by peripheral nerve damage. Peripheral nerve damage can lead to co-infiltration of neurons and other inflammatory cells, thereby altering the cellular microenvironment and affecting cellular metabolism. By elaborating on the above, we first relate chronic pain to T-cell energy metabolism. Then we summarize the molecules that have affected T-cell energy metabolism in the past five years and divide them into two categories. The first category could play a role in neuropathic pain, and we explain their roles in T-cell function and chronic pain, respectively. The second category has not yet been involved in neuropathic pain, and we focus on how they affect T-cell function by influencing T-cell metabolism. By discussing the above content, this review provides a reference for studying the direct relationship between chronic pain and T-cell metabolism and searching for potential therapeutic targets for the treatment of chronic pain on the level of T-cell energy metabolism.

LDHA as a regulator of T cell fate and its mechanisms in disease.

T cells are the main force of anti-infection and antitumor and are also involved in autoimmune diseases. During the development of these diseases, T cells need to rapidly produce large amounts of energy to satisfy their activation, proliferation, and differentiation. In this review, we introduced lactate dehydrogenase A(LDHA), predominantly involved in glycolysis, which provides energy for T cells and plays a dual role in disease by mediating lactate production, non-classical enzyme activity, and oxidative stress. Mechanistically, the signaling molecule can interact with the LDHA promoter or regulate LDHA activity through post-translational modifications. These latest findings suggest that modulation of LDHA may have considerable therapeutic effects in diseases where T-cell activation is an important pathogenesis.

Immunoregulatory mechanism of acute kidney injury in sepsis: A Narrative Review.

Sepsis acute kidney injury (SAKI) is a common complication of sepsis, accounting for 26-50 % of all acute kidney injury (AKI). AKI is an independent risk factor for increased mortality risk in patients with sepsis. The excessive inflammatory cascade reaction in SAKI is one of the main causes of kidney damage. Both the innate immune system and the adaptive immune system are involved in the inflammation process of SAKI. Under the action of endotoxin, neutrophils, monocytes, macrophages, T cells and other complex immune network reactions occur, and a large number of endogenous inflammatory mediators are released, resulting in the amplification and loss of control of the inflammatory response. The study of immune cells in SAKI will help improve the understanding of the immune mechanisms of SAKI, and will lay a foundation for the development of new diagnostic and therapeutic targets. This article reviews the role of known immune mechanisms in the occurrence and development of SAKI, with a view to finding new targets for SAKI treatment.

Efficacy and safety evaluation of dexmedetomidine for postoperative patient controlled intravenous analgesia: A systematic review and meta-analysis.

Objective: To investigate the efficacy and safety of dexmedetomidine (DEX) for postoperative patient controlled intravenous analgesia (PCIA). Measurements: Two investigators independently searched Pubmed, Embase, Scopus, Cochrane Library and CBM for randomized controlled trials of DEX for PCIA. Main results: Thirty-seven studies with a total of 5,409 patients were included in this meta-analysis. Compared with analgesics alone, DEX for PCIA reduced pain score at 24 h [mean difference (MD) = -0.70; 95% confidence interval (CI): -0.85, -0.54; p < 0.00001, I 2 = 90%] and 48 h postoperatively (MD = -0.43; 95% CI: -0.52, -0.34; p < 0.00001, I 2 = 96%). Moreover, DEX reduced analgesics consumption during the first 24 h [standardized mean difference (SMD) = -0.25; 95% CI: -0.34, -0.16; p < 0.00001, I 2 = 91%] and the number of resuscitation analgesics administered [odds ratio (OR) = 0.54; 95% CI: 0.44, 0.66; p < 0.00001, I 2 = 72%]. Furthermore, DEX improved patient satisfaction (OR = 3.55; 95% CI: 2.36, 5.35; p < 0.00001, I 2 = 60%), and reduced incidence of side effects, such as postoperative nausea and vomiting (PONV) (OR = 0.47; 95% CI: 0.39, 0.57; p < 0.00001, I 2 = 59%) and pruritus after surgery (OR = 0.45; 95% CI: 0.30, 0.68; p = 0.0001, I 2 = 0%). Besides, DEX attenuates inflammatory cytokine levels, such as IL-6 (MD = -5.73; 95% CI: -8.34, -3.12; p < 0.00001, I 2 = 91%) and TNF-α (MD = -0.63; 95% CI: -0.76, -0.50; p < 0.00001, I 2 = 89%). Finally, DEX increased the risk of bradycardia (OR = 1.66; 95% CI: 1.12, 2.45; p = 0.01, I 2 = 15%), but the complication of hypotension did not differ between the two groups (OR = 1.30; 95% CI: 0.84, 2.04; p = 0.25, I 2 = 0%). Conclusion: DEX is used for postoperative PCIA analgesia, which can significantly improve the analgesic effect, effectively control postoperative inflammatory response, reduce the dosage and adverse reactions of analgesics, and improve postoperative patient satisfaction. Of course, the impact of the immunosuppressive effect of DEX on the prognosis of patients needs further study. Systematic review registration: CRD42022340933, https://www.crd.york.ac.uk/prospero/.

EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway.

Stroke remains one of the leading reasons of mortality and physical disability worldwide. The treatment of cerebral ischemic stroke faces challenges, partly due to a lack of effective treatments. In this study, we demonstrated that autophagy was stimulated by transient middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R). Treatment with (-)-epigallocatechin-3-gallate (EGCG), a bioactive ingredient in green tea, was able to mitigate cerebral ischemia/reperfusion injury (CIRI), given the evidence that EGCG administration could reduce the infarct volume and protect poststroke neuronal loss in MCAO/R mice in vivo and attenuate cell loss in OGD/R-challenged HT22 cells in vitro through suppressing autophagy activity. Mechanistically, EGCG inhibited autophagy via modulating the AKT/AMPK/mTOR phosphorylation pathway both in vivo and in vitro models of stroke, which was further confirmed by the results that the administration of GSK690693, an AKT/AMPK inhibitor, and rapamycin, an inhibitor of mTOR, reversed aforementioned changes in autophagy and AKT/AMPK/mTOR signaling pathway. Overall, the application of EGCG relieved CIRI by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway.

Effects of Dexmedetomidine on Immune Cells: A Narrative Review.

As we all know, dexmedetomidine (DEX), as a highly selective α2 adrenergic receptor agonist, exerts sedative, anti-anxiety and hypnotic effects by inhibiting the discharge of norepinephrine neurons in locus coeruleus and GABA-related hypnotic pathways. However, the role of DEX in anti-inflammatory and immune regulation has gradually attracted the attention of researchers in recent years. The α2 adrenergic receptor is one of the members of the adrenergic receptor family, which is widely present in a variety of immune cells and mediates the biological behavior of the inflammatory immune system. At present, there have been more and more studies on the effects of DEX on immune cells and inflammatory responses, but few studies have systematically explored the anti-inflammatory and immunomodulatory effects of DEX. Here, we comprehensively review the published human and animal studies related to DEX, summarize the effects of DEX on immune cells and its role in related diseases, and propose potential research direction.

γδ T Cell in Cerebral Ischemic Stroke: Characteristic, Immunity-Inflammatory Role, and Therapy.

Gamma-delta (γδ) T cells are a small subset of T cells that are reported to have a proinflammatory role in the pathophysiology of cerebral ischemia stroke (CIS). Upon activation by interleukin-1 beta (IL-1ß), IL-23 and IL-18, γδ T cells are stimulated to secrete various cytokines, such as IL-17a, IL-21, IL-22, and interferon-gamma (IFN-γ). In addition, they all play a pivotal role in the inflammatory and immune responses in ischemia. Nevertheless, the exact mechanisms responsible for γδ T cell proinflammatory functions remain poorly understood, and more effective therapies targeting at γδ T cells and cytokines they release remain to be explored, particularly in the context of CIS. CIS is the second most common cause of death and the major cause of permanent disability in adults worldwide. In this review, we focus on the neuroinflammatory and immune functions of γδ T cells and related cytokines, intending to understand their roles in CIS, which may be crucial for the development of novel effective clinical applications.

CX3CL1 inhibits NLRP3 inflammasome-induced microglial pyroptosis and improves neuronal function in mice with experimentally-induced ischemic stroke.

AIMS: Stroke represents the second cause of mortality across the globe and develops following the interruption of cerebral blood circulation. The chemokine CX3CL1 and its receptor CX3CR1 play a fundamental role in the pathophysiology of ischemic stroke. In this study, we investigated the protective effect of CX3CL1 against cerebral ischemia both in vitro and in vivo. MAIN METHODS: We employed an in vivo mice model of middle cerebral artery occlusion(MCAO)/reperfusion and in vitro BV2 cells model of oxygen-glucose deprivation/re­oxygenation (OGD/R). Exogenous recombinant CX3CL1 (rCX3CL1) was administered into the lateral ventricle 1, 3 and 5 day(s) after reperfusion or in cell supernatant following OGD/R. Immunostaining, immunoblotting, and ELISA were performed to assess the NLRP3 inflammasome-induced pyroptosis both in vivo and in vitro. In addition, neurological deficits and infarct volume in mice were evaluated after MCAO. KEY FINDINGS: The expression of CX3CL1 was downregulated after MCAO. Exogenous rCX3CL1 significantly reduced neurological deficits and infarct lesion in mice after MCAO. Moreover, exogenous rCX3CL1 inhibited GSDMD-dependent pyroptosis in microglia. Those effects further diminished NLRP3 inflammasome and NF-κB signaling activation, and also inhibited IL-1ß and IL-18 expression both in vitro and in vivo. SIGNIFICANCE: These results demonstrated that exogenous rCX3CL1 administration after the ischemic insult exerted a long-term neuroprotective effect on post-ischemic stroke. And exogenous rCX3CL1 could inhibit NLRP3 inflammasome-induced microglial pyroptosis under ischemic conditions. Collectively, our findings showed that CX3CL1 signaling pathway can serve as a therapeutic target for promoting the functional recovery after stroke.

Evaluation of the Efficacy of Dexmedetomidine as a Local Anesthetic Adjuvant in Children: A Meta-Analysis of Randomized Controlled Trials.

Dexmedetomidine has been identified as a useful adjunct to improve the effect of nerve blocks in adults; however, its effect for children has not yet been fully investigated. This meta-analysis aimed to evaluate the reliability and efficacy of dexmedetomidine as a local anesthetic adjunct for pediatric surgeries. Eligible studies were searched in Cochrane, Embase, PubMed, and CBM. RevMan 5.4 was used to assess the risk of bias of each study and perform statistical analysis. Stata 15.0 was used to evaluate the publication bias of primary outcomes. Thirteen randomized controlled trial (RCTs) involving 722 patients aged 6 months to 12 years were harvested. Statistical analysis showed that dexmedetomidine resulted in: a significantly longer duration of analgesia (standardized mean difference [SMD], 7.16; 95% confidence interval [95%CI], 4.88 to 9.43; P < .001; I2  = 98%); a reduction in the 1-hour pain score (mean difference [MD], -0.27; 95%CI, -0.47 to -0.06; P = .01; I2  = 28%); cumulative doses of rescue analgesic required of 2 doses (risk ratio [RR], 0.26; 95%CI, 0.14 to 0.49; P < .001; I2  = 0) or 3 doses (RR, 0.04; 95%CI, 0.01 to 0.16; P < .001; I2  = 4%); the frequency of emergence agitation (RR, 0.44; 95%CI, 0.22 to 0.91; P = .03; I2  = 0); and a reduction in the onset time of blocks (mean difference -3.56; 95%CI, -6.39 to -0.74; P = .01; I2  = 90%). However, the incidence of some side effects, including hypotension, bradycardia, nausea and vomiting, pruritis, urinary retention, and respiratory depression, did not significantly differ between the dexmedetomidine group and the placebo group. Therefore, dexmedetomidine is a reliable and efficient adjunct to local anesthetics in children.