Treadmill Exercise Enhances Post-Stroke Functional Recovery in Mice via the CX3CL1/CX3CR1 Signaling Pathway.

To validate that treadmill exercise promotes neurofunctional recovery post ischemic stroke and to specifically explore the role of the CX3CL1/CX3CR1 signaling pathway in this treadmill-mediated recovery process. C57BL/6 J mice were used to establish a middle cerebral artery occlusion (MCAO) model. From days 5 to 28 post-stroke, the experimental group did 10-min treadmill sessions twice daily at 12 r/min; the control group remained inactive. On day 6 post-stroke, mice received three intraperitoneal injections of Bromodeoxyuridine (BrdU) or PBS. On days 1, 3, and 5 post-stroke, mice received intracerebroventricular injections of exogenous recombinant CX3CL1, CX3CL1 antagonist, or PBS. The modified neurological severity score (mNSS) and the corner test were used to assess sensorimotor function, and the morris water maze (MWM) test was employed to evaluate cognitive function. Western blot detected CX3CL1 and CX3CR1 protein expression, while immunofluorescence observed these proteins, neurogenesis in the subventricular zone (SVZ), rostral migratory stream (RMS), and dentate gyrus (DG), along with Iba1 and CD68 co-expression. ELISA quantified IL-1ß, IL-4, and IL-10 levels. Treadmill exercise significantly improved neurofunctional recovery in MCAO mice, enhanced neurogenesis in the RMS and SVZ, and increased the expression of CX3CL1 and CX3CR1. The CX3CL1/CX3CR1 axis enhanced the impact of treadmill exercise on neurofunctional recovery, promoting neurogenesis in the RMS and SVZ, and reducing inflammation. Additionally, this axis also enhanced neurogenesis and suppressed microglial activation in the DG induced by treadmill exercise. This study demonstrates the CX3CL1/CX3CR1 pathway as critical for treadmill-induced post-stroke recovery, indicating its potential target for exercise mimetics in rehabilitation.

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 Effect of Low-Dose Esketamine on Postoperative Neurocognitive Dysfunction in Elderly Patients Undergoing General Anesthesia for Gastrointestinal Tumors: A Randomized Controlled Trial.

Purpose: This study aims to evaluate the effects of the intraoperative application of low-dose esketamine on postoperative neurocognitive dysfunction (PND) in elderly patients undergoing general anesthesia for gastrointestinal tumors. Methods: Sixty-eight elderly patients were randomly allocated to two groups: the esketamine group (group Es) (0.25 mg/kg loading, 0.125mg/kg/h infusion) and the control group (group C) (received normal saline). The primary outcome was the incidence of delayed neurocognitive recovery (DNR). The secondary outcomes were intraoperative blood loss, the total amount of fluid given during surgery, propofol and remifentanil consumption, cardiovascular adverse events, use of vasoactive drugs, operating and anesthesia time, the number of cases of sufentanil remedial analgesia, the incidence of postoperative delirium (POD), the intraoperative hemodynamics, bispectral index (BIS) value at 0, 1, 2 h after operation and numeric rating scale (NRS) pain scores within 3 d after surgery. Results: The incidence of DNR in group Es (16.13%) was lower than in group C (38.71%) (P <0.05). The intraoperative remifentanil dosage and the number of cases of dopamine used in group Es were lower than in group C (P <0.05). Compared with group C, DBP was higher at 3 min after intubation, and MAP was lower at 30 min after extubation in group Es (P<0.05). The incidence of hypotension and tachycardia in group Es was lower than in group C (P <0.05). The NRS pain score at 3 d after surgery in group Es was lower than in group C (P <0.05). Conclusion: Low-dose esketamine infusion reduced to some extent the incidence of DNR in elderly patients undergoing general anesthesia for gastrointestinal tumors, improved intraoperative hemodynamics and BIS value, decreased the incidence of cardiovascular adverse events and the intraoperative consumption of opioids, and relieved postoperative pain.

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/.

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.

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.