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Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) is an enzyme complex with the sole function of producing superoxide anion and reactive oxygen species (ROS) at the expense of NADPH. Vital to the immune system as well as cellular signaling, NOX is also involved in the pathologies of a wide variety of disease states. Particularly, it is an integral player in many neurological diseases, including stroke, TBI, and neurodegenerative diseases. Pathologically, NOX produces an excessive amount of ROS that exceed the body's antioxidant ability to neutralize them, leading to oxidative stress and aberrant signaling. This prevalence makes it an attractive therapeutic target and as such, NOX inhibitors have been studied and developed to counter NOX's deleterious effects. However, recent studies of NOX have created a better understanding of the NOX complex. Comprised of independent cytosolic subunits, p47- , p67- , p40- and , and membrane subunits, gp91- and p22- , the NOX complex requires a unique activation process through subunit interaction. Of these subunits, p47- plays the most important role in activation, binding and translocating the cytosolic subunits to the membrane and anchoring to p22- to organize the complex for NOX activation and function. Moreover, these interactions, particularly that between p47- and p22- , are dependent on phosphorylation initiated by upstream processes involving protein kinase C (PKC). This review will look at these interactions between subunits and with PKC. It will focus on the interaction involving p47- with p22- , key in bringing the cytosolic subunits to the membrane. Furthermore, the implication of these interactions as a target for NOX inhibitors such as apocynin will be discussed as a potential avenue for further investigation, in order to develop more specific NOX inhibitors based on the inhibition of NOX assembly and activation.

Acute ischemic stroke (AIS) remains to be a challenging cerebrovascular disease. The mainstay of AIS management is endovascular reperfusion therapy, including thrombectomy and thrombolysis. However, ineffective (futile) reperfusion (FR) or reperfusion injury (RI) can be seen in a significant number of patients undergoing reperfusion strategy. In this article, we discuss two clinically relevant concepts known as \"time window\" and \"tissue window\" that can impact the clinical outcome of reperfusion therapy. We also explore patient risk factors, leading to FR and RI as well as an emerging concept of \"no-reflow phenomenon\" seen in ineffective reperfusion. These fundamental concepts provide insight into the clinical management of AIS patients and provide references for future research.

A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroinflammatory response and inflammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague–Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. Inflammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38. The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P significantly reduced cell death and attenuated the neuroinflammatory response as determined by reduced CD68 and MPO. C + P decreased ischemia-induced inflammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the co-localization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroinflammation and NLRP3 inflammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for efficacious therapy following ischemic stroke.

Gallstone disease is a common pathology of the digestive system with nearly a 10–20% incidence rate among adults. The mainstay of treatment is cholecystectomy, which is commonly associated with physical pain and may also seriously affect a patient’s quality of life. Clinical research suggests that cholelithiasis is closely related to the age, gender, body mass index, and other basic physical characteristics of patients. Clinical research further suggests that the occurrence of cholelithiasis is related to obesity, diabetes, non-alcoholic fatty liver, and other diseases. For this reason, we reviewed the following: genetic factors; excessive liver cholesterol secretion (causing cholesterol supersaturation in gallbladder bile); accelerated growth of cholesterol crystals and solid cholesterol crystals; gallbladder motility impairment; and cardiovascular factors. Herein, we summarize and analyze the causes and mechanisms of cholelithiasis, discuss its correlation with the pathogenesis of related diseases, and discuss possible mechanisms.

Ischemic stroke destroys blood–brain barrier (BBB) integrity. There are currently no effective treatments available in the clinical setting. Post-ischemia treatment with phenothiazine drugs [combined chlorpromazine and promethazine (C+P)] has been shown to be neuroprotective in stroke. The present study determined the effect of C+P in BBB integrity. Sprague-Dawley rats were divided into the following groups (n=8 each): (1) stroke, (2) stroke treated by C+P with temperature control, and (3) stroke treated by C+P without temperature control. Infarct volume and neurological deficits were measured to assess the neuroprotective effect of C+P. BBB permeability was determined by brain edema and Evans blue leakage. Expression of BBB integral molecules, including proteins of aquaporin-4 and -9 (AQP-4, AQP-9), matrix metalloproteinase-2 and -9 (MMP-2, MMP-9), zonula occludens-1 (ZO-1), claudin-1/5, occludin, and laminin were determined by Western blot. Stroke caused brain infarction and neurological deficits, as well as BBB damage, which were all attenuated by C+P through drug-induced hypothermia. When the reduced temperature was controlled to physiological levels, C+P still conferred neuroprotection, suggesting a therapeutic effect independent of hypothermia. Furthermore, C+P significantly attenuated the increase in AQP-4, AQP-9, MMP-2, and MMP-9 levels after stroke, and reversed the decrease in tight junction protein (ZO-1, claudin-1/5, occludin) and basal laminar protein (laminin) levels. This study clearly indicates a beneficial effect of C+P on BBB integrity after stroke, which may be independent of drug-induced hypothermia. These findings further prove the clinical target and cell-signal communication of C+P treatment, which may direct us closer toward the development of an efficacious neuroprotective therapy.

Peritoneal dialysis (PD) is a well-established renal replacement therapy commonly employed in clinical practice. While its primary application is in the treatment of kidney disease, its potential in addressing other systemic disorders, including neurological diseases, has garnered increasing interest. This study provides a comprehensive overview of the related technologies, unique advantages, and clinical applications of PD in the context of neurological disorders. By exploring the mechanism underlying PD, its application in neurological diseases, and associated complications, we addressed the feasibility and benefits of PD as an adjunct therapy for various neurological conditions. Our study aims to highlight its role in detoxification and symptom management, as well as its advantages over other universally accepted methods of renal replacement therapy. Our goal is to bring to the spotlight the therapeutic potential of PD in neurological diseases, such as stroke, stimulate further research, and broaden the scope of its application in the clinical setting.

Adjuvant neuroprotective therapies for acute ischemic stroke (AIS) have demonstrated benefit in animal studies, albeit without human translation. We investigated the safety and efficacy of high-flow normobaric oxygen (NBO) after endovascular recanalization in anterior circulation stroke. This is a prospective randomized controlled study. Eligible patients were randomized to receive high-flow NBO by a Venturi mask (FiO2 50%, flow 15 L/min) or routine low-flow oxygen supplementation by nasal cannula (flow 3 L/min) after vessel recanalization for 6 h. Patient demographics, procedural metrics, complications, functional outcomes, symptomatic intracranial hemorrhage (sICH), and infarct volume were assessed. A total of 91 patients were treated with high-flow NBO. NBO treatment revealed a common odds ratio of 2.2 (95% CI, 1.26 to 3.87) favoring the distribution of global disability scores on the mRS at 90 days. The mortality at 90 days was significantly lower in the NBO group than in the control group, with an absolute difference of 13.86% (rate ratio, 0.35; 95% CI, 0.13–0.93). A significant reduction of infarct volume as determined by MRI was noted in the NBO group. The median infarct volume was 9.4 ml versus 20.5 ml in the control group (beta coefficient, − 20.24; 95% CI, − 35.93 to − 4.55). No significant differences were seen in the rate of sICH, pneumonia, urinary infection, and seizures between the 2 groups. This study suggests that high-flow NBO therapy after endovascular recanalization is safe and effective in improving functional outcomes, decreasing mortality, and reducing infarct volumes in anterior circulation stroke patients within 6 h from stroke onset.

Key Points Remote ischaemic conditioning remotely triggers self-protective pathways in the brain and can be easily administered by repetitive inflation and deflation of a blood pressure cuff on the limb The exact mechanisms of signal transmission and remote organ protection are unknown, but both circulating mediators and neural mechanisms have central roles Results of a trial of RIC in acute ischaemic stroke suggest that it is of benefit when administered during ischaemia Acute RIC should be tested during the transfer of patients to comprehensive stroke centres, for use with mechanical thrombectomy, and in patients who have had a cardiac arrest Two small clinical trials showed that chronic daily RIC at home for >6 months reduced the risk of stroke and transient ischaemic attacks in patients with symptomatic intracranial atherosclerosis Chronic daily RIC is a promising therapy for chronic neurological conditions, such as white matter disease and vascular cognitive impairment Harnessing self-protective pathways in the brain could protect against neurological disease, but pharmacological attempts at such an approach have failed. In this Review, Hess et al . consider the neurological potential of remote ischaemic conditioning (RIC), a procedure in which brief ischaemia induced by vascular occlusion in the limb activates self-protective pathways and protects distant organs against longer episodes of ischaemia. Clinical trials in cardiological settings have been successful, and trials in neurological conditions suggest that RIC is a feasible option for patients with ischaemic neurological conditions. Remote ischaemic conditioning (RIC) triggers endogenous protective pathways in distant organs such as the kidney, heart and brain, and represents an exciting new paradigm in neuroprotection. RIC involves repetitive inflation and deflation of a blood pressure cuff on the limb, and is safe and feasible. The exact mechanism of signal transmission from the periphery to the brain is not known, but both humoral factors and an intact nervous system seem to have critical roles. Early-phase clinical trials have already been conducted to test RIC in the prehospital setting in acute ischaemic stroke, and in subarachnoid haemorrhage for the prevention of delayed cerebral ischaemia. Furthermore, two small randomized clinical trials in patients with symptomatic intracranial atherosclerosis have shown that RIC can reduce recurrence of stroke and have neuroprotective activity. RIC represents a highly practical and translatable therapy for acute, subacute, and chronic neurological diseases with an ischaemic or inflammatory basis. In this Review, we consider the principles and mechanisms of RIC, evidence from preclinical models and clinical trials that RIC is beneficial in neurological disease, and how the procedure might be used in the future in disorders such as vascular cognitive impairment and traumatic brain injury.

Although physical exercise has been demonstrated to augment recovery of the post-stroke brain, the question of what level of exercise intensity optimizes neurological outcomes of post-stroke rehabilitation remains unsettled. In this study, we aim to clarify the mechanisms underlying the intensity-dependent effect of exercise on neurologic function, and thereby to help direct the clinical application of exercise-based neurorehabilitation. To do this, we used a well-established rat model of ischemic stroke consisting of cerebral ischemia induction through middle cerebral artery occlusion. Ischemic rats were subsequently assigned either to a control group entailing post-stroke rest, or to one of two exercise groups distinguished by the intensity of their accompanying treadmill regimens. After 24 h of reperfusion, exercise was initiated. Infarct volume, apoptotic cell death, and neurological defects were quantified in all groups at 3 days, and motor and cognitive function were tracked up to day 28. Additionally, Western blotting was used to assess the influence of our interventions on several proteins related to synaptogenesis and neuroplasticity (growth-associated protein 43, microtubule-associated protein, postsynaptic density-95, synapsin I, hypoxia inducible factor-1α, brain-derived neurotrophic factor, nerve growth factor, tyrosine kinase B, and cAMP response element binding protein). Our results were in equal parts encouraging and surprising. Both mild and intense exercise significantly decreased infarct volume, cell death, and neurological deficits. Motor and cognitive function, as determined using an array of tests such as beam balance, forelimb placing, and the Morris water maze, were also significantly improved by both exercise protocols. Interestingly, while an obvious enhancement of neuroplasticity proteins was shown in both exercise groups, mild exercise rats demonstrated a stronger effect on the expressions of Tau (p<0.01), brain-derived neurotrophic factor (p<0.01), and tyrosine kinase B (p<0.05). These findings contribute to the growing body of literature regarding the positive effects of both mild and intense long-term treadmill exercise on brain injury, functional outcome, and neuroplasticity. Additionally, the results may provide a base for our future study regarding the regulation of HIF-1α on the BDNF/TrkB/CREB pathway in the biochemical processes underlying post-stroke synaptic plasticity.