Neuroinflammatory Biomarkers in the Brain, Cerebrospinal Fluid, and Blood After Ischemic Stroke.

The most frequent type of stroke, known as ischemic stroke (IS), is a significant global public health issue. The pathological process of IS and post-IS episodes has not yet been fully explored, but neuroinflammation has been identified as one of the key processes. Biomarkers are objective indicators used to assess normal or pathological processes, evaluate responses to treatment, and predict outcomes, and some biomarkers can also be used as therapeutic targets. After IS, various molecules are produced by different cell types, such as microglia, astrocytes, infiltrating leukocytes, endothelial cells, and damaged neurons, that participate in the neuroinflammatory response within the ischemic brain region. These molecules may either promote or inhibit neuroinflammation and may be released into extracellular spaces, including cerebrospinal fluid (CSF) and blood, due to reasons such as BBB damage. These neuroinflammatory molecules should be valued as biomarkers to monitor whether their expression levels in the blood, CSF, and brain correlate with the diagnosis and prognosis of IS patients or whether they have potential as therapeutic targets. In addition, although some molecules do not directly participate in the process of neuroinflammation, they have been reported to have potential diagnostic or therapeutic value against post-IS neuroinflammation, and these molecules will also be listed. In this review, we summarize the neuroinflammatory biomarkers in the brain, CSF, and blood after an IS episode and the potential value of these biomarkers for the diagnosis, treatment, and prognosis of IS patients.

Peripheral Organ Injury After Stroke.

Stroke is a disease with high incidence, mortality and disability rates. It is also the main cause of adult disability in developed countries. Stroke is often caused by small emboli on the inner wall of the blood vessels supplying the brain, which can lead to arterial embolism, and can also be caused by cerebrovascular or thrombotic bleeding. With the exception of recombinant tissue plasminogen activator (rt-PA), which is a thrombolytic drug used to recanalize the occluded artery, most treatments have been demonstrated to be ineffective. Stroke can also induce peripheral organ damage. Most stroke patients have different degrees of injury to one or more organs, including the lung, heart, kidney, spleen, gastrointestinal tract and so on. In the acute phase of stroke, severe inflammation occurs in the brain, but there is strong immunosuppression in the peripheral organs, which greatly increases the risk of peripheral organ infection and aggravates organ damage. Nonneurological complications of stroke can affect treatment and prognosis, may cause serious short-term and long-term consequences and are associated with prolonged hospitalization and increased mortality. Many of these complications are preventable, and their adverse effects can be effectively mitigated by early detection and appropriate treatment with various medical measures. This article reviews the pathophysiological mechanism, clinical manifestations and treatment of peripheral organ injury after stroke.

NLRP3 Knockout Protects against Lung Injury Induced by Cerebral Ischemia-Reperfusion.

Methods: C57/BL6 wild-type (WT) and NLRP3-KO mice were used to construct middle cerebral artery occlusion (MCAO) models. 2,3,5-Triphenyltetrazolium chloride (TTC) was used to evaluate brain damage, and neurological deficits were assessed. Then, lung tissue injury was examined in the different groups of mice by hematoxylin-eosin (HE) staining. Inflammation (macrophage and neutrophil infiltration, NLRP3-associated inflammatory molecules) and oxidative stress (reactive oxygen species, ROS) in the lungs were comprehensively examined by immunofluorescence staining and Western blotting. Results: First, our findings demonstrated that NLRP3 knockout had a protective effect against cerebral ischemia-reperfusion injury after MCAO. Second, by reducing brain damage after MCAO, lung inflammation was also alleviated. Immunofluorescence staining showed that NLRP3-KO-MCAO mice had reduced inflammatory effector molecule (caspase-1 and IL-1ß) expression and macrophage and neutrophil infiltration in the lung, as well as remissive oxidative stress state in the lung, compared with WT-MCAO mice. We also observed a decrease in phosphorylated p65 (p-p65) (an NF-κB factor) in NLRP3-KO-MCAO mice, suggesting that the NF-κB pathway was involved in the protective effect of NLRP3 gene knockout on stroke-induced lung injury. Conclusions: NLRP3 inflammasome knockout not only is beneficial for cerebral ischemia-reperfusion injury but also reduces the severity of poststroke lung injury by reducing brain damage. It has been confirmed that there is a relationship between central insult and peripheral organ injury, and protecting the brain can prevent peripheral organ damage.

Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke.

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a member of the NLR family of inherent immune cell sensors. The NLRP3 inflammasome can detect tissue damage and pathogen invasion through innate immune cell sensor components commonly known as pattern recognition receptors (PRRs). PRRs promote activation of nuclear factor kappa B (NF-κB) pathways and the mitogen-activated protein kinase (MAPK) pathway, thus increasing the transcription of genes encoding proteins related to the NLRP3 inflammasome. The NLRP3 inflammasome is a complex with multiple components, including an NAIP, CIITA, HET-E, and TP1 (NACHT) domain; apoptosis-associated speck-like protein containing a CARD (ASC); and a leucine-rich repeat (LRR) domain. After ischemic stroke, the NLRP3 inflammasome can produce numerous proinflammatory cytokines, mediating nerve cell dysfunction and brain edema and ultimately leading to nerve cell death once activated. Ischemic stroke is a disease with high rates of mortality and disability worldwide and is being observed in increasingly younger populations. To date, there are no clearly effective therapeutic strategies for the clinical treatment of ischemic stroke. Understanding the NLRP3 inflammasome may provide novel ideas and approaches because targeting of upstream and downstream molecules in the NLRP3 pathway shows promise for ischemic stroke therapy. In this manuscript, we summarize the existing evidence regarding the composition and activation of the NLRP3 inflammasome, the molecules involved in inflammatory pathways, and corresponding drugs or molecules that exert effects after cerebral ischemia. This evidence may provide possible targets or new strategies for ischemic stroke therapy.

Downregulation of CYP39A1 Serves as a Novel Biomarker in Hepatocellular Carcinoma with Worse Clinical Outcome.

BACKGROUND: CYP39A1 is a poorly characterized metabolic enzyme that has been investigated in a few tumors. However, the role of CYP39A1 in hepatocellular carcinoma (HCC) has not yet been clarified. In this study, the expression and clinical significance of CYP39A1 in HCC were explored. METHODS: CYP39A1 protein expression was detected in Akt/c-Met-induced HCC mice and 14 paired fresh HCC samples as well as another 159 HCC and matched noncancerous tissues. Meanwhile, the mRNA expression was analyzed by GEO and TCGA analysis and validated in 14 paired fresh HCC tissues. Furthermore, the relationships between CYP39A1 expression and clinicopathologic features as well as prognosis were analyzed. HCC cell growth changes were analyzed by cell viability assays after CYP39A1 overexpression and then validated after CYP39A1 knockout by DepMap database analysis. RESULTS: CYP39A1 protein expression was lower expressed in HCC mouse models, and its mRNA and protein expression were also downregulated in HCC compared with noncancerous liver tissues. Higher CYP39A1 expression was associated with well differentiation. Moreover, survival analysis indicated that lower CYP39A1 expression was associated with poorer overall survival. In addition, HepG2 and SMMC-7721 cell viability were inhibited after CYP39A1 overexpression. Genome-wide CRISPR/Cas9 proliferation screening indicated that knockout of CYP39A1 could promote HCC cell growth. Likewise, p-NF-κB and Nrf2 were suppressed after CYP39A1 overexpression. It is worth mentioning that total bile acid, total bilirubin, and direct bilirubin were significantly increased in the patients with low CYP39A1 expression. CONCLUSIONS: Downregulation of CYP39A1 is associated with HCC carcinogenesis, tumor differentiation, and poor overall survival, suggesting that CYP39A1 may serve as a tumor suppressor gene and novel biomarker for HCC patients.