Search

Glioma, the most prevalent primary brain tumor in adults, is characterized by significant invasiveness and resistance. Current glioma treatments include surgery, radiation, chemotherapy, and targeted therapy, but these methods often fail to eliminate the tumor completely, leading to recurrence and poor prognosis. Immune checkpoint inhibitors, a class of commonly used immunotherapeutic drugs, have demonstrated excellent efficacy in treating various solid malignancies. Recent research has indicated that unconventional levels of expression of the MAP2K3 gene closely correlates with glioma malignancy, hinting it could be a potential immunotherapy target. Our study unveiled substantial involvement of MAP2K3 in gliomas, indicating the potential of the enzyme to serve as a prognostic biomarker related to immunity. Through the regulation of the infiltration of immune cells, MAP2K3 can affect the prognosis of patients with glioma. These discoveries establish a theoretical foundation for exploring the biological mechanisms underlying MAP2K3 and its potential applications in glioma treatment.

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy.

BackgroundMatrix metalloproteinases (MMPs) are important players in the complex pathophysiology of ischemic stroke (IS). Recent studies have shown that tremendous progress has been made in the research of MMPs in IS. However, a comprehensive bibliometric analysis is lacking in this research field. This study aimed to introduce the research status as well as hotspots and explore the field of MMPs in IS from a bibliometric perspective.MethodsThis study collected 1,441 records related to MMPs in IS from 1979 to 2022 in the web of science core collection (WoSCC) database, among them the first paper was published in 1992. CiteSpace, VOSviewer, and R package “bibliometrix” software were used to analyze the publication type, author, institution, country, keywords, and other relevant data in detail, and made descriptive statistics to provide new ideas for future clinical and scientific research.ResultsThe change in the number of publications related to MMPs in IS can be divided into three stages: the first stage was from 1992 to 2012, when the number of publications increased steadily; the second stage was from 2013 to 2017, when the number of publications was relatively stable; the third stage was from 2018 to 2022, when the number of publications began to decline. The United States and China, contributing more than 64% of publications, were the main drivers for research in this field. Universities in the United States were the most active institutions and contributed the most publications. STROKE is the most popular journal in this field with the largest publications as well as the most co-cited journal. Rosenberg GA was the most prolific writer and has the most citations. “Clinical,” “Medical,” “Neurology,” “Immunology” and “Biochemistry molecular biology” were the main research areas of MMPs in IS. “Molecular regulation,” “Metalloproteinase-9 concentration,” “Clinical translation” and “Cerebral ischemia–reperfusion” are the primary keywords clusters in this field.ConclusionThis is the first bibliometric study that comprehensively mapped out the knowledge structure and development trends in the research field of MMPs in IS in recent 30 years, which will provide a reference for scholars studying this field.

The past decade has witnessed unprecedented medical progress, which has translated into cardiac surgery being increasingly common and safe. However, complications such as postoperative delirium remain a major concern. Although the pathophysiological changes of delirium after cardiac surgery remain poorly understood, it is widely thought that inflammation and oxidative stress may be potential triggers of delirium. The development of delirium following cardiac surgery is associated with perioperative risk factors. Multiple interventions are being explored to prevent and treat delirium. Therefore, research on the potential role of biomarkers in delirium as well as identification of perioperative risk factors and pharmacological interventions are necessary to mitigate the development of delirium.

Glioma is the most common primary brain tumor in the human brain. The present study was designed to explore the expression of PIMREG in glioma and its relevance to the clinicopathological features and prognosis of glioma patients. The correlations of PIMREG with the infiltrating levels of immune cells and its relevance to the response to immunotherapy were also investigated. PIMREG expression in glioma was analyzed based on the GEO, TCGA, and HPA databases. Kaplan–Meier survival analysis was used to examine the predictive value of PIMREG for the prognosis of patients with glioma. The correlation between the infiltrating levels of immune cells in glioma and PIMREG was analyzed using the CIBERSORT algorithm and TIMRE database. The correlation between PIMREG and immune checkpoints and its correlation with the patients’ responses to immunotherapy were analyzed using R software and the GEPIA dataset. Cell experiments were conducted to verify the action of PIMREG in glioma cell migration and invasion. We found that PIMREG expression was upregulated in gliomas and positively associated with WHO grade. High PIMREG expression was correlated with poor prognosis of LGG, prognosis of all WHO grade gliomas, and prognosis of recurrent gliomas. PIMREG was related to the infiltration of several immune cell types, such as M1 and M2 macrophages, monocytes and CD8+ T cells. Moreover, PIMREG was correlated with immune checkpoints in glioma and correlated with patients’ responses to immunotherapy. KEGG pathway enrichment and GO functional analysis illustrated that PIMREG was related to multiple tumor- and immune-related pathways. In conclusion, PIMREG overexpression in gliomas is associated with poor prognosis of patients with glioma and is related to immune cell infiltrates and the responses to immunotherapy.

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.

Ischemic stroke is an acute cerebrovascular disease characterized by sudden interruption of blood flow in a certain part of the brain, leading to serious disability and death. At present, treatment methods for ischemic stroke are limited to thrombolysis or thrombus removal, but the treatment window is very narrow. However, recovery of cerebral blood circulation further causes cerebral ischemia/reperfusion injury (CIRI). The endoplasmic reticulum (ER) plays an important role in protein secretion, membrane protein folding, transportation, and maintenance of intracellular calcium homeostasis. Endoplasmic reticulum stress (ERS) plays a crucial role in cerebral ischemia pathophysiology. Mild ERS helps improve cell tolerance and restore cell homeostasis; however, excessive or long-term ERS causes apoptotic pathway activation. Specifically, the protein kinase R-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways are significantly activated following initiation of the unfolded protein response (UPR). CIRI-induced apoptosis leads to nerve cell death, which ultimately aggravates neurological deficits in patients. Therefore, it is necessary and important to comprehensively explore the mechanism of ERS in CIRI to identify methods for preserving brain cells and neuronal function after ischemia.

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a potential prognostic marker and is overexpressed in various cancers. This study analyzed sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus, with external validation using the Chinese Glioma Genome Atlas (CGGA) data. CKS2 expression in the normal brain and tumor tissue was compared. cBioPortal and MethSurv were utilized to scrutinize the prognostic value of CKS2 methylation. Gene set enrichment examination and single-sample gene set enrichment analysis were employed to explore the potential biological functions of CKS2. Cell viability, colony formation, and transwell assays were conducted to evaluate the influence of CKS2 on glioma cell proliferation and invasion. Compared with normal brain tissue, the expression of CKS2 was upregulated in glioma samples (p < 0.001). Multivariate data analysis from TCGA and CGGA indicated that increased expression of CKS2 was an independent risk factor for the prognosis of overall survival in glioma patients. CKS2 methylation was negatively associated with CKS2 expression. Patients with CKS2 hypomethylation had worse overall survival compared with patients with CKS2 methylation, as suggested by the analysis of both TCGA and CGGA datasets. The expression level of CKS2 is closely related to tumor immunity, including the correlation of tumor immune cell infiltration, immune score, and co-expression of multiple immune-related genes. In addition, CKS2 is associated with several immune checkpoints and responses to the chemotherapy drug cisplatin. CKS2 knockdown impeded the expansion and aggression of glioma cell lines. The changes in CKS2 expression may provide a novel prognostic biomarker that can be used to improve patient overall survival rates.

Recent studies showed that molecule interacting with CasL2 (MICAL2) could be a novel tumor growth factor, and it is closely associated with tumor growth and invasion. However, the role it plays in glioblastoma (GBM) and its potential mechanisms are currently unknown. Our study is designed to identify the effect of MICAL2 on GBM cells and the potential mechanisms behind it. Here, we found that MICAL2 interacts with TGF receptor-type I (TGFRI) and promotes the proliferation and migration of glioblastoma through the TGF-β/p-Smad2/EMT-like signaling pathway. MICAL2-knockdown inhibited the proliferation of glioblastoma cells, which was related to cell cycle arrest and downregulation of DNA replication. The invasion abilities of U87 and U251 cells were reduced after the knockdown of MICAL2. MICAL2 promoted the growth of GBM in nude mice. High MICAL2 predicts poor outcome of GBM patients. MICAL2 could be identified as a novel promising therapeutic target for human GBM.

TUBA1C, a microtubule component, contributes to the development of several cancers. Our purpose was to study the expression of TUBA1C, its potential prognostic value, and its effects on the infiltration of immune cells of low-grade glioma (LGG). Through applying multiple bioinformatics analyses, we extracted and analyzed datasets from TCGA, TIMER, GTEx, GEPIA, and HPA to investigate the potential oncogenic mechanisms of TUBA1C, including the correlation between TUBA1C and prognosis, immune-checkpoints, tumor microenvironment (TME), and infiltration of immune cells in LGG. GO functional annotations and KEGG pathway analyses were further applied to investigate the potential action of TUBA1C in LGG. We revealed that the mRNA levels of TUBA1C were increased in LGG tumor tissues than in normal tissues. Additionally, TUBA1C was up-regulated in the grade III of LGG than in grade II. Moreover, we found that TUBA1C may be an independent prognostic factor of LGG, and high TUBA1C expression correlated to a poor prognosis of LGG. TUBA1C expression was positively associated with the infiltration of B cells, CD8 T+ cells, CD4+ T cells, macrophages, dendritic cells, and neutrophils. TUBA1C was also verified to be co-expressed with immune-related genes and immune-checkpoints. GO and KEGG pathway analyses indicated that TUBA1C may potentially regulate the pathogenesis of LGG through immune-related pathways, including chemokine pathway; JAK-STAT pathway; natural killer cell mediated cytotoxicity; T cell receptor pathway; leukocyte migration; negative regulation of immune system process; regulation of lymphocyte activation; T cell activation and other pathways. In conclusion, TUBA1C expression is increased in LGG and high TUAB1C expression is related to a poor prognosis. TUBA1C may influence tumor development by regulating the tumor-infiltrating cells in the TME. TUBA1C may be a potential target for immunotherapy.

Phosphatidylinositol binding clathrin assembly protein interacting mitotic regulator (PIMREG) localizes to the nucleus and can significantly elevate the nuclear localization of clathrin assembly lymphomedullary leukocythemia gene. Although there is some evidence to support an important action for PIMREG in the occurrence and development of certain cancers, currently no pan-cancer analysis of PIMREG is available. Therefore, we intended to estimate the prognostic predictive value of PIMREG and to explore its potential immune function in 33 cancer types. By using a series of bioinformatics approaches, we extracted and analyzed datasets from Oncomine, The Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia (CCLE) and the Human Protein Atlas (HPA), to explore the underlying carcinogenesis of PIMREG, including relevance of PIMREG to prognosis, microsatellite instability (MSI), tumor mutation burden (TMB), tumor microenvironment (TME) and infiltration of immune cells in various types of cancer. Our findings indicate that PIMREG is highly expressed in at least 24 types of cancer, and is negatively correlated with prognosis in major cancer types. In addition, PIMREG expression was correlated with TMB in 24 cancers and with MSI in 10 cancers. We revealed that PIMREG is co-expressed with genes encoding major histocompatibility complex, immune activation, immune suppression, chemokine and chemokine receptors. We also found that the different roles of PIMREG in the infiltration of different immune cell types in different tumors. PIMREG can potentially influence the etiology or pathogenesis of cancer by acting on immune-related pathways, chemokine signaling pathway, regulation of autophagy, RIG-I like receptor signaling pathway, antigen processing and presentation, FC epsilon RI pathway, complement and coagulation cascades, T cell receptor pathway, NK cell mediated cytotoxicity and other immune-related pathways. Our study suggests that PIMREG can be applied as a prognostic marker in a variety of malignancies because of its role in tumorigenesis and immune infiltration.

Ischemic stroke is one of the main issues threatening human health worldwide, and it is also the main cause of permanent disability in adults. Energy consumption and hypoxia after ischemic stroke leads to the death of nerve cells, activate resident glial cells, and promote the infiltration of peripheral immune cells into the brain, resulting in various immune-mediated effects and even contradictory effects. Immune cell infiltration can mediate neuronal apoptosis and aggravate ischemic injury, but it can also promote neuronal repair, differentiation and regeneration. The central nervous system (CNS), which is one of the most important immune privileged parts of the human body, is separated from the peripheral immune system by the blood-brain barrier (BBB). Under physiological conditions, the infiltration of peripheral immune cells into the CNS is controlled by the BBB and regulated by the interaction between immune cells and vascular endothelial cells. As the immune response plays a key role in regulating the development of ischemic injury, neutrophils have been proven to be involved in many inflammatory diseases, especially acute ischemic stroke (AIS). However, neutrophils may play a dual role in the CNS. Neutrophils are the first group of immune cells to enter the brain from the periphery after ischemic stroke, and their exact role in cerebral ischemia remains to be further explored. Elucidating the characteristics of immune cells and their role in the regulation of the inflammatory response may lead to the identification of new potential therapeutic strategies. Thus, this review will specifically discuss the role of neutrophils in ischemic stroke from production to functional differentiation, emphasizing promising targeted interventions, which may promote the development of ischemic stroke treatments in the future.

BackgroundInflammatory responses play a multiphase role in the pathogenesis of cerebral ischemic stroke (IS). Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, reduces inflammatory responses via the JAK2/STAT3 pathway. Based on its anti-inflammatory and immunosuppressive effects, we hypothesized that it may have a protective effect against stroke. The aim of this study was to investigate whether inhibition of JAK2 has a neuroprotective effect on ischemic stroke and to explore the potential molecular mechanisms.MethodsRux, MCC950 or vehicle was applied to middle cerebral artery occlusion (MCAO) mice in vivo and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. After 3 days of reperfusion, neurological deficit scores, infarct volume and brain water content were assessed. Immunofluorescence staining and western blots were used to measure the expression of NLRP3 inflammasome components. The infiltrating cells were investigated by flow cytometry. Proinflammatory cytokines were assessed by RT-qPCR. The expression of the JAK2/STAT3 pathway was measured by western blots. Local STAT3 deficiency in brain tissue was established with a lentiviral vector carrying STAT3 shRNA, and chromatin immunoprecipitation (ChIP) assays were used to investigate the interplay between NLRP3 and STAT3 signaling.ResultsRux treatment improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (P-STAT3) in neurons and microglia/macrophages. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMGB1, IL-1β, IL-2, and IL-6, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Infiltrating macrophages, B, T, cells were also reduced by Rux. Local STAT3 deficiency in brain tissue decreased histone H3 and H4 acetylation on the NLRP3 promoter and NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Rux application suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in the OGD/R model in vitro.ConclusionJAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting the expression of downstream proinflammatory cytokines and the acetylation of histones H3 and H4 on the NLRP3 promoter, resulting in the downregulation of NLRP3 inflammasome expression.

Stroke is the leading cause of disability and mortality in the world, but the pathogenesis of ischemic stroke (IS) is not completely clear and treatments are limited. Mounting evidence indicate that neovascularization is a critical defensive reaction to hypoxia that modulates the process of long-term neurologic recovery after IS. Angiogenesis is a complex process in which the original endothelial cells in blood vessels are differentiated, proliferated, migrated, and finally remolded into new blood vessels. Many immune cells and cytokines, as well as growth factors, are directly or indirectly involved in the regulation of angiogenesis. Inflammatory cells can affect endothelial cell proliferation, migration, and activation by secreting a variety of cytokines via various inflammation-relative signaling pathways and thus participate in the process of angiogenesis. However, the mechanism of inflammation-mediated angiogenesis has not been fully elucidated. Hence, this review aimed to discuss the mechanism of inflammation-mediated angiogenesis in IS and to provide new ideas for clinical treatment of IS.

Background: In addition to exploiting its ribonuclease capacity, Ribonuclease T2 (RNASET2) has been reported to exert anti-angiogenic and anti-tumorigenic effects in several tumors. However, the role of RNASET2 in gastric adenocarcinoma (GAC) remains unclear. The purpose of this study was to explore the expression, location, and clinical implications of RNASET2 in GAC.Methods: Data of RNASET2 mRNA expression in GAC and normal gastric mucosa tissues were extracted from three GSE series and 388 TCGA samples and reanalyzed. Genome-wide CRISPR/Cas9 proliferation screening datasets were used to investigate cell growth changes after RNASET2 knockout in 19 GAC cell lines. The biological processes involved in RNASET2 were studied by the bioinformatics analysis. Furthermore, the corresponding experiments including immunohistochemical staining, clinicopathological features analysis, survival curve, microvessel density detection, cell viability assay, and colony formation assay were performed to validate the expression and function of RNASET2 in GAC.Results: An abundance of RNASET2 was present in the fundus glands and pylorus glands of the normal gastric mucosa. RNASET2 mRNA and protein were down-regulated in GAC compared with adjacent non-cancerous or normal gastric mucosa tissues. The expression of RNASET2 mRNA and protein in early GAC was higher than that in advanced GAC. 79/134 gene sets involved in the early GAC pathway were enriched in the RNASET2 mRNA high expression group. Genome-wide shRNA and CRISPR/Cas9 proliferation screening showed that knockdown or knockout of RNASET2 could not significantly promote GAC cell growth. AlamarBlue cell viability assay and colony formation assay in AGS cells further validated these results. Clinicopathologic features and survival analysis demonstrated that RNASET2 protein was significantly correlated with tumor cell differentiation, Lauren's classification, and TM4SF1 protein expression, but not correlated with lymph nodal metastasis and patient's prognosis. Microvessel density detection indicated that no significant correlation was found between the expression of RNASET2 protein and the angiogenesis of GAC.Conclusions: Down-regulation of RNASET2 in GAC was only the consequence of the GAC, instead of the driver. The expression of RNASET2 could be regarded as a good biomarker for identifying the early stage of GAC.

The cerebral ischemia injury can result in neuronal death and/or functional impairment, which leads to further damage and dysfunction after recovery of blood supply. Cerebral ischemia/reperfusion injury (CIRI) often causes irreversible brain damage and neuronal injury and death, which involves many complex pathological processes including oxidative stress, amino acid toxicity, the release of endogenous substances, inflammation and apoptosis. Oxidative stress and inflammation are interactive and play critical roles in ischemia/reperfusion injury in the brain. Oxidative stress is important in the pathological process of ischemic stroke and is critical for the cascade development of ischemic injury. Oxidative stress is caused by reactive oxygen species (ROS) during cerebral ischemia and is more likely to lead to cell death and ultimately brain death after reperfusion. During reperfusion especially, superoxide anion free radicals, hydroxyl free radicals, and nitric oxide (NO) are produced, which can cause lipid peroxidation, inflammation and cell apoptosis. Inflammation alters the balance between pro-inflammatory and anti-inflammatory factors in cerebral ischemic injury. Inflammatory factors can therefore stimulate or exacerbate inflammation and aggravate ischemic injury. Neuroprotective therapies for various stages of the cerebral ischemia cascade response have received widespread attention. At present, neuroprotective drugs mainly include free radical scavengers, anti-inflammatory agents, and anti-apoptotic agents. However, the molecular mechanisms of the interaction between oxidative stress and inflammation, and their interplay with different types of programmed cell death in ischemia/reperfusion injury are unclear. The development of a suitable method for combination therapy has become a hot topic.

Stroke remains a leading cause of death, disability, and medical care burden worldwide. However, transformation from laboratory findings toward effective pharmacological interventions for clinical stroke has been unsatisfactory. Novel evidence has been gained on the underlying mechanisms and therapeutic potential related to the transient receptor potential (TRP) channels in several disorders. The TRP superfamily consists of a diverse group of Ca2+ permeable non-selective cation channels. In particular, the members of TRP subfamilies, TRP canonical (TRPC) channels and TRPC6, have been found in different cell types in the whole body and have high levels of expression in the central nervous system (CNS). Notably, the TRPCs and TRPC6 channel have been implicated in neurite outgrowth and neuronal survival during normal development and in a range of CNS pathological conditions. Recent studies have shown that suppression of TRPC6 channel degradation prevents ischemic neuronal cell death in experimental stroke. Accumulating evidence supports the important functions of TRPC6 in brain ischemia. We have highlighted some crucial advancement that points toward an important involvement of TRPCs and TRPC6 in ischemic stroke. This review will make an overview of the TRP and TRPC channels due to their roles as targets for clinical trials and CNS disorders. Besides, the primary goal is to discuss and update the critical role of TRPC6 channels in stroke and provide a promising target for stroke prevention and therapy.

Ischemic stroke is a devastating disease with long-term disability. However, the pathogenesis is unclear and treatments are limited. Meisoindigo, a second-generation derivative of indirubin, has general water solubility and is well-tolerated. Previous studies have shown that meisoindigo reduces inflammation by inhibiting leukocyte chemotaxis and migration. In the present study, we investigated the hypothesis that meisoindigo was also protective against ischemic stroke, then evaluated its underlying mechanisms. In vivo, adult male C57BL/6J wild-type mice were used to produce a middle cerebral artery occlusion (MCAO) stroke model. On day three after reperfusion, obvious improvement in neurological scores, infarct volume reduction and cerebral edema amelioration were observed in meisoindigo treatment. Moreover, immunofluorescence staining and western-blot showed that the expression of NLRP3 inflammasome and its associated proteins in neurons and microglia was inhibited by meisoindigo. The effects of Meisoindigo on NLRP3 inflammasome inactivation and increased the M2 phenotype of microglia/macrophage through shifting from a M1 phenotype, which was possibly mediated by inhibition of TLR4/NF-κB. Furthermore, we verified the inhibitory effect of meisoindigo on TLR4/NF-κB signaling pathway, and found that meisoindigo treatment could significantly suppressed the expression of TLR4/NF-κB pathway-associated proteins in a dose-dependent manner, meanwhile, which resulted in downregulation of HMGB1 and IL-1β. Next, we established an in vitro oxygen glucose deprivation/Reperfusion (OGD/R) model in HT-22 and BV2 cells to simulate ischemic conditions. Cytotoxicity assay showed that meisoindigo substantially improved relative cell vitality and in HT-22 and BV2 cells following OGD/R in vitro. After suffering OGD/R, the TLR4/NF-κB pathway was activated, the expression of NLRP3 inflammasome-associated proteins and M1 microglia/macrophage were increased, but meisoindigo could inhibit above changes in both HT-22 and BV2 cells. Additionally, though lipopolysaccharide stimulated the activation of TLR4 signaling in OGD/R models, meisoindigo co-treatment markedly reversed the upregulation of TLR4 and following activation of NLRP3 inflammasome and polarization of M1 microglia/macrophages mediated by TLR4. Overall, we demonstrate for the first time that meisoindigo post-treatment alleviates brain damage induced by ischemic stroke in vivo and in vitro experiments through blocking activation of the NLRP3 inflammasome and regulating the polarization of microglia/macrophages via inhibition of the TLR4/NF-κB signaling pathway.

After ischemic stroke, the integrity of the blood-brain barrier is compromised. Peripheral immune cells, including neutrophils, T cells, B cells, dendritic cells, and macrophages, infiltrate into the ischemic brain tissue and play an important role in regulating the progression of ischemic brain injury. In this review, we will discuss the role of different immune cells after stroke in the secondary inflammatory reaction and focus on the phenotypes and functions of macrophages in ischemic stroke, as well as briefly introduce the anti-ischemic stroke therapy targeting macrophages.

Hypoxic ischemic encephalopathy (HIE) is a type of neonatal brain injury, which occurs due to lack of supply and oxygen deprivation to the brain. It is associated with a high morbidity and mortality rate. There are several therapeutic strategies that can be used to improve outcomes in patients with HIE. These include cell therapies such as marrow mesenchymal stem cells (MSCs) and umbilical cord blood stem cells (UCBCs), which are being incorporated into the new protocols for the prevention of ischemic brain damage. The focus of this review is to discuss the mechanism of oxidative stress in HIE and summarize the current available treatments for HIE. We hope that a better understanding of the relationship between oxidative stress and HIE will provide new insights on the potential therapy of this devastating condition.

High-mobility group box 1 protein (HMGB1) is a novel, cytokine-like, and ubiquitous, highly conserved, nuclear protein that can be actively secreted by microglia or passively released by necrotic neurons. Ischemic stroke is a leading cause of death and disability worldwide, and the outcome is dependent on the amount of hypoxia-related neuronal death in the cerebral ischemic region. Acting as an endogenous danger-associated molecular pattern (DAMP) protein, HMGB1 mediates cerebral inflammation and brain injury and participates in the pathogenesis of ischemic stroke. It is thought that HMGB1 signals via its presumed receptors, such as toll-like receptors (TLRs), matrix metalloproteinase (MMP) enzymes, and receptor for advanced glycation end products (RAGEs) during ischemic stroke. In addition, the release of HMGB1 from the brain into the bloodstream influences peripheral immune cells. However, the role of HMGB1 in ischemic stroke may be more complex than this and has not yet been clarified. Here, we summarize and review the research into HMGB1 in ischemic stroke.

Toxoplasma gondii (T. gondii) is a worldwide zoonotic parasite that can infect almost warm-blood animals, including humans, which seriously affect the health of host. Cats are known to be the only definitive host of T. gondii and continuously excrete highly infectious oocysts. This parasite carried by the companion animals leads to a great public health risk. However, there is little information on epidemiology of T. gondii in urban cats in Kunming, Southwest China. In the present study, a total of 231 serum and fecal samples were collected in Kunming aera, and then seroprevalence of T. gondii IgG antibodies in serum and molecular investigation in feces were analyzed to elucidate T. gondii infection in urban cats. The results revealed that 168 of 231 cats (72.7%) were positive for T. gondii antibodies, and 1 of 74 cat feces (1.4%) also showed a positive PCR for T. gondii DNA. The positive fecal sample was sequenced and then phylogenetically analyzed, and the isolate of T. gondii in the present study was closely related to T. gondii strain CN. In addition, the food, water and age of cats were identified as the risk factor for seropositivity. Overall, our findings indicate the widespread occurrence of T. gondii infection in urban cats in Kunming, Southwest China and identify food, water and age are the risk factors associated with T. gondii infection, which can provide effective information for developing strategies to prevent and control this zoonosis.

Paxlovid (nirmatrelvir/ritonavir) is an antiviral drug used to treat COVID-19, nirmatrelvir, a SARS-CoV-2 main protease inhibitor, works by inhibiting viral replication in the early stages, and ritonavir is a strong cytochrome P450 (CYP) 3A inhibitor that helps the nirmatrelvir reach and maintain the therapeutic concentrations. Paxlovid has a potential risk of drug interaction by elevating the plasma concentration of other drugs metabolized by CYP3A, like tacrolimus. This report examines the case of a 57-year-old female lung transplant patient self-administered Paxlovid for 5 days without discontinuing tacrolimus. She presented to the hospital with symptoms of headache, dizziness, palpitations, abdominal distension, nausea, vomiting, and diarrhea. The patient presented with tacrolimus toxicity and the blood concentration of tacrolimus was measured at 106 ng/mL. Urgent medical intervention was initiated, and Rifampin was administered to induce enzyme activity and rapidly decrease the concentration of tacrolimus. By adjusting the tacrolimus dosage, the final concentration was brought within the appropriate range. Clinical pharmacists should prioritize medication education for transplant patients to prevent severe drug interactions and minimize the impact on the patient’s overall well-being.

PurposeAdding pelvic lymph node dissection (PLND) to cystectomy offers significant survival benefit. However, it remains unclear whether this benefit persists in all histologic types. The aim of the study was to examine the impact of PLND on overall survival (OS) after cystectomy in bladder carcinoma patients with histological variants.MethodsWithin the Surveillance, Epidemiology and End Results database, we identified 16,880 bladder carcinoma patients receiving cystectomy between 2004 and 2015. Patients were stratified according to the following histologic types: transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, neuroendocrine carcinoma, signet ring cell carcinoma, pseudosarcomatous carcinoma, and other histology. Cox regression models were used to evaluate the effect of PLND on OS stratified by histologic type.ResultsHistologic types were significantly associated with the presence of lymph node metastasis in patients with bladder carcinoma (P < 0.001). In multivariable Cox regression analyses, PLND compared with non-PLND was associated with OS benefit in patients with transitional cell carcinoma (hazard ratio [HR], 0.595; 95% confidence interval [95% CI], 0.557–0.634 [P < 0.001]), squamous cell carcinoma (HR, 0.646; 95% CI, 0.494–0.846 [P = 0.002]), and signet ring cell carcinoma (HR, 0.233; 95% CI, 0.107–0.504 [P < 0.001]), whereas no significant differences in OS were observed in other histological subsets.DiscussionOur analyses revealed a significant OS benefit from PLND in patients with transitional cell carcinoma, squamous cell carcinoma, and signet ring cell carcinoma. However, a survival benefit of PLND in patients with other histologic types was not demonstrated.