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Ischemic stroke is characterized by high morbidity, mortality and disability rate worldwide. Because of its complexity in pathogenesis and lack of effective therapeutic strategies and drugs, great breakthrough has not yet been made in the treatment of cerebral ischemic stroke. Therefore, to explore a more effective and safer therapeutic strategy for cerebral ischemic stroke has been the focus of numerous researchers. Neuroprotective effects of sonic hedgehog (Shh) signaling pathway in ischemic stroke have been reported in recent studies, but have not been fully elucidated. In our review, we elaborate the roles of Shh signaling in ischemic stroke from different aspects, including oxidative stress, excitotoxicity, neuroinflammation, apoptosis, angiogenesis, neuroplasticity, neurogenesis, astrogliosis and oligodendrogenesis. Meanwhile, Shh signaling based therapeutic approaches for cerebral ischemic stroke are also included in our review. We hope it will benefit the readers to better understand the roles of Shh signaling pathway in cerebral ischemic stroke and provide more comprehensive insights for basic research and novel strategies for the clinical treatment of cerebral ischemic stroke. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke is a leading cause of permanent disability and death globally. The nucleotide‐biding oligomaerization domain (NOD)‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome is a multi‐protein complex that plays a role in ischemic stroke. Recently, research on the role of NLRP3 in ischemic stroke has developed rapidly worldwide. However, there is no bibliometric analysis of NLRP3 in ischemic stroke to date. Aim: Through bibliometric analysis, the aim of this study was to assess the current state of research on NLRP3 in the field of ischemic stroke research worldwide over the past 12 years and to identify important results, major research areas, and emerging trends. Methods: Publications related to NLRP3 in ischemic stroke from January 1, 2011 to December 31, 2022 were obtained from the Web of Science Core Collection (WoSCC). We used HistCite, VOSviewer, CiteSpace, and Bibliometrix for bibliometric analysis and visualization. The Total Global Citation Score (TGCS) was employed to assess the impact of publications. Results: We found that research of NLRP3 in ischemic stroke developed rapidly starting in 2011. 601 relevant studies have been published in 245 journals over the past 12 years. Journal of Neuroinflammation and International Immunopharmacology were the most productive journals and Journal of Neuroinflammation was the most cited journal. Additionally, Stroke and Journal of Cerebral Blood Flow & Metabolism were the most co‐cited journal. The most productive country was China (records = 430) and the most productive university was the Zhejiang University (records = 24). Arumugam TV (TGCS = 949) was the most cited author in this field. NLRP3 inflammasome activation, nf–κb, oxidative stress, and inflammation were the knowledge bases for the research in this field. Conclusion: This study is a scientometric study utilizing quantitative and qualitative methods to comprehensively review the publications on NLRP3 in ischemic stroke. This information provides a reference for scholars to further study NLRP3 in ischemic stroke. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide, with late detection, ineffective treatment and poor overall survival. Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, holds great potential for treatment of HCC. Although some patients respond well to ICIs, many fail to obtain a significant benefit. It is therefore of great interest to find appropriate markers to stratify patient responses to immunotherapy and to explore suitable targets for modulating the TME and immune cell infiltration. ATP6V1F encodes a constituent of vacuolar ATPase (V-ATPase). V-ATPase-mediated acidification of organelles is required for intracellular processes such as zymogen activation, receptor-mediated endocytosis, protein sorting and synaptic vesicle proton gradient generation. In this study, we confirmed for the first time that ATP6V1F is overexpressed in HCC and related to poor prognosis in these patients. We identified that overexpression of ATP6V1F is associated with infiltration of some immune cells and expression of several immune checkpoints. Furthermore, we explored the possible mechanisms of action of ATP6V1F. Finally, we conducted in vitro experiments, including wound healing, Transwell invasion, and apoptosis assays, to verify that ATP6V1F promotes development of HCC by promoting migration and invasion and inhibiting apoptosis of HCC cells. Our findings will contribute to providing precise immunotherapy to patients with HCC. [ABSTRACT FROM AUTHOR]

The gene expression profile of abdominal aortic aneurysm (AAA) neck is not fully understood. The etiology of AAA is considered to be related to atherosclerosis and the inflammatory response, involving congenital, genetic, metabolic, and other factors. The level of proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to those of cholesterol, oxidized low-density lipoprotein, and triglycerides. PCSK9 inhibitors have significant effects on lowering LDL-cholesterol, reversing atherosclerotic plaques, and reducing the risk of cardiovascular events and have been approved by several lipid-lowering guidelines. This work was aimed to investigate the potential role of PCSK9 in the neck of AAA. We extracted the expression dataset (GSE47472) containing 14 AAA patients and 8 donors and single-cell RNAseq (scRNA-seq) data (GSE164678) of CaCl2-induced (AAA) samples from the Gene Expression Omnibus dataset. Through bioinformatics methods, we found that PCSK9 was up-regulated in the proximal neck of human AAA. In AAA, PCSK9 was mainly expressed in fibroblasts. Additionally, immune check-point PDCD1LG2 was also expressed higher in AAA neck than donor, while CTLA4, PDCD1, and SIGLEC15 were down-regulated in AAA neck. The expression of PCSK was correlated with PDCD1LG2, LAG3, and CTLA4 in AAA neck. Additionally, some ferroptosis-related genes were also down-regulated in AAA neck. PCSK9 was also correlated with ferroptosis-related genes in AAA neck. In conclusion, PCSK9 was highly expressed in AAA neck, and may exert its role through interacting with immune check-points and ferroptosis-related genes. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most prevalent cerebral cancer in adults without proven therapy. Chimeric antigen receptor T cell treatment has demonstrated good clinical success in hematologic cancers. The application of chimeric antigen receptor T cell therapy to solid tumors, such as glioblastoma, is currently the subject of scientific investigation. The creation of chimeric antigen receptor T cells and its iterations are briefly described in this article. Specifically, this study addresses the obstacles and hurdles faced and glioblastoma targets studied in recent years. This review provides the reader with a comprehensive understanding of the current state of chimeric antigen receptor T cell therapy for glioblastoma and a clear understanding of each therapeutic target. Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood–brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM. [ABSTRACT FROM AUTHOR]

High‐fat diet (HFD) consumption is known to be associated with ovulatory disorders among women of reproductive age. Previous studies in animal models suggest that HFD‐induced microglia activation contributes to hypothalamic inflammation. This causes the dysfunction of the hypothalamic–pituitary–ovarian (HPO) axis, leading to subfertility. Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a novel class of lipid‐soluble antidiabetic drugs that target primarily the early proximal tubules in kidney. Recent evidence revealed an additional expression site of SGLT2 in the central nervous system (CNS), indicating a promising role of SGLT2 inhibitors in the CNS. In type 2 diabetes patients and rodent models, SGLT2 inhibitors exhibit neuroprotective properties through reduction of oxidative stress, alleviation of cerebral atherosclerosis and suppression of microglia‐induced neuroinflammation. Furthermore, clinical observations in patients with polycystic ovary syndrome (PCOS) demonstrated that SGLT2 inhibitors ameliorated patient anthropometric parameters, body composition and insulin resistance. Therefore, it is of importance to explore the central mechanism of SGLT2 inhibitors in the recovery of reproductive function in patients with PCOS and obesity. Here, we review the hypothalamic inflammatory mechanisms of HFD‐induced microglial activation, with a focus on the clinical utility and possible mechanism of SGLT2 inhibitors in promoting reproductive fitness. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) initiates a programmed cell death through apoptosis, autophagy, and ferroptosis, which results in neuronal damage and brain injury. However, existing methods for in situ detection of ferroptosis are currently insufficient. Therefore, we constructed a series of hydrogen peroxide (H 2 O 2 —one of the major ROS) probes (QH 2 O 2 , MQH 2 O 2 , and BQH 2 O 2) with quinoline derivatives as two-photon fluorophores and boronate as the recognition domain. Experimental results indicated that the linear response range of the probe MQH 2 O 2 to H 2 O 2 increased from < 10–300 μM as compared with the probe QH 2 O 2. Moreover, the linear correlation coefficient also increased from 0.9012 to 0.999, indicating that the ratiometric fluorescent probe has built-in corrections for environmental interference, which allows a more accurate fluorescence analysis. Modification of the probe by connecting triethylene glycol monomethyl ether (BQH 2 O 2) increased the lipophilic index of the probe to 2.01, which enhanced its ability to cross the blood–brain barrier. Therefore, the developed probe is useful for analyzing the H 2 O 2 production during an ischemic stroke and its fluctuation with ferroptosis. [Display omitted] • Two-photon H 2 O 2 probes were constructed. • The probe were modified to exhibit a ratiometric response. • The probes were used to detect H 2 O 2 during an IS-induced ferroptosis. [ABSTRACT FROM AUTHOR]

A near infrared photoelectrochemical (PEC) and colorimetric dual-mode aptasensor was fabricated for efficiently determining osteopontin (OPN). Er-MOFs and Au 2 Pt nanoparticles were successfully synthesized. The gold nanoparticles (AuNPs) modified Er-MOF (Er-MOFs@AuNPs) nanocomposites were introduced into the glassy carbon electrode (GCE) to construct a photoelectrochemical sensing interface. OPN aptamer (Apt1) was immobilized onto the Er-MOFs@AuNPs based photoelectrochemical platform through Au-S bond for the selectively recognizing osteopontin. Au 2 Pt-labeled OPN aptamer (Au 2 Pt-Apt2) was subsequently captured onto the OPN/Apt1/MOFs@AuNPs/GCE surface to form a sandwich sensing interface, leading to an enhancement on the photocurrent response. Interestingly, Au 2 Pt nanozyme which possesses peroxidase activity could produce a solution color change in the presence of 3,3′,5,5′-tetramethylbenzidine (TMB) and hydrogen peroxide. The variations of photocurrent response and absorbance can be employed for the quantitative detection of OPN. Under the optimal conditions, the PEC and colorimetric sensing strategies show linear responses towards OPN in the concentration range of 0.01 ∼ 25 ng mL−1 and 1 ∼ 850 ng mL−1, respectively. The calculated determination limits were 2.6 pg mL−1 and 0.04 ng mL−1. The PEC and colorimetric dual-mode sensing platform can provide no crosstalk results and can be mutually verified, thus effectively improving the accuracy and reliability for the determination of OPN. [Display omitted] • Er-MOFs@AuNPs nanocomposites and Au 2 Pt nanozyme were successfully synthesized • Near-infrared photoelectrochemical response was obtained from the photocurrent variation of Er-MOFs@AuNPs interface • A colorimetric response was obtained from the catalytic oxidation of TMB with Au 2 Pt nanozyme • A PEC and colorimetric dual-mode aptasensor was developed for the high-performance determination of osteopontin [ABSTRACT FROM AUTHOR]

Research in the areas of inflammation and mitochondrial stress in ischemic stroke is rapidly expanding, but a comprehensive overview that integrates bibliometric trends with an in-depth review of molecular mechanisms is lacking. To map the evolving landscape of research using bibliometric analysis and to detail the molecular mechanisms that underpin these trends, emphasizing their implications in ischemic stroke. We conducted a bibliometric analysis to identify key trends, top contributors, and focal research themes. In addition, we review recent research advances in mitochondrial stress and inflammation in ischemic stroke to gain a detailed understanding of the pathophysiological processes involved. Our integrative approach not only highlights the growing research interest and collaborations but also provides a detailed exploration of the molecular mechanisms that are central to the pathology of ischemic stroke. This synthesis offers valuable insights for researchers and paves the way for targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background and Purpose: Stroke is associated with high disability and mortality rates and increases the incidence of organ-related complications. Research has revealed that the outcomes and prognosis of stroke are regulated by the state of the intestinal microbiota. However, the possibility that the manipulation of the intestinal microbiota can alter sex-related stroke outcomes remain unknown.Methods: To verify the different effects of microbiota from different sexes on stroke outcomes, we performed mouse fecal microbiota transplantation (FMT) and established a model of ischemic stroke. Male and female mice received either male or female microbiota through FMT. Ischemic stroke was triggered by MCAO (middle cerebral artery occlusion), and sham surgery served as a control. Over the next few weeks, the mice underwent neurological evaluation and metabolite and inflammatory level detection, and we collected fecal samples for 16S ribosomal RNA analysis.Results: We found that when the female mice were not treated with FMT, the microbiota (especially the Firmicutes-to-Bacteroidetes ratio) and the levels of three main metabolites tended to resemble those of male mice after experimental stroke, indicating that stroke can induce an ecological imbalance in the biological community. Through intragastric administration, the gut microbiota of male and female mice was altered to resemble that of the other sex. In general, in female mice after MCAO, the survival rate was increased, the infarct area was reduced, behavioral test performance was improved, the release of beneficial metabolites was promoted and the level of inflammation was mitigated. In contrast, mice that received male microbiota were much more hampered in terms of protection against brain damage and the recovery of neurological function.Conclusion: A female-like biological community reduces the level of systemic proinflammatory cytokines after ischemic stroke. Poor stroke outcomes can be positively modulated following supplementation with female gut microbiota. [ABSTRACT FROM AUTHOR]

Glioma is the common, most aggressive and poorest prognostic tumor type in the brain. More and more biomarkers associated with glioma treatment, prognosis, and immunity are being discovered. Here, we aimed to explore the underlying biological functions and prognostic predictive value of Apolipoprotein L4 (APOL4) in glioma. We downloaded the expression data of APOL4 and clinical information from several databases and used R software for preprocessing. The clinical significance of APOL4 in a glioma outcome was explored by the Cox regression analysis and Kaplan–Meier survival analysis. In addition, immune infiltrates and microenvironmental indicators were assessed by CIBERSORT and TIMER. GO and KEGG analyses were used to analyze the potential functions of APOL4 in gliomas. APOL4 expression was increased in glioma specimens compared to normal tissues and correlated dramatically with the WHO grade. A survival analysis showed a shorter overall survival (OS) in glioma patients with APOL4 overexpression, and a Cox regression analysis showed that APOL4 was an independent prognostic factor for the OS of glioma patients. GSEA, GO, and KEGG enrichment analyses showed remarkable enrichment in immune-related pathways. APOL4 expression was positively correlated with immune infiltration (including DC cells, neutrophils, CD8+ T cells, B cells, macrophages, CD4+ T cells, etc.) and microenvironmental parameters (including immune, stromal, and ESTIMATE scores) in gliomas. Glioma patients with a higher expression of APOL4 may be more sensitive to immune checkpoint inhibitors (ICI). In conclusion, these findings suggest that APOL4 is associated with the tumor grade and immune infiltrates; APOL4 may be a new and potential biomarker for therapeutic and prognostic evaluations that may further suggest the therapeutic efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

• Expression of STAT3 was upregulated in ischemic penumbra post stroke. • STAT3 blockade aggravates ischemic injury in vivo and in vitro. • STAT3 deletion skewed the microglia/macrophage toward M1 polarization. Background: Subtypes of microglia/macrophage regulate the inflammation in the opposite direction during ischemic stroke. JAK2/STAT3 signaling pathway participates in the development of stroke-related inflammation via ischemic stimulation. However, the relationship between JAK2/STAT3 pathway and microglia/macrophage phenotype transformation is unclear. Methods: This study established a transient middle cerebral artery occlusion (tMCAO) model in male STAT3f/f and STAT3f/f LysMcre+ mice and evaluated the neurological deficit on the 3rd day using Longa score. The brains were stained by TTC to determine the infarction volume. Western blotting and QPCR were used to determine the expression of JAK2/STAT3 pathway and microglia/macrophage-related markers. Immunofluorescence staining was used to detect the levels of polarization-related indexes. QPCR also assessed the effect of STAT3 knockout on inflammatory factors in the infarction. Moreover, established the OGD/R model using BV2 cells to further verify the role of STAT3 on microglia/macrophage polarization. Results: For the conditioned STAT3-KO mice, the infarction was significantly increased after MCAO, accompanied by the aggravation of neurological deficit. Higher expression of iNOS and CD16/32 than Arg-1, Ym-1, and CD206 in vivo and in vitro , and decreased p-STAT3/STAT3 ratio in STAT3f/f LysMcre+ mice, while the p-JAK2/JAK2 ratio increased. In addition, increased M1/M2 ratio and elevated expression of IL-1β, IL-6, TNF-α with STAT3 deletion, as well as increased CD68+/iNOS+ cell numbers. Conclusion: Collectively, these results reveal that JAK2/STAT3 signaling pathway regulates the microglia/macrophage polarization (skewing toward the M2 polarization) during the CIRI, thus alleviating brain damage. Therefore, approaches targeting JAK2/STAT3 activation are promising therapies for ischemic stroke. [ABSTRACT FROM AUTHOR]

Cell division cycle-associated (CDCA) gene family members are essential cell proliferation regulators and play critical roles in various cancers. However, the function of the CDCA family genes in gliomas remains unclear. This study aims to elucidate the role of CDCA family members in gliomas using in vitro and in vivo experiments and bioinformatic analyses. We included eight glioma cohorts in this study. An unsupervised clustering algorithm was used to identify novel CDCA gene family clusters. Then, we utilized multi-omics data to elucidate the prognostic disparities, biological functionalities, genomic alterations, and immune microenvironment among glioma patients. Subsequently, the scRNA-seq analysis and spatial transcriptomic sequencing analysis were carried out to explore the expression distribution of CDCA2 in glioma samples. In vivo and in vitro experiments were used to investigate the effects of CDCA2 on the viability, migration, and invasion of glioma cells. Finally, based on ten machine-learning algorithms, we constructed an artificial intelligence-driven CDCA gene family signature called the machine learning-based CDCA gene family score (MLCS). Our results suggested that patients with the higher expression levels of CDCA family genes had a worse prognosis, more activated RAS signaling pathways, and more activated immunosuppressive microenvironments. CDCA2 knockdown inhibited the proliferation, migration, and invasion of glioma cells. In addition, the MLCS had robust and favorable prognostic predictive ability and could predict the response to immunotherapy and chemotherapy drug sensitivity. • An integration analysis of CDCA gene family in gliomas by multiple omics data. • Novel CDCA family clusters with distinct signaling, genomic features, TIME, and prognosis. • Experiments showed CDCA2 acted as an oncogene in gliomas by RAS signaling. • An artificial intelligence-driven CDCA family signature was developed. • The MLCS was a stable and robust biomarker for prognosis and immunotherapy. [ABSTRACT FROM AUTHOR]

• This study was the first to link the causal relationship among uric acid, T2DM, and ischemic stroke with its subtypes using Mendelian randomization. • The causal relationship between uric acid and ischemic stroke, especially LAS and SVS, was elucidated by Two-sample Mendelian randomization. • Two-step mediation analysis revealing that the impact of uric acid on LAS and SVS risk was partly mediated through T2DM. This study conducts a systematic investigation into the causal relationships between plasma uric acid levels and subtypes of ischemic stroke (IS), as well as the extent to which Type 2 diabetes mellitus (T2DM) mediates this relationship. There is a known association between Uric acid and IS but whether they have a causal relationship remains unclear. This study aims to determine whether a genetic predisposition to uric acid is causally linked to IS, including three subtypes, and to determine the mediating role of T2DM. Bidirectional Mendelian randomization (MR) analyses was initially used to explore the causal relationship between uric acid and three subtypes of IS. Two-step MR methods were then used to investigate the role of T2DM in mediating the effect of uric acid and IS with its subtypes. A primary analysis showed uric acid had a markedly causal association with IS (IVW, OR 1.23; 95 % CI, 1.13 − 1.34; p = 6.39 × 10-9), and two subtypes of IS, Large-vessel atherosclerotic stroke LAS (IVW, OR 1.25; 95 % CI, 1.03 − 1.53; p = 0.026) and small vessel stroke (SVS) (IVW, OR 1.20; 95 % CI, 1.00 − 1.43; p = 0.049), but not with cardioembolic stroke (CES)(IVW, OR 1.00; 95 % CI, 0.87 − 1.15; p = 0.993). Two-step MR results showed that T2DM mediated the association between uric acid and LAS and SVS, accounting for 13.85 % (p = 0.025) and 13.57 % (p = 0.028), respectively. The study suggests that genetic predisposition to uric acid is linked to a greater risk of IS, especially LAS and SVS. T2DM might mediate a significant proportion of the associations between uric acid and LAS as well as SVS. [ABSTRACT FROM AUTHOR]

[Display omitted] Combination chemotherapy is a promising strategy for cancer treatment in clinics especially when multidrug-resistant cancer is emerging. One significant challenge remains in achieving sufficient multi-drug delivery into tumor cells to maximize the synergetic therapeutic effect, as it is hard to concentrate drugs in drug-resistant cancer. Therefore herein, metal–organic framework (MOF)-based polymer-coated hybrid nanoparticles (NPs) were devised and constructed for the co-delivery of doxorubicin and cisplatin to enhance combination therapy of multidrug-resistant cancer. The MOF@polymer nanocarrier combined the merits of high multi-drug loading capacity, physiological stability, and tumor microenvironment pH-responsiveness, facilitating simultaneous delivery of drugs into cancer cells and making the most of synergistic antitumor effect. Remarkably, this hybrid nanocarrier maintains a negative surface charge during circulation to guarantee a stable and prolonged process in vivo, and then exposes inner positive MOF after degradation of the outer polymer in the acidic tumor microenvironment to promote multi-drug release, cellular internalization, nuclear localization, and tumor penetration. In vitro and in vivo studies with drug-resistant MCF-7/ADR cancer suggested that the nanocarrier could achieve increased accumulation of drugs in solid tumors, remarkable tumor elimination results as well as minimized side effects, indicating an improved efficacy and safety of combination chemotherapy. MOF@polymer hybrid nanocarriers provide new insights into the development of stimuli-responsive co-delivery systems of multiple drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The gut-brain-microbiota axis (GBMAx) coordinates bidirectional communication between the gut and brain, and is increasingly recognized as playing a central role in physiology and disease. MicroRNAs are important intracellular components secreted by extracellular vesicles (EVs), which act as vital mediators of intercellular and interspecies communication. This review will present current advances in EV-derived microRNAs and their potential functional link with GBMAx. We propose that EV-derived microRNAs comprise a novel regulatory system for GBMAx, and a potential novel therapeutic target for modifying GBMAx in clinical therapy. [ABSTRACT FROM AUTHOR]

Designing functionalized MOFs with specific reactivity and NIR photoelectrochemical and fluorescent response is critical for developing biosensing systems. Herein, SCy7, a conjugate macrocycle ligand with a specific fluorescence responsive group to HClO, was designed and synthesized. Responsive Nd-MOF nanorods were successfully prepared by using SCy7 as the organic ligand and Nd3+ as the metal central ion. Nd-MOF nanorods show good absorption characteristics in the wavelength range of 200–1200 nm with a band gap of 0.89 eV. Nd-MOF nanorods were employed as a photoactive material to construct a near-infrared photoelectrochemical cytosensor for MCF-7 cells by integrated with an aptamer. The photocurrent variation exhibits a good linear response to MCF-7 cells in the concentration range of 50–1.0 × 107 cells mL−1, and a comparatively low detection limit of 18 cells mL−1 (S/N = 3). The NIR PEC cytosensor was also employed for monitoring endogenous HClO released from MCF-7 cells as being stimulated by PMA. HClO is an electron acceptor that can convert the anodic photocurrent into cathodic photocurrent, thus achieving monitoring HClO through the conversion of photocurrent polarity. Furthermore, Nd-MOF was coated with F127 to improve its hydrophilicity and biocompatibility, and to provide a Nd-MOF@F127 with a fluorescence emission peak at 830 nm. Nd-MOF@F127 show specific fluorescence response to HClO, and thus was successfully used in imaging HClO variation in cells and breast cancer bearing mice. [Display omitted] • Nd-MOF nanorods with specific response to HClO were successfully synthesized. • A NIR PEC cytosensor based on Nd-MOF was developed for MCF-7 cells assaying. • Real-time monitoring HClO was achieved by photocurrent polarity conversion. • Fluorescence imaging HClO in cells and mice was performed by using Nd-MOF@F127. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) is a form of stroke associated with high mortality and morbidity. Despite advances in treatment for SAH, the prognosis remains poor. We have previously demonstrated that glycine, a non-essential amino acid is involved in neuroprotection following intracerebral hemorrhage via the Phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling pathway. However, whether it has a role in inducing neuroprotection in SAH is not known. The present study was designed to investigate the role of glycine in SAH. In this study, we show that glycine can reduce brain edema and protect neurons in SAH via a novel pathway. Following a hemorrhagic episode, there is evidence of downregulation of S473 phosphorylation of AKT (p-AKT), and this can be reversed with glycine treatment. We also found that administration of glycine can reduce neuronal cell death in SAH by activating the AKT pathway. Glycine was shown to upregulate miRNA-26b, which led to PTEN downregulation followed by AKT activation, resulting in inhibition of neuronal death. Inhibition of miRNA-26b, PTEN or AKT activation suppressed the neuroprotective effects of glycine. Glycine treatment also suppressed SAH-induced M1 microglial polarization and thereby inflammation. Taken together, we conclude that glycine has neuroprotective effects in SAH and is mediated by the miRNA-26b/PTEN/AKT signaling pathway, which may be a therapeutic target for treatment of SAH injury. [ABSTRACT FROM AUTHOR]

Venous thromboembolism is a sudden cardiovascular disease that can lead to death, and its pathologic development is closely related to vascular viscosity and inflammation. However, direct evidence from in vivo is really scarce. The key limitation is that the combined probes cannot detect multiple markers simultaneously, which may lead to unreliable results. Therefore, to develop a single probe that can simultaneously monitor the variations of viscosity in the vascular microenvironment as well as inflammation level during venous thrombosis. A dual-responsive two-photon fluorescent probe, Cou-ONOO , was designed and synthesized. Cou-ONOO provides a visualization tool for monitoring the viscosity of the vascular as well as the inflammatory marker ONOO‾ during thromboembolism via dual-channel simultaneous imaging. As a single probe that can recognize dual targets, Cou-ONOO effectively avoids the problems from unreliable results caused by complex synthesis and differences in intracellular localization, diffusion, and metabolism of different dyes as using combinatorial probes. Using Cou-ONOO , simultaneous imaging the variations of viscosity and ONOO‾at the cellular and tissue levels was successfully performed. In addition, Cou-ONOO also successfully visualized and tracked the viscosity of the vascular microenvironment and ONOO‾ during venous embolism in mice. Experimental results show that both viscosity and inflammation are abnormally overexpressed in the microenvironment at the thrombus site during venous thrombosis. An intuitive visualization tool to elucidate the variations of viscosity as well as inflammation level in the vascular microenvironment during thrombosis was provided, which will facilitate a better clinical understanding of the pathological process of thrombosis. [Display omitted] •A dual response two-photon fluorescent probe for viscosity and ONOO‾ was prepared • Mitochondrial viscosity and ONOO‾ in a venous thromboembolism were imaged simultaneously • Tracking ONOO‾ and viscosity changes during venous thromboembolism formation was achieved [ABSTRACT FROM AUTHOR]

Abstract CCR2 could recruit immune cells migrating into brain after ischemic stroke. It is unclear whether and why Propagermanium (PG, a CCR2 inhibitor) is able to protect against ischemic injury. Middle cerebral artery occlusion (MCAO) and reperfusion injury in C57BL/6 J male mice were performed in vivo to mimic ischemic stroke. Cultured BV2 microglia exposed to oxygen and glucose deprivation (OGD)/reoxygenation injury, LPS or IL-4 incubation were served in vitro. TTC staining, neurological score, brain water content, and MRI scan were performed to evaluate stroke outcome. Real time PCR, ELISA, and immunofluorescence were used to estimate inflammatory cytokines expression and releasing. Western blot was utilized to detect pSTAT1/STAT1 expression. Compared with MCAO mice, PG treatment significantly reduced infarction size and brain edema, improved neurological behavior at 72 h after MCAO. For inflammatory response, PG treatment inhibited inflammatory cytokines releasing, such as TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17, and IL-23. Further studies indicated that PG treatment downregulated mRNA expression of pro-inflammatory iNOS and CD86, and inhibited CD16 expressed in microglia. In vitro, PG incubation inhibited BV2 polarized to pro-inflammatory phenotype through STAT1 downregulation, while had no obvious effect on anti-inflammatory phenotype. Our observations suggest that CCR2 inhibitor PG downregulated pro-inflammatory microglia polarization for decreasing pro-inflammatory microglia phenotype marker, and thereafter inhibited inflammatory responses after MCAO in a STAT1-dependent manner. Highlights • Propagermanium reduced infarction and inhibited cytokines mRNA and release. • Propagermanium inhibited pro-inflammatory microglia polarization. • Propagermanium downregulated p-STAT1 expression in BV2 cells. [ABSTRACT FROM AUTHOR]

• Supramolecular coordination complexes have made incredible strides in biomedical applications in recent years. • Through modulating the building blocks, the photophysical properties of supramolecular coordination complexes could be finely tuned. • The NIR bio-window provides more accurate imaging and photo-treatment option compared with traditional ultraviolet-visible region. In the past decade, the metallacycles/metallacages have attracted unremitting interest in biomedical fields, yet visual tracking of their in vivo delivery, targeting ability, biodistribution and therapeutic evaluation are still hampered by their short emission wavelengths. More recently, the near-infrared biochannel (NIR, 0.7–1.7 μm) especially the NIR-II region (1.0–1.7 μm) provides deeper tissue penetration and higher contrast than traditional UV–Vis region for in vivo imaging. In this context, we provide a comprehensive and systematic insight into the development of NIR metallacycles/metallacages for biomedical applications. Finally, we also discuss the challenges and prospects of NIR metallacycles/metallacages for future biomedical research and clinical translation. [ABSTRACT FROM AUTHOR]

• A dual-sensing response fluorescence probe for HClO and viscosity was developed. • The probe has the ability to accurately evaluate the level of cellular inflammation. • The probe may be a tool for diagnosing and monitoring abdominal aortic aneurysm. The evaluation of the inflammatory response in the abdominal aortic aneurysm (AAA) is a great challenge. Optical imaging probes enable us to detect and reveal the physiological and pathological functions of analytes of interest in a non-invasive and longitudinal manner at the molecular level. However, optical imaging probes usually use a single action mechanism, which is easy to produce false positive or false negative phenomenon, resulting inadequate accuracy and sensitivity. On the contrary, fluorescent probes with two interaction sensing mechanisms provide different fluorescence signals or amplify response signals, which is beneficial to track multiple analytes meantime or improve the selectivity and sensitivity of chemical sensors. In this work, a dual-sensing fluorescent probe (Vis-HClO) was successfully constructed by combining photoinduced electron transfer with torsional charge transfer (PET-TICT). The results show that only in the environment of high viscosity and the presence of hypochlorite (HClO), the PET and TICT of Vis-HClO are broken at the same time, thus releasing obvious red fluorescence. In addition, using QCy7 as a fluorescent group, not only gives the probe a large Stokes shift, reduces the crosstalk and self-absorption of excitation and emission spectra, but also its positively charged indole quaternary ammonium heterocycle can be used as a mitochondrial targeting group to improve the sensitivity of HClO detection. In the process of inflammation, the intracellular viscosity level and HClO content increase at the same time, while the viscosity changes are not obvious in other physiological or pathological processes such as oxidative stress, so as to ensure the accurate imaging analysis of the cellular inflammatory process. [ABSTRACT FROM AUTHOR]

The diagnostic, monitoring and therapeutic options for cancers currently remain limited. These limitations represent a large threat to human health. Adaptive immunity, which is dependent on diverse repertoires of B cell receptors (BCRs) and T cell receptors (TCRs), plays a critical role in the anti-tumor immune response. Modulation and surveillance of adaptive immunity has become a powerful weapon to combat cancers. Recently, the high-throughput sequencing of immune repertoire (HTS-IR) technology, which provides a robust tool for deep sequencing repertoires of BCRs or TCRs, has been applied in the development of tumor biomarkers and immunotherapeutics for cancers. This review will first provide an overview of the advancement of HTS-IR technology at the population-cell and single-cell levels. It will then provide a current summary of the applications of HTS-IR technology in the diagnosis and monitoring of minimal residual disease (MRD), focusing on immune reconstitution after the treatment of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in B/T-cell malignancies, and the precise detection of tumor-infiltrating lymphocytes (TILs) in non-B/T-cell malignancies. Finally, current advances of HTS-IR technology in cancer immunotherapeutic applications, such as therapeutic antibodies, CAR-T cell based-adoptive immunotherapies, and neoantigen-specific TCR-T cell-based adoptive immunotherapies, will be introduced. [ABSTRACT FROM AUTHOR]

• The importance of molecular imaging-guided Pt(II) metallacycles/metallacages chemotherapy, which can precisely provide powerful tools for monitoring and evaluating their biodistribution and therapy efficiency. • The importance of the combination of Pt(II) metallacycles/metallacages with phototherapy. The synergistic chemo-phototherapy demonstrated advantages to address the issues of chemotherapy. • The combination of chemo-phototherapy and imaging platform can be readily built from the Pt(II) metallacycles/metallacages, which could show huge potentials in molecular imaging, materials science, and biomedicine. Platinum-based coordination chemistry has laid the foundation for the development of numerous metal complexes and provoked their applications in cancer chemotherapy. It is noteworthy that Pt(II) metallacyles/metallacages formed through coordination-driven self-assembly exhibit improved optical properties and superior anticancer efficacies in comparison with their precursors. To this end, the employment of metallacycles/metallacages as chemotherapy agents, imaging contrasts and multifunctional theranostic platforms has attracted tremendous attention. In this context, we provide an insight into the progression of Pt(II) metallacycles/metallacages from mono-chemotherapeutic agents to versatile imaging contrasts and theranostic platforms. [ABSTRACT FROM AUTHOR]

• A LRET-based fluorescent probe based on UCNPs and carbon dots was prepared. • Fluorescence assay of CA125 was successfully performed using UCNPs/CDs based probe. • High performances were obtained for fluorescence assay of CA125 even in serum samples. CA125 is the most widely used biomarker for the early detection of ovarian cancer. Luminescence resonance energy transfer (LRET)-based probes show pronounced specificity and simplicity for CA125 detection, but they suffer from strong interference from autofluorescence of biosamples. To resolve this problem, near-infrared (NIR)-excitable upconversion nanoparticles (UCNPs) was employed as energy donor to fabricate CA125 biosensor. Carbon dots (CDs) were utilized as energy acceptor for the overlap between the upconversion luminescence (UCL) spectrum of UCNPs and the absorption spectrum of CDs. Aptamer-modified UCNPs were combined with CDs through π-π stacking interaction, which triggered the LRET process and induce UCL quenching with a high quenching efficiency of up to 90%. In presence of CA125, the formation of CA125-aptamer complex blocked the π-π stacking and recovered UCL. The UCL intensity increased linearly with the logarithm of CA125 concentration in the range from 0.01 to 100 U·mL−1. A detection limit of 9.0 × 10−3 U·mL−1 was obtained. This probe is also available for CA125 detection in human serum and may be a useful tool for the early detection of ovarian cancer. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most malignant brain tumor. Owing to its highly infiltrative nature and restrictive blood-brain tumor barrier (BBTB), the current treatment strategies, including surgery and the following chemoradiotherapy, offer very low efficacy. Therefore, it is highly desirable to develop novel multifunctional theranostic agents for visualized diagnosis and treatment of GBM. In this work, a phototheranostic nanoprobe (CH4T@MOF-PEG-AE), constructed of Fe-based metal-organic framework (MOF) nanoparticles loaded with a small-molecule near-infrared II (NIR-II) fluorophore (CH4T), is rationally designed and modified with tumor-targeting AE105 peptide for efficiently targeting the over-expressed urokinase Plasminogen Activator Receptor (uPAR) on GBM. The nanoplatform combines advantages of high penetration depth of magnetic resonance (MR) imaging with high detection sensitivity and spatiotemporal resolution of NIR-II fluorescence imaging, enabling it to diagnose and delineate GBM accurately. Besides, in vivo studies reveal that CH4T@MOF-PEG-AE can realize MR/NIR-II imaging-guided photothermal therapy (PTT), achieving successful ablation of U87MG tumors. More importantly, the nanoprobes can efficiently transport across the BBTB facilitated by active tumor-targeting and enrich in the orthotopic GBM tumors, being capable of guiding the surgical resection of GBM via real-time intraoperative NIR-II imaging. Our work provides new insights into developing theranostic nanoplatforms for efficient diagnosis and treatment of GBM. Unlabelled Image • Glioblastoma targeted phototheranostic metal-organic framework nanoprobes were designed and fabricated. • Diagnostic magnetic resonance and near-infrared II dual-modal imaging of glioblastoma was successfully realized. • The nanoprobes exhibited highly effective image-guided photothermal therapy of glioblastoma. • The surgical resection of orthotopic glioblastoma was performed with the nanoprobe-based near-infrared II imaging guidance. [ABSTRACT FROM AUTHOR]

• ReS 2 nanosheets were exfoliated with assistance of DMimBr ionic liquid. • Photoelectrochemical charactersitics of ReS 2 nanosheets were investigated. • Sandwich-type PEC immunosensor based on ReS 2 nanosheets was fabricated. • High-performance determination of CEA was achieved. Photoelectrochemical (PEC) sensing system has received much more attention as a powerful strategy for detecting trace substances. Herein, a sandwich-type PEC immunosensor constructed by two-dimension rhenium disulfite nanosheets (2D-ReS 2) was developed for high-performance detection of carcinoembryonic antigen (CEA). 2D-ReS 2 was facilely exfoliated from bulk crystals by ultrasonication in a mixture of 1,3-di-(3-mercaptopropyl)-imidazolium bromide (DMimBr) ionic liquid and alcohol. Then, ReS 2 nanosheets were modified onto a glassy carbon electrode surface to construct an interface for fabricating a sandwich-type PEC immunosensing platform which has been accomplished by successive immobilizing anti-CEA antibody (Ab1), binding CEA and capturing the alkaline phosphatase labeled CEA antibody (ALP-Ab2). The introduced alkaline phosphatase can efficiently catalyze vitamin C magnesium phosphate to afford ascorbic acid (AA). Ascorbic acid can serve as an electron donor to capture holes photogenerated from ReS 2 nanosheets to produce photocurrent signal for CEA detection. The PEC immunosensor shows superior stability, selectivity, sensitivity, and accuracy for CEA determination. An extremely low detection limit of 0.468 pg mL−1 with a broad linear range of 0.0005 ∼ 10.0 ng mL−1 can be obtained for CEA determination. The PEC immunosensor can be applied for determining CEA in human serum samples with good selectivity and accuracy, demonstrating promising potential in biomedical analysis. [ABSTRACT FROM AUTHOR]

Background: Inhibition of p38 MAPK signalling leads to glioblastoma multiform (GBM) tumourigenesis. Nevertheless, the molecular mechanism that induces p38 MAPK signalling pathway silencing during GBM genesis has yet to be determined. Identifying new factors that can regulate p38 MAPK signalling is important for tumour treatment. Methods: Flow cytometry, TUNEL assays, immunofluorescence, JC-1 assays, and western blot analyses were used to detect the apoptosis of GBM cells. The specific methods used to detect autophagy levels in GBM cells were western blot analysis, LC3B protein immunofluorescence, LC3B puncta assays and transmission electron microscopy. The functions of these critical molecules were further confirmed in vivo by intracranial xenografts in nude mice. Tumour tissue samples and clinical information were used to identify the correlation between RND2 and p62 and LC3B expression, survival time of patients, and tumour volumes in clinical patients. Results: By summarizing data from the TCGA database, we found that expression of the small GTPase RND2 was significantly increased in human glioblastomas. Our study demonstrated that RND2 functions as an endogenous repressor of the p38 MAPK phosphorylation complex. RND2 physically interacted with p38 and decreased p38 phosphorylation, thereby inhibiting p38 MAPK signalling activities. The forced expression of RND2 repressed p38 MAPK signalling, which inhibited glioblastoma cell autophagy and apoptosis in vitro and induced tumour growth in the xenografted mice in vivo. By contrast, the downregulation of RND2 enhanced p38 MAPK signalling activities and promoted glioma cell autophagy and apoptosis. The inhibition of p38 phosphorylation abolished RND2 deficiency-mediated GBM cell autophagy and apoptosis. Most importantly, our study found that RND2 expression was inversely correlated with patient survival time and was positively correlated with tumour size. Conclusions: Our findings revealed a new function for RND2 in GBM cell death and offered mechanistic insights into the inhibitory effects of RND2 with regard to the regulation of p38 MAPK activation. [ABSTRACT FROM AUTHOR]

Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life. Many stroke victims are left with long-term neurological dysfunction, which adversely affects the well-being of the individual and the broader socioeconomic impact. Currently, post-stroke brain dysfunction is a major and difficult area of treatment. Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autism, refractory depression, epilepsy, and Alzheimer's disease. It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as altering neurotransmitters and the plasticity of central neurons. In animal models of acute ischemic stroke, vagus nerve stimulation has been shown to reduce infarct size, reduce post-stroke neurological damage, and improve learning and memory capacity in rats with stroke by reducing the inflammatory response, regulating blood-brain barrier permeability, and promoting angiogenesis and neurogenesis. At present, vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation. Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in improving upper limb motor and cognitive abilities in stroke patients. Further clinical studies have shown that non-invasive vagus nerve stimulation, including ear/cervical vagus nerve stimulation, can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect. In this paper, we first describe the multiple effects of vagus nerve stimulation in stroke, and then discuss in depth its neuroprotective mechanisms in ischemic stroke. We go on to outline the results of the current major clinical applications of invasive and non-invasive vagus nerve stimulation. Finally, we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends. We believe that vagus nerve stimulation, as an effective treatment for stroke, will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Background: Neuronal apoptosis plays an essential role in the pathogenesis of brain injury after subarachnoid hemorrhage (SAH). BAP1 (BRCA1-associated protein 1) is considered to exert pro-apoptotic effects in multiple diseases. However, evidence supporting the effect of BAP1 on the apoptotic response to SAH is lacking. Therefore, we aimed to confirm the role of BAP1 in SAH-induced apoptosis., Methods: Enzyme-linked immunosorbent assay (ELISA) was used to detect BAP1 expression in the cerebrospinal fluid. Endovascular perforation was performed in mice to induce SAH. Lentiviral short hairpin RNA targeting BAP1 mRNA was transduced into the ipsilateral cortex of mice with SAH to investigate the role of BAP1 in neuronal damage. Luciferase and coimmunoprecipitation assays were performed to investigate the mechanism through which BAP1 participates in hemin-induced SAH., Results: First, BAP1 expression was upregulated in the cerebrospinal fluid of patients with SAH and positively associated with unfavorable outcomes. ATF2 (activating transcription factor-2) then regulated BAP1 expression by binding to the BAP1 promoter. In addition, BAP1 overexpression enhanced P53 activity and stability by reducing P53 proteasome-mediated degradation. Subsequently, elevated P53 promoted neuronal apoptosis via the P53 pathway. Inhibition of the neuronal BAP1/P53 axis significantly reduced neurological deficits and neuronal apoptosis and improved neurological dysfunction in mice after SAH., Conclusions: Our results suggest that the neuronal ATF2/BAP1 axis exerts a brain-damaging effect by modulating P53 activity and stability and may be a novel therapeutic target for SAH., Competing Interests: None.

Targeting Ca 2+ /calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pu, Feng, Gu, Smerin, Jian, Xiong and Wei.)

Ischemic stroke, a disease with high mortality and disability rate worldwide, currently has no effective treatment. The systemic inflammation response to the ischemic stroke, followed by immunosuppression in focal neurologic deficits and other inflammatory damage, reduces the circulating immune cell counts and multiorgan infectious complications such as intestinal and gut dysfunction dysbiosis. Evidence showed that microbiota dysbiosis plays a role in neuroinflammation and peripheral immune response after stroke, changing the lymphocyte populations. Multiple immune cells, including lymphocytes, engage in complex and dynamic immune responses in all stages of stroke and may be a pivotal moderator in the bidirectional immunomodulation between ischemic stroke and gut microbiota. This review discusses the role of lymphocytes and other immune cells, the immunological processes in the bidirectional immunomodulation between gut microbiota and ischemic stroke, and its potential as a therapeutic strategy for ischemic stroke., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Stroke is the fifth leading cause of death worldwide, and the functional status of the gut plays a key role in patients' prognosis. Recent publications have explored the gut association with stroke, but few articles have been published that specifically address a comprehensive bibliometric analysis of the gut microbiota and its association with stroke. To address this gap, we used bibliometric methods to examine the landscape of research concerning the gut and stroke over approximately two decades, utilizing the Web of Science Core Collection (WoSCC). On November 1, 2022, a search was conducted for English-language articles published between 2002 and 2022, with only including original articles. Visual and statistical analyses were performed using CiteSpace, VOSviewer, and Bibliometrix 4.1.0 Package. After screening relevant articles, the results revealed that the number of articles published in this field has progressively increased during the last two decades. In particular, the total number of publications rapidly increased year by year from 2014. Among them, China ranked first in the world with a total of 227 publications. Authorship analysis highlighted Wang Z as the most prolific author, with 18 publications and an H-index of 14, highlighting significant contributions to this field. Meanwhile, the Southern Medical University of China was identified as the most productive institution. Moreover, analysis of keywords revealed that 'cerebral ischemia', 'intestinal microbiota', 'gut microbiota', and 'trimethylamine N-oxide' were popular topics searched, and research on the relationship between stroke and the gut continues to be a research hotspot. In summary, this study presents an overview of the progress and emerging trends in research on the relationship between stroke and gut health over the past two decades, providing a valuable resource for researchers aiming to understand the current state of the field and identify potential directions for future studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Ferroptosis is a form of non-apoptotic programmed cell death, and its mechanisms mainly involve the accumulation of lipid peroxides, imbalance in the amino acid antioxidant system, and disordered iron metabolism. The primary organelle responsible for coordinating external challenges and internal cell demands is the endoplasmic reticulum, and the progression of inflammatory diseases can trigger endoplasmic reticulum stress. Evidence has suggested that ferroptosis may share pathways or interact with endoplasmic reticulum stress in many diseases and plays a role in cell survival. Ferroptosis and endoplasmic reticulum stress may occur after ischemic stroke. However, there are few reports on the interactions of ferroptosis and endoplasmic reticulum stress with ischemic stroke. This review summarized the recent research on the relationships between ferroptosis and endoplasmic reticulum stress and ischemic stroke, aiming to provide a reference for developing treatments for ischemic stroke.

Autophagy has been described to be both protective and pathogenic in cerebral ischemia/reperfusion (I/R) injury. The underlying association between autophagy and ferroptosis in ischemic stroke has not yet been clearly investigated. The purpose of this study was to explore the role of autophagy-related gene 5 (ATG5) in experimental ischemic stroke. After injection of ATG5 shRNA lentivirus, mice underwent surgery for transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. The infarct volume, neurological function, apoptosis, reactive oxygen species (ROS), autophagy, and ferroptosis levels were evaluated. After MCAO, ATG5-knockdown mice had a smaller infarct size and fewer neurological deficits than wild-type mice. The levels of apoptosis and ROS in ischemic mouse brains were alleviated through ATG5 knockdown. The expression of LC3 I/II was reduced through ATG5 knockdown after MCAO. Additionally, the expression of beclin1 and LC3 II was increased after I/R, but the increase was counteracted by preconditioning with ATG5 knockdown. After ischemic stroke, the levels of Fe 2+ and malondialdehyde (MDA) were increased, but they were reduced by ATG5 knockdown. Similarly, the expression of glutathione peroxidase 4 (GPX4) and glutathione (GSH) was decreased by I/R but elevated by ATG5 knockdown. The present study shows that ATG5 knockdown attenuates autophagy-induced ferroptosis, which may offer a novel potential approach for ischemic stroke treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis. Therefore, neural regeneration may be a promising target for treatment of many neurological illnesses. The regenerative capacity of adult neural stem cells can be characterized by two states: quiescent and active. Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool. Active adult neural stem cells are characterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits. This review focuses on differences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis. Furthermore, we discuss the physiological significance and underlying advantages of these differences. Due to the limited number of adult neural stem cells studies, we referred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms., Competing Interests: None

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Chen, Wang, Zhu, Gu, Li, Xiong, Chen and Jian.)

Postoperative cognitive dysfunction (POCD) is a cluster of cognitive problems that may arise after surgery. POCD symptoms include memory loss, focus inattention, and communication difficulties. Inflammasomes, intracellular multiprotein complexes that control inflammation, may have a significant role in the development of POCD. It has been postulated that the NLRP3 inflammasome promotes cognitive impairment by triggering the inflammatory response in the brain. Nevertheless, there are many gaps in the current literature to understand the underlying pathophysiological mechanisms and develop future therapy. This review article underlines the limits of our current knowledge about the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome and POCD. We first discuss inflammasomes and their types, structures, and functions, then summarize recent evidence of the NLRP3 inflammasome's involvement in POCD. Next, we propose a hypothesis that suggests the involvement of inflammasomes in multiple organs, including local surgical sites, blood circulation, and other peripheral organs, leading to systemic inflammation and subsequent neuronal dysfunction in the brain, resulting in POCD. Research directions are then discussed, including analyses of inflammasomes in more clinical POCD animal models and clinical trials, studies of inflammasome types that are involved in POCD, and investigations into whether inflammasomes occur at the surgical site, in circulating blood, and in peripheral organs. Finally, we discuss the potential benefits of using new technologies and approaches to study inflammasomes in POCD. A thorough investigation of inflammasomes in POCD might substantially affect clinical practice.

Objective: The mechanisms underpinning Moyamoya disease (MMD) remain unclear, and effective biomarkers remain unknown. The purpose of this study was to identify novel serum biomarkers of MMD., Methods: Serum samples were collected from 23 patients with MMD and 30 healthy controls (HCs). Serum proteins were identified using tandem tandem-mass-tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) in the serum samples were identified using the SwissProt database. The DEPs were assessed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, Gene Ontology (GO), and protein-protein interaction (PPI) networks, and hub genes were identified and visualized using Cytoscape software. Microarray datasets GSE157628, GSE189993, and GSE100488 from the Gene Expression Omnibus (GEO) database were collected. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were identified, and miRNA targets of DEGs were predicted using the miRWalk3.0 database. Serum apolipoprotein E (APOE) levels were compared in 33 MMD patients and 28 Moyamoya syndrome (MMS) patients to investigate the potential of APOE to be as an MMD biomarker., Results: We identified 85 DEPs, of which 34 were up- and 51 down-regulated. Bioinformatics analysis showed that some DEPs were significantly enriched in cholesterol metabolism. A total of 1105 DEGs were identified in the GSE157628 dataset (842 up- and 263 down-regulated), whereas 1290 were identified in the GSE189993 dataset (200 up- and 1,090 down-regulated). The APOE only overlaps with the upregulated gene expression in Proteomic Profiling and in GEO databases. Functional enrichment analysis demonstrated that APOE was associated with cholesterol metabolism. Moreover, 149 miRNAs of APOE were predicted in the miRWalk3.0 database, and hsa-miR-718 was the only DE-miRNA overlap identified in MMD samples. Serum APOE levels were significantly higher in patients with MMD than in those without. The performance of APOE as an individual biomarker to diagnose MMD was remarkable., Conclusions: We present the first description of the protein profile of patients with MMD. APOE was identified as a potential biomarker for MMD. Cholesterol metabolism was found to potentially be related to MMD, which may provide helpful diagnostic and therapeutic insights for MMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Xu, Sun, Duan, Xiao, Ren, Zhou, Yan, Li, Xiong and Zeng.)

Recently, newly developed carbon-based nanomaterials known as carbon dots (CDs) have generated significant interest in nanomedicine. However, current knowledge regarding CD research in the biomedical field is still lacking. An overview of the most recent development of CDs in biomedical research is given in this review article. Several crucial CD applications, such as biosensing, bioimaging, cancer therapy, and antibacterial applications, are highlighted. Finally, CD-based biomedicine's challenges and future potential are also highlighted to enrich biomedical researchers' knowledge about the potential of CDs and the need for overcoming various technical obstacles.

Although metallacycle-based supramolecular photosensitizers (PSs) have attracted increasing attention in biomedicine, their clinical translation is still hindered by their inherent dark toxicity. Herein, we report what to our knowledge is the first example of a molecular engineering approach to building blocks of metallacycles for constructing a series of supramolecular PSs (RuA-RuD), with the aim of simultaneously reducing dark toxicity and enhancing phototoxicity, and consequently obtaining high phototoxicity indexes (PI). Detailed in vitro investigations demonstrate that RuA-RuD display high cancer cellular uptake and remarkable antitumor activity even under hypoxic conditions. Notably, RuD exhibited no dark toxicity and displayed the highest PI value (≈406). Theoretical calculations verified that RuD has the largest steric hindrance and the lowest singlet-triplet energy gap (ΔE ST , 0.61 eV). Further in vivo studies confirmed that RuD allows safe and effective phototherapy against A549 tumors., (© 2023 Wiley-VCH GmbH.)

Abstract: Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective treatment. Mild cognitive impairment (MCI) is an early disease that may progress to AD. The effective diagnosis of AD and MCI in the early stage has important clinical significance., Methods: To this end, this paper proposed a hypergraph-based netNMF (HG-netNMF) algorithm for integrating structural magnetic resonance imaging (sMRI) of AD and MCI with corresponding gene expression profiles., Results: Hypergraph regularization assumes that regions of interest (ROIs) and genes were located on a non-linear low-dimensional manifold and can capture the inherent prevalence of two modalities of data and mined high-order correlation features of the two data. Further, this paper used the HG-netNMF algorithm to construct a brain structure connection network and a protein interaction network (PPI) with potential role relationships, mine the risk (ROI) and key genes of both, and conduct a series of bioinformatics analyses., Conclusion: Finally, this paper used the risk ROI and key genes of the AD and MCI groups to construct diagnostic models. The AUC of the AD group and MCI group were 0.8 and 0.797, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhuang, Tian, Xiong, Li, Chen, Chen, Chen and Li.)

Introduction: This article aimed to investigate the effects of the endoscopic-assisted microsurgery technique on the resection of large (Koos grade IV) vestibular schwannoma (VS) and provide a prognosis analysis of the patients., Methods: A retrospective analysis of the use of the endoscopic-assisted microsurgery technique in 16 cases of large vestibular schwannoma surgery was carried out. Intraoperative nerve electrophysiological monitoring was conducted to explore the effect of neuroendoscopy on the resection of internal auditory canal tumors, protection of the facial nerve, and minimizing postoperative complications., Results: Tumors were completely removed in all 16 cases, and the facial nerve was anatomically preserved in 14 cases (87.5%). There was no postoperative cerebrospinal fluid leakage and no intracranial infection complications occurred.Following the House-Brackmann (H-B) grading system, post-operative facial nerve function was grade I in 5 cases, grade II in 6 cases, grade III in 3 cases, and grade V in 2 cases. As a result, the preservation rate of facial nerve function (H-B grade I-II) was 68.8%. All 16 patients were followed up for 3 to 24 months, and no tumor recurrence was found on enhanced MRI., Discussion: Using the endoscopic-assisted microsurgery technique in the retrosigmoid approach has many advantages over the microscopic-only approach. When compared to the microscopy-only approach, the endoscope can provide a wide-angle surgical field superior to that of a microscope in areas such as the internal auditory canal in the resection of large VS, minimize iatrogenic injuries, ensure complete removal of internal auditory canal tumors, and well as reducing postoperative complications such as cerebrospinal fluid leakage and the loss of facial and auditory nerve functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Xiong, Jian and Du.)

Cerebral ischemic stroke is characterized by acute ischemia in a certain part of the brain, which leads to brain cells necrosis, apoptosis, ferroptosis, pyroptosis, etc. At present, there are limited effective clinical treatments for cerebral ischemic stroke, and the recovery of cerebral blood circulation will lead to cerebral ischemia-reperfusion injury (CIRI). Cerebral ischemic stroke involves many pathological processes such as oxidative stress, inflammation, and mitochondrial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), as one of the most critical antioxidant transcription factors in cells, can coordinate various cytoprotective factors to inhibit oxidative stress. Targeting Nrf2 is considered as a potential strategy to prevent and treat cerebral ischemia injury. During cerebral ischemia, Nrf2 participates in signaling pathways such as Keap1, PI3K/AKT, MAPK, NF-κB, and HO-1, and then alleviates cerebral ischemia injury or CIRI by inhibiting oxidative stress, anti-inflammation, maintaining mitochondrial homeostasis, protecting the blood-brain barrier, and inhibiting ferroptosis. In this review, we have discussed the structure of Nrf2, the mechanisms of Nrf2 in cerebral ischemic stroke, the related research on the treatment of cerebral ischemia through the Nrf2 signaling pathway in recent years, and expounded the important role and future potential of the Nrf2 pathway in cerebral ischemic stroke.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pang, Li, Zhang, Wang, Lang, Han, Liu, Xiong, Gu and Wu.)

Liver hepatocellular carcinoma (LIHC) is a malignancy with a high mortality and morbidity rate worldwide. However, the pathogenesis of LIHC has still not been thoroughly studied. Transmembrane and coiled-coil domains 3 (TMCO3) encodes a monovalent cation, a member of the proton transducer 2 (CPA2) family of transporter proteins. In the present study, TMCO3 expression and its relationship with cancer prognosis, as well as its immunological role in LIHC were studied by bioinformatic analysis. We found the significant overexpression of TMCO3 in LIHC in the TCGA, HCCDB, and GEO databases. In LIHC patients, high TMCO3 expression was related to poorer overall survival (OS) and TMCO3 had good predictive accuracy for prognosis. Moreover, TMCO3 was linked to the infiltrates of certain immune cells in LIHC. The correlation of TMCO3 with immune checkpoints was also revealed. Moreover, patients with LIHC with low TMCO3 expression showed a better response to immune checkpoint blockade (ICB) than those with LIHC with high TMCO3 expression. GO and KEGG enrichment analyses indicated that TMCO3 was probably involved in the microtubule cytoskeleton organization involved in mitosis, small GTPase mediated signal transduction, and TGF-β pathway. In conclusion, TMCO3 may be a potential biomarker for LIHC prognosis and immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Zhu, Feng, Wang, Ye and Xiong.)

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders of the central nervous system (CNS). Increasing evidence supports the view that dysfunction of innate immune cells initiated by accumulated and misfolded proteins plays essential roles in the pathogenesis and progression of these diseases. The TLR family was found to be involved in the regulation of microglial function in the pathogenesis and progression of AD or PD, making it as double-edged sword in these diseases. Altered function of peripheral innate immune cells was found in AD and PD and thus contributed to the development and progression of AD and PD. Alteration of different subsets of T cells was found in the peripheral blood and CNS in AD and PD. The CNS-infiltrating T cells can exert both neuroprotective and neurotoxic effects in the pathogenesis and progression. Here, we review recent evidences for the roles of innate and adaptive immune cells in the pathogenesis and progression of AD and PD., Competing Interests: There are no conflicts of interest to disclose relevant to this paper., (Copyright © 2022 Boyuan Huang et al.)