De novo identification of mammalian ciliary motility proteins using cryo-EM.

Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned periodically by microtubule inner proteins (MIPs). Here we present an atomic model of the 48-nm repeat of a mammalian DMT, derived from a cryoelectron microscopy (cryo-EM) map of the complex isolated from bovine respiratory cilia. The structure uncovers principles of doublet microtubule organization and features specific to vertebrate cilia, including previously unknown MIPs, a luminal bundle of tektin filaments, and a pentameric dynein-docking complex. We identify a mechanism for bridging 48- to 24-nm periodicity across the microtubule wall and show that loss of the proteins involved causes defective ciliary motility and laterality abnormalities in zebrafish and mice. Our structure identifies candidate genes for diagnosis of ciliopathies and provides a framework to understand their functions in driving ciliary motility.

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.

Sphingosine kinases regulate ER contacts with late endocytic organelles and cholesterol trafficking.

Membrane contact sites (MCS), close membrane apposition between organelles, are platforms for interorganellar transfer of lipids including cholesterol, regulation of lipid homeostasis, and co-ordination of endocytic trafficking. Sphingosine kinases (SphKs), two isoenzymes that phosphorylate sphingosine to the bioactive sphingosine-1-phosphate (S1P), have been implicated in endocytic trafficking. However, the physiological functions of SphKs in regulation of membrane dynamics, lipid trafficking and MCS are not known. Here, we report that deletion of SphKs decreased S1P with concomitant increases in its precursors sphingosine and ceramide, and markedly reduced endoplasmic reticulum (ER) contacts with late endocytic organelles. Expression of enzymatically active SphK1, but not catalytically inactive, rescued the deficit of these MCS. Although free cholesterol accumulated in late endocytic organelles in SphK null cells, surprisingly however, cholesterol transport to the ER was not reduced. Importantly, deletion of SphKs promoted recruitment of the ER-resident cholesterol transfer protein Aster-B (also called GRAMD1B) to the plasma membrane (PM), consistent with higher accessible cholesterol and ceramide at the PM, to facilitate cholesterol transfer from the PM to the ER. In addition, ceramide enhanced in vitro binding of the Aster-B GRAM domain to phosphatidylserine and cholesterol liposomes. Our study revealed a previously unknown role for SphKs and sphingolipid metabolites in governing diverse MCS between the ER network and late endocytic organelles versus the PM to control the movement of cholesterol between distinct cell membranes.

Yin Yang 1 controls cerebellar astrocyte maturation.

Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.

Recent advances in BCRP-induced breast cancer resistance treatment with marine-based natural products.

Breast cancer is the prominent cause of cancer-related death in women globally in terms of incidence and mortality. Despite, recent advances in the management of breast cancer, there are still a lot of cases of resistance to medicines, which is currently one of the biggest problems faced by researchers across the globe. Out of several mechanisms, breast cancer resistance protein (BCRP) arbitrated drug resistance is a major concern. Hormonal, cytotoxic and immunotherapeutic drugs are used in the systemic therapy of breast cancer. It is vital to choose drugs based on the clinical and molecular attributes of the tumor to provide better treatment with greater efficacy and minimal harm. Given the aforementioned necessity, the use of marine flora in treating breast cancer cannot be neglected. The scientists also stressed the value of marine-derived goods in avoiding breast cancer resistance. Future research into the identification of anticancer drugs will heavily draw upon the marine environment's ample supply of marine-derived natural products (MNPs), which have a wide range of biological functions. Cell cycle arrest, induction of apoptosis and anti-angiogenic, anti-proliferative and anti-metastasis actions are all part of their processes. The overview of breast cancer, the mechanisms underlying its resistance, recent clinical trials based on marine-derived products in breast cancer and the use of marine products in the treatment of breast cancer are highlighted in this paper. Moreover, the authors also emphasised the importance of marine-derived products in preventing breast cancer resistance.

Molecular Hybridization of Alkaloids Using 1,2,3-Triazole-Based Click Chemistry.

Alkaloids found in multiple species, known as 'driver species', are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click chemistry is a highly efficient and versatile reaction targeting specific areas, making it a valuable tool for creating complex natural products and diverse molecular structures. It has been used to create hybrid alkaloids that address their limitations and serve as potential drugs that mimic natural products. In this review, we highlight the recent advancements made in modifying alkaloids using click chemistry and their potential medicinal applications. We discuss the significance, current trends, and prospects of click chemistry in natural product-based medicine. Furthermore, we have employed computational methods to evaluate the ADMET properties and drug-like qualities of hybrid molecules.

Neuronal contact upregulates astrocytic sphingosine-1-phosphate receptor 1 to coordinate astrocyte-neuron cross communication.

Astrocytes, the most abundant glial cells in the mammalian brain, directly associate with and regulate neuronal processes and synapses and are important regulators of brain development. Yet little is known of the molecular mechanisms that control the establishment of astrocyte morphology and the bi-directional communication between astrocytes and neurons. Here we show that neuronal contact stimulates expression of S1PR1, the receptor for the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P), on perisynaptic astrocyte processes and that S1PR1 drives astrocyte morphological complexity and morphogenesis. Moreover, the S1P/S1PR1 axis increases neuronal contact-induced expression of astrocyte secreted synaptogenic factors SPARCL1 and thrombospondin 4 that are involved in neural circuit assembly. Our findings have uncovered new functions for astrocytic S1PR1 signaling in regulation of bi-directional astrocyte-neuron crosstalk at the nexus of astrocyte morphogenesis and synaptogenesis.

Influence of the Gut Microbiota on the Development of Neurodegenerative Diseases.

Neurodegenerative disorders are marked by neuronal death over time, causing a variety of cognitive and motor dysfunctions. Protein misfolding, neuroinflammation, and mitochondrial and protein clearance system dysfunction have all been identified as common pathways leading to neurodegeneration in recent decades. An altered microbiome of the gut, which is considered to play a central role in diseases as well as health, has recently been identified as another potential feature seen in neurodegenerative disorders. An array of microbial molecules that are released in the digestive tract may mediate gut-brain connections and permeate many organ systems, including the nervous system. Furthermore, recent findings from clinical as well as preclinical trials suggest that the microbiota of the gut plays a critical part in gut-brain interplay and that a misbalance in the composition of the gut microbiome may be linked to the etiology of neurological disorders (majorly neurodegenerative health problems); the underlying mechanism of which is still unknown. The review aims to consider the association between the microbiota of the gut and neurodegenerative disorders, as well as to add to our understanding of the significance of the gut microbiome in neurodegeneration and the mechanisms that underlie it. Knowing the mechanisms behind the gut microbiome's role and abundance will provide us with new insights that could lead to novel therapeutic strategies.

Evaluation of the Pharmacokinetics of the Pancreastatin Inhibitor PSTi8 Peptide in Rats: Integration of In Vitro and In Vivo Findings.

PSTi8 is a pancreastatin inhibitory peptide that is effective in the treatment of diabetic models. This study investigates the pharmacokinetic (PK) properties of PSTi8 in Sprague Dawley rats, for the first time. In vitro and in vivo PK studies were performed to evaluate the solubility, stability in plasma and liver microsomes, plasma protein binding, blood-plasma partitioning, bioavailability, dose proportionality, and gender difference in PK. Samples were analyzed using the validated LC-MS/MS method. The solubility of PSTi8 was found to be 9.30 and 25.75 mg/mL in simulated gastric and intestinal fluids, respectively. The protein binding of PSTi8 was estimated as >69% in rat plasma. PSTi8 showed high stability in rat plasma and liver microsomes and the blood-plasma partitioning was >2. The bioavailability of PSTi8 after intraperitoneal and subcutaneous administration was found to be 95.00 ± 12.15 and 78.47 ± 17.72%, respectively, in rats. PSTi8 showed non-linear PK in dose proportionality studies, and has no gender difference in the PK behavior in rats. The high bioavailability of PSTi8 can be due to high water solubility and plasma protein binding, low clearance and volume of distribution. Our in vitro and in vivo findings support the development of PSTi8 as an antidiabetic agent.

Appraisal of the Antioxidant Activity, Polyphenolic Content, and Characterization of Selected Himalayan Herbs: Anti-Proliferative Potential in HepG2 Cells.

Natural antioxidants derived from plants have played a vital role in preventing a wide range of human chronic conditions and provide novel bioactive leads for investigators in pharmacotherapy discovery. This work was designed to examine the ethnopharmacological role of Urtica dioica (UD), Capsella bursa-pastoris (CBP), and Inula racemosa (IR). The total phenolic and flavonoid contents (TPC and TFC) were illustrated through colorimetric assays, while the antioxidant activity was investigated through DPPH and ABTS assays. The evaluation of phytochemicals by FT-IR of UD and CBP revealed high contents of aliphatic amines, while IR showed a major peak for ketones. The antioxidant activity, TPC and TFC were highest in the ethanol extract of UD, followed by CBP, and IR showed the lowest activity. All of the extracts revealed significant antioxidant capacities along a dosage gradient. Through a HPLC analysis at a wavelength of 280 nm, UD leaves demonstrated an intense peak of quercetin, and the peak for rutin was less intense. CBP (whole plant), instead, demonstrated a major yield of rutin, and a peak for quercetin was not observed in CBP. IR (rhizomes) showed both quercetin and rutin. All of the extracts were significantly cytotoxic to HepG2 cells after 48 h with the trend IR > UD > CBP. The outcomes of this study may be effective in the selection of specific plants as realistic sources of the bioactive components that might be useful in the nutraceutical progression and other biomedical efficacies.

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc1/b6f.

Oxygenic respiration and photosynthesis based on quinone redox reactions face a danger of wasteful energy dissipation by diversion of the productive electron transfer pathway through the generation of reactive oxygen species (ROS). Nevertheless, the widespread quinone oxido-reductases from the cytochrome bc family limit the amounts of released ROS to a low, perhaps just signaling, level through an as-yet-unknown mechanism. Here, we propose that a metastable radical state, nonreactive with oxygen, safely holds electrons at a local energetic minimum during the oxidation of plastohydroquinone catalyzed by the chloroplast cytochrome b6f This intermediate state is formed by interaction of a radical with a metal cofactor of a catalytic site. Modulation of its energy level on the energy landscape in photosynthetic vs. respiratory enzymes provides a possible mechanism to adjust electron transfer rates for efficient catalysis under different oxygen tensions.

Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone.

Preclinical Research & Development Withanolide A (WA), a steroidal lactone is a major bioactive constituent of Withania somnifera (L.) with remarkable neuropharmacological activity. In this study, we investigated the permeability, plasma protein binding (PPB), blood partitioning, intravenous (i.v.), and oral pharmacokinetics as well as i.v. tissue distribution (TD) of pure WA in a rat model. The PPB, RBCs partitioning, and permeability of WA were determined by Ultra Performance Liquid Chromatography (UPLC) method. However, the pharmacokinetics and TD of WA were evaluated by validated and sensitive liquid chromatography coupled mass spectrometry (LC-ESI-MS/MS) method. The PPB and permeability of WA were determined by equilibrium dialysis and parallel artificial membrane permeability assay method, respectively. The results demonstrated that WA has high PPB and passive permeability. Furthermore, WA was found to have fast equilibration between RBCs and plasma. Following i.v. (2 mg/kg) and per-oral (25 mg/kg) administration of WA, the max concentration (Cmax ) in plasma was found as 85.53 ± 6.54 and 48.04 ±5.78 ng/mL, respectively. The TD study results indicated that WA has a rapid and wide TD. The maximum concentration in various tissues was found in following order: Clung > Cliver > Ckidney ≈ Cspleen > Cheart > Cbrain . The preclinical in vitro, as well as pharmacokinetics and TD results, are anticipated to support the future preclinical and clinical application of WA.

Trans-membrane Signaling in Photosynthetic State Transitions: REDOX- AND STRUCTURE-DEPENDENT INTERACTION IN VITRO BETWEEN STT7 KINASE AND THE CYTOCHROME b6f COMPLEX.

Trans-membrane signaling involving a serine/threonine kinase (Stt7 in Chlamydomonas reinhardtii) directs light energy distribution between the two photosystems of oxygenic photosynthesis. Oxidation of plastoquinol mediated by the cytochrome b6f complex on the electrochemically positive side of the thylakoid membrane activates the kinase domain of Stt7 on the trans (negative) side, leading to phosphorylation and redistribution ("state transition") of the light-harvesting chlorophyll proteins between the two photosystems. The molecular description of the Stt7 kinase and its interaction with the cytochrome b6f complex are unknown or unclear. In this study, Stt7 kinase has been cloned, expressed, and purified in a heterologous host. Stt7 kinase is shown to be active in vitro in the presence of reductant and purified as a tetramer, as determined by analytical ultracentrifugation, electron microscopy, and electrospray ionization mass spectrometry, with a molecular weight of 332 kDa, consisting of an 83.41-kDa monomer. Far-UV circular dichroism spectra show Stt7 to be mostly α-helical and document a physical interaction with the b6f complex through increased thermal stability of Stt7 secondary structure. The activity of wild-type Stt7 and its Cys-Ser mutant at positions 68 and 73 in the presence of a reductant suggest that the enzyme does not require a disulfide bridge for its activity as suggested elsewhere. Kinase activation in vivo could result from direct interaction between Stt7 and the b6f complex or long-range reduction of Stt7 by superoxide, known to be generated in the b6f complex by quinol oxidation.

RelB/p50 complexes regulate cytokine-induced YKL-40 expression.

The secreted protein, YKL-40, has been proposed as a biomarker of a variety of human diseases characterized by ongoing inflammation, including chronic neurologic pathologies such as multiple sclerosis and Alzheimer's disease. However, inflammatory mediators and the molecular mechanism responsible for enhanced expression of YKL-40 remained elusive. Using several mouse models of inflammation, we now show that YKL-40 expression correlated with increased expression of both IL-1 and IL-6. Furthermore, IL-1 together with IL-6 or the IL-6 family cytokine, oncostatin M, synergistically upregulated YKL-40 expression in both primary human and mouse astrocytes in vitro. The robust cytokine-driven expression of YKL-40 in astrocytes required both STAT3 and NF-κB binding elements of the YKL-40 promoter. In addition, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IκBα. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-κB and instead required subunits RelB and p50. Mechanistically, we show that IL-1-induced RelB/p50 complex formation was further promoted by oncostatin M and that these complexes directly bound to the YKL-40 promoter. Moreover, we found that expression of RelB was strongly upregulated during inflammation in vivo and by IL-1 in astrocytes in vitro. We propose that IL-1 and the IL-6 family of cytokines regulate YKL-40 expression during sterile inflammation via both STAT3 and RelB/p50 complexes. These results suggest that IL-1 may regulate the expression of specific anti-inflammatory genes in nonlymphoid tissues via the canonical activation of the RelB/p50 complexes.

Polymer-Based Drug Delivery Systems for Cancer Therapeutics.

Chemotherapy together with surgery and/or radiotherapy are the most common therapeutic methods for treating cancer. However, the off-target effects of chemotherapy are known to produce side effects and dose-limiting toxicities. Novel delivery platforms based on natural and synthetic polymers with enhanced pharmacokinetic and therapeutic potential for the treatment of cancer have grown tremendously over the past 10 years. Polymers can facilitate selective targeting, enhance and prolong circulation, improve delivery, and provide the controlled release of cargos through various mechanisms, including physical adsorption, chemical conjugation, and/or internal loading. Notably, polymers that are biodegradable, biocompatible, and physicochemically stable are considered to be ideal delivery carriers. This biomimetic and bio-inspired system offers a bright future for effective drug delivery with the potential to overcome the obstacles encountered. This review focuses on the barriers that impact the success of chemotherapy drug delivery as well as the recent developments based on natural and synthetic polymers as platforms for improving drug delivery for treating cancer.

Metabolic and Phenotypic Changes Induced during N-Acetylglucosamine Signalling in the Fungal Pathogen Candida albicans.

The human commensal yeast Candida albicans is pathogenic and results in a variety of mucosal and deep tissue problems when the host is immunocompromised. Candida exhibits enormous metabolic flexibility and dynamic morphogenetic transition to survive under host niche environmental conditions and to cause virulence. The amino sugar N-acetylglucosamine (GlcNAc) available at the host infection sites, apart from acting as an extremely good carbon and nitrogen source, also induces cellular signalling in this pathogen. In C. albicans, GlcNAc performs multifaceted roles, including GlcNAc scavenging, GlcNAc import and metabolism, morphogenetic transition (yeast-hyphae and white-opaque switch), GlcNAc-induced cell death (GICD), and virulence. Understanding the molecular mechanism(s) involved in GlcNAc-induced cellular processes has become the main focus of many studies. In the current study, we focused on GlcNAc-induced metabolic changes associated with phenotypic changes. Here, we employed gas chromatography-mass spectrometry (GC-MS), which is a high-throughput and sensitive technology, to unveil global metabolomic changes that occur in GlcNAc vs. glucose grown conditions in Candida cells. The morphogenetic transition associated with metabolic changes was analysed by high-resolution field emission scanning electron microscopy (FE-SEM). Metabolite analysis revealed the upregulation of metabolites involved in the glyoxylate pathway, oxidative metabolism, and fatty acid catabolism to probably augment the synthesis of GlcNAc-induced hypha-specific materials. Furthermore, GlcNAc-grown cells showed slightly more sensitivity to amphotericin B treatment. These results all together provide new insights into the development of antifungal therapeutics for the control of candidiasis in humans.

Total wash elimination for solid phase peptide synthesis.

We present a process for solid phase peptide synthesis (SPPS) that completely eliminates all solvent intensive washing steps during each amino acid addition cycle. A key breakthrough is the removal of a volatile Fmoc deprotection base through bulk evaporation at elevated temperature while preventing condensation on the vessel surfaces with a directed headspace gas flushing. This process was demonstrated at both research and production scales without any impact on product quality and when applied to a variety of challenging sequences (up to 89 amino acids in length). The overall result is an extremely fast, high purity, scalable process with a massive waste reduction (up to 95%) while only requiring 10-15% of the standard amount of base used. This transformation of SPPS represents a step-change in peptide manufacturing process efficiency, and should encourage expanded access to peptide-based therapeutics.

Toxicological Profile of Polyethylene Terephthalate (PET) Microplastic in Ingested Drosophila melanogaster (Oregon R+) and Its Adverse Effect on Behavior and Development.

Microplastics are readily available in the natural environment. Due to the pervasiveness of microplastic pollution, its effects on living organisms necessitate further investigation. The size, time of exposure, and amount of microplastic particles appear to be the most essential factor in determining their toxicological effects, either organismal or sub-organismal. For our research work, we preferred to work on a terrestrial model organism Drosophila melanogaster (Oregon R+). Therefore, in the present study, we characterized 2-100 µm size PET microplastic and confirmed its accumulation in Drosophila, which allowed us to proceed further in our research work. At larger dosages, research on locomotory activities such as climbing, jumping, and crawling indicated a decline in physiological and neuromuscular functions. Our studies also determined retarded development in flies and decreased survival rate in female flies after exposure to the highest concentration of microplastics. These experimental findings provide insight into the possible potential neurotoxic effects of microplastics and their detrimental effects on the development and growth of flies.

Therapeutic Potential of Green-Engineered ZnO Nanoparticles on Rotenone-Exposed D. melanogaster (Oregon R+): Unveiling Ameliorated Biochemical, Cellular, and Behavioral Parameters.

Nanotechnology holds significant ameliorative potential against neurodegenerative diseases, as it can protect the therapeutic substance and allow for its sustained release. In this study, the reducing and capping agents of Urtica dioica (UD), Matricaria chamomilla (MC), and Murraya koenigii (MK) extracts were used to synthesize bio-mediated zinc oxide nanoparticles (ZnO-NPs) against bacteria (Staphylococcus aureus and Escherichia coli) and against rotenone-induced toxicities in D. melanogaster for the first time. Their optical and structural properties were analyzed via FT-IR, DLS, XRD, EDS, SEM, UV-Vis, and zeta potential. The antioxidant and antimicrobial properties of the fabricated ZnO-NPs were evaluated employing cell-free models (DPPH and ABTS) and the well diffusion method, respectively. Rotenone (500 µM) was administered to Drosophila third instar larvae and freshly emerged flies for 24-120 h, either alone or in combination with plant extracts (UD, MC, an MK) and their biogenic ZnO-NPs. A comparative study on the protective effects of synthesized NPs was undertaken against rotenone-induced neurotoxic, cytotoxic, and behavioral alterations using an acetylcholinesterase inhibition assay, dye exclusion test, and locomotor parameters. The findings revealed that among the plant-derived ZnO-NPs, MK-ZnO NPs exhibit strong antimicrobial and antioxidant activities, followed by UD-ZnO NPs and MC-ZnO NPs. In this regard, ethno-nano medicinal therapeutic uses mimic similar effects in D. melanogaster by suppressing oxidative stress by restoring biochemical parameters (AchE and proteotoxicity activity) and lower cellular toxicity. These findings suggest that green-engineered ZnO-NPs have the potential to significantly enhance outcomes, with the promise of effective therapies for neurodegeneration, and could be used as a great alternative for clinical development.

A complex of nuclear factor I-X3 and STAT3 regulates astrocyte and glioma migration through the secreted glycoprotein YKL-40.

Nuclear factor I-X3 (NFI-X3) is a newly identified splice variant of NFI-X that regulates expression of several astrocyte-specific markers, such as glial fibrillary acidic protein. Here, we identified a set of genes regulated by NFI-X3 that includes a gene encoding a secreted glycoprotein YKL-40. Although YKL-40 expression is up-regulated in glioblastoma multiforme, its regulation and functions in nontransformed cells of the central nervous system are widely unexplored. We find that expression of YKL-40 is activated during brain development and also differentiation of neural progenitors into astrocytes in vitro. Furthermore, YKL-40 is a migration factor for primary astrocytes, and its expression is controlled by both NFI-X3 and STAT3, which are known regulators of gliogenesis. Knockdown of NFI-X3 and STAT3 significantly reduced YKL-40 expression in astrocytes, whereas overexpression of NFI-X3 dramatically enhanced YKL-40 expression in glioma cells. Activation of STAT3 by oncostatin M induced YKL-40 expression in astrocytes, whereas expression of a dominant-negative STAT3 had a suppressive effect. Mechanistically, NFI-X3 and STAT3 form a complex that binds to weak regulatory elements in the YKL-40 promoter and activates transcription. We propose that NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression.