Deficiency of CAMSAP2 impairs olfaction and the morphogenesis of mitral cells.

In developing olfactory bulb (OB), mitral cells (MCs) remodel their dendrites to establish the precise olfactory circuit, and these circuits are critical for individuals to sense odors and elicit behaviors for survival. However, how microtubules (MTs) participate in the process of dendritic remodeling remains elusive. Here, we reveal that calmodulin-regulated spectrin-associated proteins (CAMSAPs), a family of proteins that bind to the minus-end of the noncentrosomal MTs, play a crucial part in the development of MC dendrites. We observed that Camsap2 knockout (KO) males are infertile while the reproductive tract is normal. Further study showed that the infertility was due to the severe defects of mating behavior in male mice. Besides, mice with loss-of-function displayed defects in the sense of smell. Furthermore, we found that the deficiency of CAMSAP2 impairs the classical morphology of MCs, and the CAMSAP2-dependent dendritic remodeling process is responsible for this defect. Thus, our findings demonstrate that CAMSAP2 plays a vital role in regulating the development of MCs.

CAMSAP1 role in orchestrating structure and dynamics of manchette microtubule minus-ends impacts male fertility during spermiogenesis.

The manchette is a crucial transient structure involved in sperm development, with its composition and regulation still not fully understood. This study focused on investigating the roles of CAMSAP1 and CAMSAP2, microtubule (MT) minus-end binding proteins, in regulating manchette MTs, spermiogenesis, and male fertility. The loss of CAMSAP1, but not CAMSAP2, disrupts the well-orchestrated process of spermiogenesis, leading to abnormal manchette elongation and delayed removal, resulting in deformed sperm nuclei and tails resembling oligoasthenozoospermia symptoms. We investigated the underlying molecular mechanisms by purifying manchette assemblies and comparing them through proteomic analysis, and results showed that the absence of CAMSAP1 disrupted the proper localization of key proteins (CEP170 and KIF2A) at the manchette minus end, compromising its structural integrity and hindering MT depolymerization. These findings highlight the significance of maintaining homeostasis in manchette MT minus-ends for shaping manchette morphology during late spermiogenesis, offering insights into the molecular mechanisms underlying infertility and sperm abnormalities.

Influencing factors of inter-nursing lateral violence: A qualitative systematic review.

BACKGROUND: Lateral violence is a global social problem that has attracted considerable attention in the field of public health. This has seriously affected the quality of care, the safety of patients' lives and the career development of nurses. OBJECTIVE: To systematically evaluate the factors influencing of nursing lateral violence and provide evidence for preventing and reducing inter-nursing lateral violence. METHODS: A systematic review of qualitative study was performed in accordance with the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) guidelines. We collected qualitative studies on the factors influencing of inter-nursing lateral violence by searching PubMed, EMbase, The Cochrane Library, Web of Science, CINAHL, Science Direct, WanFang Data, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP) and Chinese Biomedical Literature Database (CBM). Data from inception to September 2023. Literature screening and data extraction were independently conducted by two reviewers. The Critical Appraisal Skills Program (CASP) scale was employed to assess the quality of the studies, including objectives, methodologies, designs, results and contributions. RESULTS: A total of 25 studies involving 882 participants were included. The results of the thematic analysis indicated that inter-nursing lateral violence was influenced by hospital management, perpetrators, victims and sociodemographic factors. CONCLUSION: Inter-nursing lateral violence was influenced by multidimensional factors. To reduce the occurrence of horizontal violence among nurses, hospitals need to explore the establishment and improvement of a horizontal violence resolution mechanism, and schools should pay attention to the joint support and education of nursing students, create a good working environment and harmonious nursing culture, and promote mutual respect among nurses. RELEVANCE TO CLINICAL PRACTICE: This review emphasises the importance of the influencing factors of horizontal violence among nurses, analyses the importance of influencing factors from different perspectives, and proposes corresponding measures to reduce inter-nursing lateral violence. NO PATIENT OR PUBLIC CONTRIBUTION: This study was mostly a literature review; neither patients nor pertinent staff were involved in either the design or conduct of the investigation.

Loading dynamics of one SARS-CoV-2-derived peptide into MHC-II revealed by kinetic models.

Major histocompatibility complex class II (MHC-II) plays an indispensable role in activating CD4+ T cell immune responses by presenting antigenic peptides on the cell surface for recognition by T cell receptors. The assembly of MHC-II and antigenic peptide is therefore a prerequisite for the antigen presentation. To date, however, the atomic-level mechanism underlying the peptide-loading dynamics for MHC-II is still elusive. Here, by constructing Markov state models based on extensive all-atom molecular dynamics simulations, we reveal the complete peptide-loading dynamics into MHC-II for one SARS-CoV-2 S-protein-derived antigenic peptide (235ITRFQTLLALHRSYL249). Our Markov state model identifies six metastable states (S1-S6) during the peptide-loading process and determines two dominant loading pathways. The peptide could potentially approach the antigen-binding groove via either its N- or C-terminus. Then, the consecutive insertion of several anchor residues into the binding pockets profoundly dictates the peptide-loading dynamics. Notably, the MHC-II αA52-E55 motif could guide the peptide loading into the antigen-binding groove via forming ß-sheets conformation with the incoming peptide. The rate-limiting step, namely S5→S6, is mainly attributed to a considerable desolvation penalty triggered by the binding of the peptide C-terminus. Moreover, we further examined the conformational changes associated with the peptide exchange process catalyzed by the chaperon protein HLA-DM. A flipped-out conformation of MHC-II αW43 captured in S1-S3 is considered a critical anchor point for HLA-DM to modulate the structural dynamics. Our work provides deep structural insights into the key regulatory factors in MHC-II responsible for peptide recognition and guides future design for peptide vaccines against SARS-CoV-2.

Cepharanthine suppresses proliferation and metastasis and enhances apoptosis by regulating JAK2/Stat3 pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a familiar malignant tumor, and cepharanthine (CEP) was proven to prevent the malignant activity of multiple cancer cells, including HCC. However, there are few reports on the regulatory role of CEP in HCC. After treatment with CEP or/and JAK2/Stat3 inhibitor (AG490), the associative functions were assessed by MTT, wound healing, Trans well, and Hochest33342-PI double staining in HCC cells. Then the levels of CDK4, MMP-9, Bcl-2, p-JAK2/JAK2, and p-Stat3/Stat3 were monitored via western blot. Besides, the HCC xenograft model was constructed to verify the effects of CEP on tumor growth and the JAK/Stat3 pathway. CEP could restrain proliferation and metastasis and facilitate apoptosis in HCC cells. CEP also reduced Bcl-2 (anti-apoptosis), CDK4 (proliferation), and MMP-9 (invasion) expressions, and inhibited JAK2 and Stat3 phosphorylation. Besides, CEP suppressed HCC progression by JAK2/Stat3 pathway. Moreover, CEP inhibited the growth of subcutaneous HCC xenografts and reduced p-JAK2 and p-Stat3 in tumor tissues. CEP could suppress HCC progression by attenuating the JAK2/Stat3 pathway, indicating that CEP might be a therapeutic drug for HCC patients.

Mechanism of REST/NRSF regulation of clustered protocadherin α genes.

Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5-1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDHα genes. Thus, REST/NRSF represses PCDHα gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.

CAMSAP1 breaks the homeostatic microtubule network to instruct neuronal polarity.

The establishment of axon/dendrite polarity is fundamental for neurons to integrate into functional circuits, and this process is critically dependent on microtubules (MTs). In the early stages of the establishment process, MTs in axons change dramatically with the morphological building of neurons; however, how the MT network changes are triggered is unclear. Here we show that CAMSAP1 plays a decisive role in the neuronal axon identification process by regulating the number of MTs. Neurons lacking CAMSAP1 form a multiple axon phenotype in vitro, while the multipolar-bipolar transition and radial migration are blocked in vivo. We demonstrate that the polarity regulator MARK2 kinase phosphorylates CAMSAP1 and affects its ability to bind to MTs, which in turn changes the protection of MT minus-ends and also triggers asymmetric distribution of MTs. Our results indicate that the polarized MT network in neurons is a decisive factor in establishing axon/dendritic polarity and is initially triggered by polarized signals.

Distinct metabolic biomarkers to distinguish IgG4-related disease from Sjogren's syndrome and pancreatic cancer and predict disease prognosis.

BACKGROUND: The pathogenesis of immunoglobulin G4-related disease (IgG4-RD) remains unclear. IgG4-RD often mimics other diseases, including pancreatic cancer (PC) and Sjogren's syndrome (SS), which may easily lead to misdiagnosis. This study was performed to explore the metabolite changes and potential biomarkers of IgG4-RD and other misdiagnosed diseases. METHODS: Untargeted liquid chromatography-tandem mass spectrometry metabolomics profiling of plasma samples from a cohort comprising healthy controls (HCs) and patients with IgG4-RD (n = 87), PC (n = 33), and SS (n = 31) was performed. A random forest machine learning model was used to verify the relevance of the identified metabolites in the diagnosis of different diseases and the prediction of disease prognosis. RESULTS: The ATP-binding cassette transporter pathway was found to be most closely related to IgG4-RD, which was significantly up-regulated in the IgG4-RD group than in all the matched groups. Five metabolites were proved to be valuable biomarkers for IgG4-RD. Caftaric acid, maltotetraose, D-glutamic acid, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphoserine, and hydroxyproline were useful in distinguishing between IgG4-RD, PC, SS, and HC [area under the curve (AUC) = 1]. A combination of phenylalanine betaine, 1-(1z-hexadecenyl)-sn-glycero-3-phosphocholine, Pi 40:8, uracil, and N1-methyl-2-pyridone-5-carboxamide showed a moderate value in predicting relapse in patients with IgG4-RD (AUC = 0.8). CONCLUSIONS: Our findings revealed the metabolite changes of IgG4-RD and provide new insights for deepening our understanding of IgG4-RD despite the lack of validation in external cohorts. Metabolomic biomarkers have significance in the clinical diagnosis and disease prognosis of IgG4-RD.

Dynamics of peptide loading into major histocompatibility complex class I molecules chaperoned by TAPBPR.

Major histocompatibility complex class I (MHC-I) molecules display antigenic peptides on the cell surface for T cell receptor scanning, thereby activating the immune response. Peptide loading into MHC-I molecules is thus a critical step during the antigen presentation process. Chaperone TAP-binding protein related (TAPBPR) plays a critical role in promoting high-affinity peptide loading into MHC-I, by discriminating against the low-affinity ones. However, the complete peptide loading dynamics into TAPBPR-bound MHC-I is still elusive. Here, we constructed kinetic network models based on hundreds of short-time MD simulations with an aggregated simulation time of ∼21.7 µs, and revealed, at atomic level, four key intermediate states of one antigenic peptide derived from melanoma-associated MART-1/Melan-A protein during its loading process into TAPBPR-bound MHC-I. We find that the TAPBPR binding at the MHC-I pocket-F can substantially reshape the distant pocket-B via allosteric regulations, which in turn promotes the following peptide N-terminal loading. Intriguingly, the partially loaded peptide could profoundly weaken the TAPBPR-MHC stability, promoting the dissociation of the TAPBPR scoop-loop (SL) region from the pocket-F to a more solvent-exposed conformation. Structural inspections further indicate that the peptide loading could remotely affect the SL binding site through both allosteric perturbations and direct contacts. In addition, another structural motif of TAPBPR, the jack hairpin region, was also found to participate in mediating the peptide editing. Our study sheds light on the detailed molecular mechanisms underlying the peptide loading process into TAPBPR-bound MHC-I and pinpoints the key structural factors responsible for dictating the peptide-loading dynamics.

Erratum: Serum Prohibitin 2/PHB2 in Parkin-Mediated Mitophagy: A Potential Therapeutic Target for Non-Small Cell Lung Carcinoma.

The authors requested replacing Figure 2 as there was an error. The details of this error are as follows: Representative picture of transwell migration assay, A549 control group (Figure 2E). Representative picture of wound healing assay, 24h, A549 negative control group (Figure 2C). The above pictures were repeated within their own group (control group and negative control group). Representative picture of wound healing assay, 0h, A549 si-PHB2 group (Figure 2C). The authors used the wrong picture during data handling. Changes do not influence the results of the paper. In the original experiment, H1299 and A549 cells were divided into 4 groups (Control, si-PHB2, +PHB2, and negative control). Transwell migration assay and wound healing assay were performed 5 times. In addition, these results have been repeated by another research group (PHB2 promotes tumorigenesis via RACK1 in non-small cell lung cancer, Theranostics 2021, Vol. 11, Issue 7). Reference: Han Zhang, Chuntong Yin, Xin Liu, Xue Bai, Lei Wang, Honglin Xu, Jin Ju, Linyou Zhang. Prohibitin 2/PHB2 in Parkin-Mediated Mitophagy: A Potential Therapeutic Target for Non-Small Cell Lung Carcinoma.  Med Sci Monit. 2020; 26: e923227. DOI: 10.12659/MSM.923227.

PLAC8, a new marker for human interstitial extravillous trophoblast cells, promotes their invasion and migration.

Proper differentiation of trophoblast cells in the human placenta is a prerequisite for a successful pregnancy, and dysregulation of this process may lead to malignant pregnancy outcomes, such as preeclampsia. Finding specific markers for different types of trophoblast cells is essential for understanding trophoblast differentiation. Here, we report that placenta-specific protein 8 (PLAC8) is specifically expressed in the interstitial extravillous trophoblast cells (iEVTs) on the fetomaternal interface. Using model systems, including placental villi-decidua co-culture, iEVTs induction by using primary trophoblast cells or explants, etc., we found that PLAC8 promotes invasion and migration of iEVTs. Mechanistically, time-lapse imaging, GTPase activity assay, co-immunoprecipitation and RNA-seq studies show that PLAC8 increases the Cdc42 and Rac1 activities, and further induces the formation of filopodia at the leading edge of the migratory trophoblast cells. More interestingly, PLAC8 is significantly upregulated under hypoxia and expression of PLAC8 is higher in iEVTs from preeclamptic placentas when compared with those from the normal control placentas. Together, PLAC8 is a new marker for iEVTs and plays an important role in promoting trophoblast invasion and migration.

Prohibitin 2/PHB2 in Parkin-Mediated Mitophagy: A Potential Therapeutic Target for Non-Small Cell Lung Carcinoma.

BACKGROUND Mitophagy, a selective autophagy process, plays various roles in tumors. Prohibitin 2 (PHB2) is an inner-mitochondrial membrane protein that participates in parkin-induced mitophagy. However, the role of PHB2 in non-small cell lung carcinoma (NSCLC) has not been previously reported. MATERIAL AND METHODS PHB2 protein or PHB2-mRNA in NSCLC and paired normal tissues was determined by Western blot, qRT-PCR, and immunohistochemical staining. Cell proliferation was detected by CCK-8 assay. Cell migration was evaluated by wound healing and transwell migration assays. A 3D live-cell confocal system was used to monitor autophagic flux. Mitochondrial autolysosomes were observed by transmission electron microscopy (TEM). Finally, we performed JC-1 assay to measure mitochondrial membrane potential (MMP). RESULTS The level of PHB2 was significantly increased in human NSCLC specimens compared to paired adjacent specimens. Inhibition of PHB2 expression attenuated mitophagy in A549 and H1299 cells, as indicated by decreased levels of LC3 II/I and parkin markers and increased level of p62 protein. Furthermore, the inhibition caused reduction in mitochondrial autolysosomes and autophagic flux, as shown by TEM and live-cell imaging, respectively. In addition, PHB2 inhibition caused a remarkable increase in MMP and suppressed the proliferation and migration of A549 and H1299 cells. CONCLUSIONS Our results suggest that downregulation of PHB2 reduced parkin-mediated mitophagy, which suppressed proliferation and migration of A549 and H1299 cells.

CAMSAP3 accumulates in the pericentrosomal area and accompanies microtubule release from the centrosome via katanin.

The epithelium has an apico-basal axis polarity that plays an important role in absorption, excretion and other physiological functions. In epithelial cells, a substantial number of non-centrosomal microtubules (MTs) are scattered in the cytoplasm with an apico-basal polarity and reorientate as epithelial cells perform different functions. Several previous studies have found that non-centrosomal MTs are nucleated at the centrosome, and then released and translocated elsewhere. However, the detailed process and molecular mechanism remain largely unknown. In this study, we found that Nezha, also called calmodulin-regulated spectrin-associated protein 3 (CAMSAP3), a non-centrosomal MT minus-end protein, accumulates in the pericentrosomal area and accompanies the release of MTs from the centrosome; whereas depletion of CAMSAP3 prevented MT release and instead caused focusing of MTs at centrosomes. Further studies demonstrated that CAMSAP3 precisely coordinates with dynein and katanin to regulate the MT detachment process. In conclusion, our results indicate that CAMSAP3 is a key molecule for generation of non-centrosomal MTs.

Transient Cataluminescence on Flowerlike MgO for Discrimination and Detection of Volatile Organic Compounds.

Methodologies for simple and rapid identification of gas compounds are needed in the fields of environmental and security. Here, a new and simple method for the discrimination of gas compounds was designed through an interesting transient cataluminescence (TRCTL) phenomenon on the highly efficient MgO materials. The flowerlike MgO with high CTL activity was controllably synthesized via a facile and time-saving aqueous precipitation route and characterized by scanning electron microscopy, powder X-ray diffractometry, high-resolution transmission electron microscopy, and N2 adsorption measurements, etc. With flowerlike MgO working as the sensing material, the newly developed CTL gas sensor exhibited highly active, ultrafast, and characteristic responses toward many analytes; the TRCTL curves thus were obtained and 10 VOCs have been successfully identified. Parallel experimental results show that the controllable synthesis of flowerlike MgO can greatly enhance the discrimination capacities for VOCs. Further, the TRCTL of CHCl3 and C2H5OC2H5 were taken as typical examples to illustrate the possible sensing mechanism, which could contribute to explaining processes of catalytic oxidations. We expect this novel TRCTL concept will be of practical importance for applications including gas detection, gas discrimination, and research of chemical kinetics processes.

Cryo-electron microscopy study of insect cell-expressed enterovirus 71 and coxsackievirus a16 virus-like particles provides a structural basis for vaccine development.

UNLABELLED: Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two most common etiological agents responsible for the epidemics of hand, foot, and mouth disease (HFMD), a childhood illness with occasional severe neurological complications. A number of vaccine candidates against EV71 or CA16 have been reported; however, no vaccine is currently available for clinical use. Here, we generated a secreted version of EV71 and CA16 virus-like particles (VLPs) using a baculovirus-insect cell expression system and reconstructed the three-dimensional (3D) structures of both VLPs by cryo-electron microscopy (cryo-EM) single-particle analysis at 5.2-Å and 5.5-Å resolutions, respectively. The reconstruction results showed that the cryo-EM structures of EV71 and CA16 VLPs highly resemble the recently published crystal structures for EV71 natural empty particles and CA16 135S-like expanded particles, respectively. Our cryo-EM analysis also revealed that the majority of previously identified linear neutralizing epitopes are well preserved on the surface of EV71 and CA16 VLPs. In addition, both VLPs were able to induce efficiently neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71- and CA16-associated HFMD. IMPORTANCE: The recent outbreaks of hand, foot, and mouth disease (HFMD) in the Asia Pacific region spurred the search for effective vaccines against EV71 and CA16 viruses, the two most common etiological agents responsible for HFMD. In this paper, we show that secreted versions of EV71 and CA16 VLPs generated in the baculovirus-insect cell expression system highly resemble the crystal structures of their viral conterparts and that the majority of previously identified linear neutralizing epitopes are well preserved on the VLP surfaces. In addition, the generated VLPs can efficiently induce neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71- and CA16-associated HFMD.

Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8+ T cells.

Several studies have demonstrated an apparent link between positive selection on hematopoietic cells (HCs) and an "innate" T-cell phenotype. Whereas conventional CD8(+) T cells are primarily selected on thymic epithelial cells (TECs) and certain innate T cells are exclusively selected on HCs, MHC class Ib-restricted CD8(+) T cells appear to be selected on both TECs and HCs. However, whether TEC- and HC-selected T cells represent distinct lineages or whether the same T-cell precursors have the capacity to be selected on either cell type is unknown. Using an M3-restricted T-cell receptor transgenic mouse model, we demonstrate that not only are MHC class Ib-restricted CD8(+) T cells capable of being selected on either cell type but that selecting cell type directly affects the phenotype of the resulting CD8(+) T cells. M3-restricted CD8(+) T cells selected on HCs acquire a more activated phenotype and possess more potent effector functions than those selected on TECs. Additionally, these two developmental pathways are active in the generation of the natural pool of M3-restricted CD8(+) T cells. Our results suggest that these two distinct populations may allow MHC class Ib-restricted CD8(+) T cells to occupy different immunological niches playing unique roles in immune responses to infection.

ChIP-seq analysis found IL21R, a target gene of GTF2I-the susceptibility gene for primary biliary cholangitis in Chinese Han.

AIMS: Aimed to identify a new susceptibility gene associated with primary biliary cholangitis (PBC) in Chinese Han and investigate the possible mechanism of that gene in PBC. METHODS: A total of 466 PBC and 694 healthy controls (HC) were included in our study, and genotyping GTF2I gene variants by Sequenom. CD19 + B cells were isolated for Chromatin immunoprecipitation sequencing (ChIP-seq). Additionally, MEME-ChIP was utilized to perform searches for known motifs and de novo motif discovery. The GTF2I ChIP-seq of hematopoietic cell line (K562) results were obtained from ENCODE (GSE176987, GSE177691). The Genomic HyperBrowser was used to determine overlap and hierarchal clustering between ours and ENCODE datasets. RESULTS: The frequency of the rs117026326 variant T allele was significantly higher in PBC patients than that in HC (20.26% compared with 13.89%, Pc = 1.09E-04). Furthermore, we observed an elevated proportion of GTF2I binding site located in the upstream and 5' UTR of genes in PBC in comparison with HC. Additionally, an in-depth analysis of IL21R region revealed that GTF2I might bind to the IL21R promoter to regulate the expression of the IL21R, with four peaks of GTF2I binding sites, including three increased binding sites in upstream, one increased binding site in 5' UTR. Motif analysis by MEME-ChIP uncovered five significant motifs. A significant overlap between our ChIP and GSE176987, GSE17769 were found by the Genomic HyperBroswer. CONCLUSIONS: Our study confirmed that GTF2I was associated with PBC in Chinese Han. Furthermore, our gene function analysis indicated that IL21R may be the target gene regulated by GTF2I.

Identification of Curcumin Targets in the Brain of Epileptic Mice Using DARTS.

Curcumin, a compound derived from turmeric, is traditionally utilized in East Asian medicine for treating various health conditions, including epilepsy. Despite its involvement in numerous cellular signaling pathways, the specific mechanisms and targets of curcumin in epilepsy treatment have remained unclear. Our study focused on identifying the primary targets and functional pathways of curcumin in the brains of epileptic mice. Using drug affinity responsive target stabilization (DARTS) and affinity chromatography, we identified key targets in the mouse brain, revealing 232 and 70 potential curcumin targets, respectively. Bioinformatics analysis revealed a strong association of these proteins with focal adhesions and cytoskeletal components. Further experiments using DARTS, along with immunofluorescence staining and cell migration assays, confirmed curcumin's ability to regulate the dynamics of focal adhesions and influence cell migration. This study not only advances our understanding of curcumin's role in epilepsy treatment but also serves as a model for identifying therapeutic targets in neurological disorders.

Immune cells and related cytokines in dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a non-ischemic cardiomyopathy involving one or more underlying etiologies. It is characterized by structural and functional dysfunction of the myocardium, potentially leading to fibrosis and ventricular remodeling, and an elevated risk of heart failure (HF). Although the pathogenesis of DCM remains unknown, compelling evidence suggests that DCM-triggered immune cells and inflammatory cascades play a crucial role in the occurrence and development of DCM. Various factors are linked to myocardial damage, inducing aberrant activation of the immune system and sustained inflammatory responses in DCM. The investigation of the immunopathogenesis of DCM also contributes to discovering new biomarkers and therapeutic targets. This review examines the roles of immune cells and related cytokines in DCM pathogenesis and explores immunotherapy strategies in DCM.

Guizhitongluo Tablet inhibits atherosclerosis and foam cell formation through regulating Piezo1/NLRP3 mediated macrophage pyroptosis.

BACKGROUND: Atherosclerosis (AS) is the main pathological basis for the development of cardiovascular diseases. Vascular inflammation is an important factor in the formation of AS, and macrophage pyroptosis plays a key role in AS due to its unique inflammatory response. Guizhitongluo Tablet (GZTLT) has shown clinically effective in treating patients with AS, but its mechanism is elusive. PURPOSE: This study was to determine the effects of GZTLT on atherosclerotic vascular inflammation and pyroptosis and to understand its underlying mechanism. MATERIALS AND METHODS: The active constituents of GZTLT were analysed by means of UPLC-HRMS. In vivo experiments were performed using ApoE-/- mice fed a high fat diet for 8 weeks, followed by treatment with varying concentrations of GZTLT orally by gavage and GsMTx4 (GS) intraperitoneally and followed for another 8 weeks. Oil red O, Haematoxylin-eosin (HE) and Masson staining were employed to examine the lipid content, plaque size, and collagen fibre content of the mouse aorta. Immunofluorescence staining was utilised to identify macrophage infiltration, as well as the expression of Piezo1 and NLRP3 proteins in aortic plaques. The levels of aortic inflammatory factors were determined using RT-PCR and ELISA. In vitro, foam cell formation in bone marrow-derived macrophages (BMDMs) was observed using Oil Red O staining. Intracellular Ca2+ measurements were performed to detect the calcium influx in BMDMs, and the expression of NLRP3 and its related proteins were detected by Western blot. RESULTS: The UPLC-HRMS analysis revealed 31 major components of GZTLT. Our data showed that GZTLT inhibited aortic plaque formation in mice and increased plaque collagen fibre content to stabilise plaques. In addition, GZTLT could restrain the expression of serum lipid levels and suppress macrophage foam cell formation. Further studies found that GZTLT inhibited macrophage infiltration in aortic plaques and suppressed the expression of inflammatory factors. It is noteworthy that GZTLT can restrain Piezo1 expression and reduce Ca2+ influx in BMDMs. Additionally, we found that GZTLT could regulate NLRP3 activation and pyroptosis by inhibiting Piezo1. CONCLUSION: The present study suggests that GZTLT inhibits vascular inflammation and macrophage pyroptosis through the Piezo1/NLRP3 signaling pathway, thereby delaying AS development. Our finding provides a potential target for AS treatment and drug discovery.