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Leonurine refers to the desiccated aerial portion of a plant in the Labiatae family. The primary bioactive constituent of Leonurine is an alkaloid, Leonurine alkaloid (Leo), renowned for its substantial therapeutic efficacy in the treatment of gynecological disorders, in addition to its broad-spectrum antineoplastic capabilities. Over recent years, the pharmacodynamic mechanisms of Leo have garnered escalating scholarly interest. Leo exhibits its anticancer potential by means of an array of mechanisms, encompassing the inhibition of neoplastic cell proliferation, induction of both apoptosis and autophagy, and the containment of oncogenic cell invasion and migration. The key signal transduction pathways implicated in these processes include the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), the Phosphoinositide3-Kinase/Serine/ Threonine Protein Kinase (PI3K/AKT), the Signal Transducer and Activator of Transcription 3 (STAT3), and the Mitogen-Activated Protein/Extracellular SignalRegulated Kinase (MAP/ERK). This paper commences with an exploration of the principal oncogenic cellular behaviors influenced by Leo and the associated signal transduction pathways, thereby scrutinizing the mechanisms of Leo in the antineoplastic sequence of events. The intention is to offer theoretical reinforcement for the elucidation of more profound mechanisms underpinning Leo’s anticancer potential and correlating pharmaceutical development. [ABSTRACT FROM AUTHOR]

TP53-induced glycolysis and apoptosis regulator (TIGAR) mainly regulates pentose phosphate pathway by inhibiting glycolysis, so as to synthesize ribose required by DNA, promote DNA damage repair and cell proliferation, maintain cell homeostasis and avoid body injury. Its physiological functions include anti-oxidative stress, reducing inflammation, maintaining mitochondrial function, inhibiting apoptosis, reducing autophagy etc. This paper reviews the research of TIGAR in neurological diseases, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), seizures and brain tumors, aiming to provide reference for the development of new therapeutic targets. [ABSTRACT FROM AUTHOR]

Molecular signal transmission in cell is very crucial for information exchange. How to understand its transmission mechanism has attracted many researchers. In this paper, we prove that signal transmission problem between neural tumor molecules and drug molecules can be achieved by synchronous control. To achieve our purpose, we derive the Fokker-Plank equation by using the Langevin equation and theory of random walk, this is a model which can express the concentration change of neural tumor molecules. Second, according to the biological character that vesicles in cell can be combined with cell membrane to release the cargo which plays a role of signal transmission, we preliminarily analyzed the mechanism of tumor-drug molecular interaction. Third, we propose the view of synchronous control which means the process of vesicle docking with their target membrane is a synchronization process, and we can achieve the precise treatment of disease by using synchronous control. We believe this synchronous control mechanism is reasonable and two examples are given to illustrate the correctness of our results obtained in this paper. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma, also known as PTC, is one of the commonest malignancies in the endocrine system. Long non-coding RNAs (lncRNAs) in PTC could maintain proliferative signaling, induce therapeutic resistance, activate invasion and migration, and sustain stem cell-like characteristics. In this paper, results showed that lncRNA forkhead box P4 antisense RNA 1 (FOXP4-AS1) is downregulated in PTC tissues and cell lines. Patients in TCGA cohort with a higher FOXP4-AS1 expression showed a higher disease-free interval (DFI) rate, and the expression of FOXP4-AS1 is shown to be linked to the clinical stage, T stage, N stage, and extraglandular invasion condition of the TC patients. FOXP4-AS1 is localized in the cell cytoplasmic domain of PTC cells. Functionally, upregulated FOXP4-AS1 inhibited PTC cell proliferation, apoptosis, and migration, whereas it downregulated FOXP4-AS1-promoted progression of PTC. In vivo assay also confirmed the tumor inhibitory effect of FOXP4-AS1 in PTC growth. Mechanism analysis indicated that FOXP4-AS1 can play its functions by regulating the AKT signaling pathway, and AKT inhibitor treatment could attenuate the impact of FOXP4-AS1 on PTC progression. Furthermore, FOXP4-AS1 also negatively regulates the expression of its host gene FOXP4. Collectively, we showed that FOXP4-AS1 inhibited PTC progression although AKT signaling and FOXP4-AS1 plays a tumor-suppressor role in PTC tumorigenesis. [ABSTRACT FROM AUTHOR]

Wound healing of the skin is a complex process that is still not well-understood. Wound management is expensive for both individuals and the health system overall, and can reduce quality of life for patients. Given these significant socio-economic impacts, wound healing has long been a focus of scientific research. Recent in vivo mouse studies have identified two key regions in wounded skin tissue: A non-proliferative leading edge that actively migrates into wounded space, and a proliferative hub in which cells have enhanced mitotic properties. This work uses mathematical and computational modelling to investigate the effect of changing the mechanical characteristics of cells in these two key regions. In this paper we explore what characteristics are sufficient for wound healing, particularly focusing on cell proliferation, since wounds are not able to repair successfully without sufficient levels of cell division. By considering contact inhibited proliferation, where small cells are unable to divide, we find that a quiescent region develops if the proliferative hub is able to grow over time, essentially limiting the number of cells that are able to divide. In contrast, if the size of the proliferative hub is kept below some threshold, then contact inhibition has a less significant role in wound repair. This work builds upon existing cellbased computational studies of wound healing and could be modified to investigate different stages of wound healing, impaired healing and wound treatments. [ABSTRACT FROM AUTHOR]

Glycans are involved in many biological phenomena, including signal transduction, cell adhesion, immune response or differentiation. Although a few papers have reported on the role of glycans in the development and proper functioning of the insect midgut, no data are available regarding the localization of the glycan structures on the surface of the cells in the gut of insects. In this paper, we analyzed the spatial distribution of glycans present on the surface of the midgut cells in larvae of the cotton leafworm Spodoptera littoralis, an important agricultural pest insect worldwide. For this purpose, we established primary midgut cell cultures, probed these individual cells that are freely suspended in liquid medium with a selection of seven fluorescently labeled lectins covering a range of different carbohydrate binding specificities [mannose oligomers (GNA and HHA), GalNAc/Gal (RSA and SSA), GlcNAc (WGA and Nictaba) and Neu5Ac(a-2,6)Gal/GalNAc (SNA-I)], and visualized the interaction of these lectins with the different zones of the midgut cells using confocal microscopy. Our analysis focused on the typical differentiated columnar cells with a microvillar brush border at their apical side, which are dominantly present in the Lepidopteranmidgut and function in food digestion and absorption, and as well as on the undifferentiated stem cells that are important for midgut development and repair. Confocal microscopy analyses showed that the GalNAc/Gal-binding lectins SSA and RSA and the terminal GlcNAc-recognizing WGA bound preferentially to the apical microvillar zone of the differentiated columnar cells as compared to the basolateral pole. The reverse result was observed for the mannose-binding lectins GNA and HHA, as well as Nictaba that binds preferentially to GlcNAc oligomers. Furthermore, differences in lectin binding to the basal and lateral zones of the cell membranes of the columnar cells were apparent. In the midgut stem cells, GNA and Nictaba bound more strongly to the membrane of these undifferentiated cells compared to the microvillar pole of the columnar cells, while SSA, HHA, WGA, and SNA-I showed stronger binding to the microvilli. Our results indicated that polarization of the midgut cells is also reflected by a specific distribution of glycans, especially between the basal and microvillar pole. The data are discussed in relation to the functioning and development of the insect midgut. [ABSTRACT FROM AUTHOR]

In view of the highly increased prevalence of papillary thyroid carcinoma (PTC) year by year, it is of great importance to explore new molecular targets for anticancer strategies. Emerging evidence indicates that circular RNAs (circRNAs), characterized by a closed-loop structure and high stability, play important roles in tumorigenesis and development of human cancer by regulating multiple complex biological processes, such as cellular proliferation, metastasis, and metabolism. A comprehensive understanding of the roles of circRNAs will facilitate the development of promising future therapeutic strategies for treating cancers, including PTC. In this paper, we review the profile of circRNA in PTC, its regulatory roles, and the pathological mechanism as well as their related clinical significance. In addition, challenges of this specific field are discussed. [ABSTRACT FROM AUTHOR]

Pituitary adenomas (PAs) are a neoplastic proliferation of anterior pituitary. Signature of Notch pathway relies upon the histopathological type of PAs. The details of Notch pathway that are involved in the migration and invasion of Pas are still unclear. This paper filters and testifies the relation between Notch signaling pathway and the migration/invasion in subtypes of PAs. The diversity of genes and pathways is investigated based on transcriptome data of 60 patients by KEGG pathway analysis and GSEA. A series of functional experiments demonstrate the role of candidate genes by overexpression and antibody blocking in GH3 cell line. Volcano map and GSEA results exhibit the differential and the priority of Jagged1 canonical Notch Ligand (JAG1) in the Notch pathway combined with clinical features. JAG1 is involved in epithelial–mesenchymal transition (EMT) in PAs by correlation analysis of RNA-seq data. Progression-free survival (PFS) of patients with high JAG1 was shorter than patients with low JAG1 according to follow-up data (P = 0.006). Furthermore, overexpression and antibody blocking experiments in GH3 cell line indicate that JAG1 could promote cell proliferation, migration, and G1/S transition. Double luciferase reporter assay gives manifests that JAG1 is the target gene of miR-424-3p, and mimics or inhibitor of miR-424-3p can regulate the level of JAG1 which, in turn, affects cell proliferation and the levels of MMP2 and VIM in GH3 cell line, respectively. Our study delves into the relation between the Notch signaling pathway and cell proliferation and EMT in PAs, providing a potential treatment through targeting JAG1. [ABSTRACT FROM AUTHOR]

N 6-methyladenosine (m6A) is one of the most widely studied epigenetic modifications, which plays an important role in many biological processes, such as splicing, RNA localization, and degradation. Studies have shown that m6A on lncRNA has important functions, including regulating the expression and functions of lncRNA, regulating the synthesis of pre-mRNA, promoting the proliferation of cancer cells, and affecting cell differentiation and many others. Although a number of methods have been proposed to predict m6A RNA methylation sites, most of these methods aimed at general m6A sites prediction without noticing the uniqueness of the lncRNA methylation prediction problem. Since many lncRNAs do not have a polyA tail and cannot be captured in the polyA selection step of the most widely adopted RNA-seq library preparation protocol, lncRNA methylation sites cannot be effectively captured and are thus likely to be significantly underrepresented in existing experimental data affecting the accuracy of existing predictors. In this paper, we propose a new computational framework, LITHOPHONE , which stands for l ong noncod i ng RNA me th ylati o n sites p rediction from sequence c h aracteristics and gen o mic i n formation with an e nsemble predictor. We show that the methylation sites of lncRNA and mRNA have different patterns exhibited in the extracted features and should be differently handled when making predictions. Due to the used experiment protocols, the number of known lncRNA m6A sites is limited, and insufficient to train a reliable predictor; thus, the performance can be improved by combining both lncRNA and mRNA data using an ensemble predictor. We show that the newly developed LITHOPHONE approach achieved a reasonably good performance when tested on independent datasets (AUC: 0.966 and 0.835 under full transcript and mature mRNA modes, respectively), marking a substantial improvement compared with existing methods. Additionally, LITHOPHONE was applied to scan the entire human lncRNAome for all possible lncRNA m6A sites, and the results are freely accessible at: http://180.208.58.19/lith/. [ABSTRACT FROM AUTHOR]

Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed sofar. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent. [ABSTRACT FROM AUTHOR]

Pancreatic regeneration is a complex process observed in both normal and pathological conditions. The aim of this review is to provide a comprehensive understanding of the emergence of a functionally active population of insulin- secreting β-cells in the adult pancreas. The renewal of β-cells is governed by a multifaceted interaction between cellular sources of genetic and epigenetic factors. Understanding the development and heterogeneity of β-cell populations is crucial for functional β-cell regeneration. The functional mass of pancreatic β-cells increases in situations such as pregnancy and obesity. However, the specific markers of mature β-cell populations and postnatal pancreatic progenitors capable of increasing self-reproduction in these conditions remain to be elucidated. The capacity to regenerate the β-cell population through various pathways, including the proliferation of preexisting β-cells, β-cell neogenesis, differentiation of β-cells from a population of progenitor cells, and transdifferentiation of non-β-cells into β-cells, reveals crucial molecular mechanisms for identifying cellular sources and inducers of functional cell renewal. This provides an opportunity to identify specific cellular sources and mechanisms of regeneration, which could have clinical applications in treating various pathologies, including in vitro cell-based technologies, and deepen our understanding of regeneration in different physiological conditions. [ABSTRACT FROM AUTHOR]

The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors, combined with the prevalent late-stage diagnosis, poses significant challenges for clinical management. Genomic sequencing endeavors have revealed extensive alterations in key signaling pathways that regulate cellular proliferation and survival. Initiatives to engineer therapies targeting these dysregulated pathways are underway, with several candidate molecules progressing to clinical evaluation phases, including FDA approval for agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wildtype, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to their enhanced stability in biological fluids and their important roles in intracellular and intercellular signaling within HNC contexts, are now recognized as potent biomarkers for disease management, catalyzing further refined diagnostic and therapeutic strategies, edging closer to the personalized medicine desideratum. Enhanced comprehension of the genomic and immunological landscapes characteristic of HNC is anticipated to facilitate a more rigorous assessment of targeted therapies benefits and limitations, optimize their clinical deployment, and foster innovative advancements in treatment approaches. This review presents an update on the molecular mechanisms and mutational spectrum of HNC driving the oncogenesis of head and neck malignancies and explores their implications for advancing diagnostic methodologies and precision therapeutics. [ABSTRACT FROM AUTHOR]

Cancer arises from multiple genetic errors occurring in a single stem cell (clonality). Every time DNA replicates, mistakes occur. Thus, agents can increase the risk of cancer either by directly damaging DNA (DNA-reactive carcinogens) or increasing the number of DNA replications (increased cell proliferation). Increased cell proliferation can be achieved either by direct mitogenesis or cytotoxicity with regenerative proliferation. Human carcinogens have a mode of action of DNA reactivity, immunomodulation (mostly immunosuppression), increased estrogenic activity (mitogenesis), or cytotoxicity and regeneration. By focusing on screening for these four effects utilizing in silico, in vitro, and short-term in vivo assays, a biologically based screening for human chemical carcinogens can be accomplished with greater predictivity than the traditional 2-year bioassay with considerably less cost, less time, and the use of fewer animals. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved cellular process in which cytoplasmic materials are degraded and recycled as energy sources when nutrient supplies are lacking. Established tumor cells require autophagy for cell growth and tumor promotion. In particular, the survival of pancreatic tumor cells appears to be strongly dependent on autophagy, referred to as autophagy addiction. This dependency of pancreatic tumor cells on autophagy may be a candidate target for pancreatic tumor therapy. EI24 (etoposide-induced gene 2.4 kb; PIG8, p53-induced gene 8) acts as a tumor suppressor, inhibiting cell growth and inducing apoptosis in breast, cervical, and prostate cancer cells. However, recent papers have reported that EI24 is an essential component of the autophagy pathway. This newly discovered role of EI24 as a component of autophagy may act as a tumor promoter, which is contradictory to its known role as a tumor suppressor. We investigated the role of EI24 as a component of autophagy in pancreatic tumor cell proliferation. Here, we demonstrated that knockdown of EI24 using siRNA in pancreatic tumor cells led to impaired autophagy at a late step (increase in LC3-II and accumulation of p62 and autolysosomes). EI24 deficiency in pancreatic tumor cell lines inhibited cell proliferation. We confirmed that loss of EI24 inhibited pancreatic cell proliferation using the CRISPR-Cas9 system. However, loss of EI24 in other cell lines did not affect cell proliferation. Taken together, our results suggest that EI24 acts as a tumor promoter in pancreatic tumor cells, and studying the role of EI24 in reference to its cellular context may lead to a useful therapeutic target. [ABSTRACT FROM AUTHOR]

Malformations of cortical development (MCDs), a complex family of rare disorders, result from alterations of one or combined developmental steps, including progenitors proliferation, neuronal migration and differentiation. They are an important cause of childhood epilepsy and frequently associate cognitive deficits and behavioral alterations. Though the physiopathological mechanisms of epilepsy in MCD patients remain poorly elucidated, research during the past decade highlighted the contribution of some factors that will be reviewed in this paper and that include: (i) the genes that caused the malformation, that can be responsible for a significant reduction of inhibitory cells (e.g., ARX gene) or be inducing cell-autonomous epileptogenic changes in affected neurons (e.g., mutations on the mTOR pathway); (ii) the alteration of cortical networks development induced by the malformation that will also involve adjacent or distal cortical areas apparently sane so that the epileptogenic focus might be more extended that the malformation or even localized at distance from it; (iii) the normal developmental processes that would influence and determine the onset of epilepsy in MCD patients, particularly precocious in most of the cases. [ABSTRACT FROM AUTHOR]

Chondroitin sulfate synthase 3 (CHSY3) is an important enzyme that regulates glycosylation, but its role in tumors has not been determined. Here, we showed that high CHSY3 expression promotes proliferation in gastric cancer (GC) cells and is associated with poor prognosis in GC patients. We analyzed the immunohistochemistry data of 150 gastric cancer patients to determine the clinicopathological and survival significance of CHSY3. Immunofluorescence was used to detect the colocalization of CHSY3 with infiltrating immune cells. Additionally, CHSY3 was predominantly found in tumor tissues and showed higher abundance compared to matched adjacent tissues. High CHSY3 expression was associated with more advanced tumor stage, higher recurrence risk and worse survival. Immunohistochemistry and bioinformatic analysis revealed that CHSY3 expression was significantly positively correlated with tumor-associated macrophage (TAM) infiltration. Moreover, after knocking down CHSY3, the proliferation of cells was decreased, and the migration ability was reduced, as shown by scratch, monoclonal and transwell assays. In conclusion, this study revealed that CHSY3 has a tumor-promoting effect on GC, suggesting a novel therapeutic strategy against this disease. [ABSTRACT FROM AUTHOR]

Introduction: While radiotherapy has long been recognized for its ability to directly ablate cancer cells through necrosis or apoptosis, radiotherapy-induced abscopal effect suggests that its impact extends beyond local tumor destruction thanks to immune response. Cellular proliferation and necrosis have been extensively studied using mathematical models that simulate tumor growth, such as Gompertz law, and the radiation effects, such as the linear-quadratic model. However, the effectiveness of radiotherapy-induced immune responses may vary among patients due to individual differences in radiation sensitivity and other factors. Methods: We present a novel macroscopic approach designed to quantitatively analyze the intricate dynamics governing the interactions among the immune system, radiotherapy, and tumor progression. Building upon previous research demonstrating the synergistic effects of radiotherapy and immunotherapy in cancer treatment, we provide a comprehensive mathematical framework for understanding the underlying mechanisms driving these interactions. Results: Our method leverages macroscopic observations and mathematical modeling to capture the overarching dynamics of this interplay, offering valuable insights for optimizing cancer treatment strategies. One shows that Gompertz law can describe therapy effects with two effective parameters. This result permits quantitative data analyses, which give useful indications for the disease progression and clinical decisions. Discussion: Through validation against diverse data sets from the literature, we demonstrate the reliability and versatility of our approach in predicting the time evolution of the disease and assessing the potential efficacy of radiotherapyimmunotherapy combinations. This further supports the promising potential of the abscopal effect, suggesting that in select cases, depending on tumor size, it may confer full efficacy to radiotherapy. [ABSTRACT FROM AUTHOR]

Phosphatase and tensin homologue deleted on chromosome ten (PTEN) was initially recognized as a significant regulator of cancer suppression and could impede cancer cell survival, proliferation, and energy metabolism. PTEN is highly expressed in neurons and performs crucial functions in neurogenesis, synaptogenesis, and neuronal survival. Disruption of PTEN activity may also result in abnormal neuronal function and is associated with various neurological disorders, including stroke, seizures, and autism. Although several studies have shown that PTEN is involved in the development and degenerative processes of the nervous system, there is still a lack of in-depth studies that summarize and analyse patterns of cooperation between authors, institutions, countries, and journals, as well as research hotspots and trends in this important field. To identify and further visualize the cooperation and comprehend the development and trends of PTEN in the nervous system, especially in neural development and neurological diseases, we used a bibliometric analysis to identify relevant publications on this topic. We first found that the number of publications displayed a growing trend with time, but this was not stable. Universities, institutions, and authors from the United States are leading in this area of research. In addition, many cutting-edge research results have been discovered, such as key regulatory molecules and cellular mechanisms of PTEN in the nervous system, which may provide novel intervention targets and precise therapeutic strategies for related pathological injuries and diseases. Finally, the literature published within the last 5 years is discussed to identify future research trends regarding PTEN in the nervous system. Taken together, our findings, analysed using bibliometrics, may reflect research hotspots and trends, providing a reference for studying PTEN in the nervous system, especially in neural development and neurological diseases. These findings can assist new researchers in developing their research interests and gaining basic information. Moreover, our findings also may provide precise clinical guidelines and strategies for treating nervous system injuries and diseases caused by PTEN dysfunction. [ABSTRACT FROM AUTHOR]

Thyroid hormones are involved in many biological processes such as neurogenesis, metabolism, and development. However, compounds called endocrine disruptors can alter thyroid hormone signaling and induce unwanted effects on human and ecosystems health. Regulatory tests have been developed to detect these compounds but need to be significantly improved by proposing novel endpoints and key events. The Xenopus Eleutheroembryonic Thyroid Assay (XETA, OECD test guideline no. 248) is one such test. It is based on Xenopus laevis tadpoles, a particularly sensitive model system for studying the physiology and disruption of thyroid hormone signaling: amphibian metamorphosis is a spectacular (thus easy to monitor) life cycle transition governed by thyroid hormones. With a long-term objective of providing novel molecular markers under XETA settings, we propose first to describe the differential effects of thyroid hormones on gene expression, which, surprisingly, are not known. After thyroid hormones exposure (T3 or T4), whole tadpole RNAs were subjected to transcriptomic analysis. By using standard approaches coupled to system biology, we found similar effects of the two thyroid hormones. They impact the cell cycle and promote the expression of genes involves in cell proliferation. At the level of the whole tadpole, the immune system is also a prime target of thyroid hormone action. [ABSTRACT FROM AUTHOR]

MYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4 decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for "MYC oncogene") have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC's physiological functions become co-opted for tumour initiation and maintenance. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) possess the ability to self-renew and differentiate into multiple cell types, making them highly suitable for use as seed cells in tissue engineering. These can be derived from various sources and have been found to play crucial roles in several physiological processes, such as tissue repair, immune regulation, and intercellular communication. However, the limited capacity for cell proliferation and the secretion of senescence-associated secreted phenotypes (SASPs) pose challenges for the clinical application of MSCs. In this review, we provide a comprehensive summary of the senescence characteristics of MSCs and examine the different features of cellular microenvironments studied thus far. Additionally, we discuss the mechanisms by which cellular microenvironments regulate the senescence process of MSCs, offering insights into preserving their functionality and enhancing their effectiveness. [ABSTRACT FROM AUTHOR]

The central nervous system areas displaying the highest structural and functional complexity correspond to the so called cortices, i.e., concentric alternating neuronal and fibrous layers. Corticogenesis, i.e., the development of the cortical organization, depends on the temporal-spatial organization of several developmental events: (a) the duration of the proliferative phase of the neuroepithelium, (b) the relative duration of symmetric (expansive) versus asymmetric (neuronogenic) sub phases, (c) the spatial organization of each kind of cell division, (e) the time of determination and cell cycle exit and (f) the time of onset of the post-mitotic neuronal migration and (g) the time of onset of the neuronal structural and functional differentiation. The first five events depend on molecular mechanisms that perform a fine tuning of the proliferative activity. Changes in any of them significantly influence the cortical size or volume (tangential expansion and radial thickness), morphology, architecture and also impact on neuritogenesis and synaptogenesis affecting the cortical wiring. This paper integrates information, obtained in several species, on the developmental roles of cell proliferation in the development of the optic tectum (OT) cortex, a multilayered associative area of the dorsal (alar) midbrain. The present review (1) compiles relevant information on the temporal and spatial organization of cell proliferation in different species (fish, amphibians, birds, and mammals), (2) revises the main molecular events involved in the isthmic organizer (IsO) determination and localization, (3) describes how the patterning installed by IsO is translated into spatially organized neural stem cell proliferation (i.e., by means of growth factors, receptors, transcription factors, signaling pathways, etc.) and (4) describes the morpho- and histogenetic effect of a spatially organized cell proliferation in the above mentioned species. A brief section on the OT evolution is also included. This section considers how the differential operation of cell proliferation could explain differences among species. [ABSTRACT FROM AUTHOR]

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5- dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Pleiotrophin (PTN) is a secreted growth factor, and also a cytokine, associated with the extracellular matrix, which has recently starting to attract attention as a significant neuromodulator with multiple neuronal functions during development. PTN is expressed in several tissues, where its signals are generally related with cell proliferation, growth, and differentiation by acting through different receptors. In Central Nervous System (CNS), PTN exerts post-developmental neurotrophic and -protective effects, and additionally has been involved in neurodegenerative diseases and neural disorders. Studies in Drosophila shed light on some aspects of the different levels of regulatory control of PTN invertebrate homologs. Specifically in hippocampus, recent evidence from PTN Knock-out (KO) mice involves PTN functioning in learning and memory. In this paper, we summarize, discuss, and contrast the most recent advances and results that lead to proposing a PTN as a neuromodulatory molecule in the CNS, particularly in hippocampus. [ABSTRACT FROM AUTHOR]

Research suggesting the beneficial effects of yoga on myriad aspects of psychological health has proliferated in recent years, yet there is currently no overarching framework by which to understand yoga's potential beneficial effects. Here we provide a theoretical framework and systems-based network model of yoga that focuses on integration of top-down and bottom-up forms of self-regulation. We begin by contextualizing yoga in historical and contemporary settings, and then detail how specific components of yoga practice may affect cognitive, emotional, behavioral, and autonomic output under stress through an emphasis on interoception and bottom-up input, resulting in physical and psychological health. The model describes yoga practice as a comprehensive skillset of synergistic process tools that facilitate bidirectional feedback and integration between high- and low-level brain networks, and afferent and re-afferent input from interoceptive processes (somatosensory, viscerosensory, chemosensory). From a predictive coding perspective we propose a shift to perceptual inference for stress modulation and optimal self-regulation. We describe how the processes that sub-serve self-regulation become more automatized and efficient over time and practice, requiring less effort to initiate when necessary and terminate more rapidly when no longer needed. To support our proposed model, we present the available evidence for yoga affecting self-regulatory pathways, integrating existing constructs from behavior theory and cognitive neuroscience with emerging yoga and meditation research. This paper is intended to guide future basic and clinical research, specifically targeting areas of development in the treatment of stress-mediated psychological disorders. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a diverse tumor microenvironment. The heterogeneous cellular composition of PDAC makes it challenging to study molecular features of tumor cells using extracts from bulk tumor. The metabolic features in tumor cells from clinical samples are poorly understood, and their impact on clinical outcomes are unknown. Our objective was to identify the metabolic features in the tumor compartment that are most clinically impactful. Methods: A computational deconvolution approach using the DeMixT algorithm was applied to bulk RNASeq data from The Cancer Genome Atlas to determine the proportion of each gene's expression that was attributable to the tumor compartment. A machine learning algorithm designed to identify features most closely associated with survival outcomes was used to identify the most clinically impactful metabolic genes. Results: Two metabolic subtypes (M1 and M2) were identified, based on the pattern of expression of the 26 most important metabolic genes. The M2 phenotype had a significantly worse survival, which was replicated in three external PDAC cohorts. This PDAC subtype was characterized by net glycogen catabolism, accelerated glycolysis, and increased proliferation and cellular migration. Single cell data demonstrated substantial intercellular heterogeneity in the metabolic features that typified this aggressive phenotype. Conclusion: By focusing on features within the tumor compartment, two novel and clinically impactful metabolic subtypes of PDAC were identified. Our study emphasizes the challenges of defining tumor phenotypes in the face of the significant intratumoral heterogeneity that typifies PDAC. Further studies are required to understand the microenvironmental factors that drive the appearance of the metabolic features characteristic of the aggressive M2 PDAC phenotype. [ABSTRACT FROM AUTHOR]

A wide variety of studies have reported some form of non-chemical or nonaqueous communication between physically isolated organisms, eliciting changes in cellular proliferation, morphology, and/or metabolism. The sources and mechanisms of such signalling pathways are still unknown, but have been postulated to involve vibration, volatile transmission, or light through the phenomenon of ultraweak photon emission. Here, we report non-chemical communication between isolated mitochondria from MCF7 (cancer) and MCF10A (non-cancer) cell lines. We found that mitochondria in one cuvette stressed by an electron transport chain inhibitor, antimycin, alters the respiration of mitochondria in an adjacent, but chemically and physically separate cuvette, significantly decreasing the rate of oxygen consumption compared to a control (p = <0.0001 in MCF7 and MCF10A mitochondria). Moreover, the changes in O2-consumption were dependent on the origin of mitochondria (cancer vs. non-cancer) as well as the presence of "ambient" light. Our results support the existence of non-chemical signalling between isolated mitochondria. The experimental design suggests that the non-chemical communication is light-based, although further work is needed to fully elucidate its nature. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension has characteristic changes to the mechanical environment, extracellular matrix, and cellular proliferation. In order to develop a culture system to investigate extracellular matrix (ECM) compositional-dependent changes in pulmonary arterial hypertension, we decellularized and characterized protein and lipid profiles from healthy and Sugen-Chronic Hypoxia rat lungs. Significant changes in lipid profiles were observed in intact Sugen-Hypoxia lungs compared with healthy controls. Decellularized lung matrix retained lipids in measurable quantities in both healthy and Sugen-Chronic Hypoxia samples. Proteomics revealed significantly changed proteins associated with pulmonary arterial hypertension in the decellularized Sugen-Chronic Hypoxia lung ECM. We then investigated the potential role of healthy vs. Sugen-Chronic Hypoxia ECM with controlled substrate stiffness to determine if the ECM composition regulated endothelial cell morphology and phenotype. CD117+ rat lung endothelial cell clones were plated on the variable stiffness gels and cellular proliferation, morphology, and gene expression were quantified. Sugen-Chronic Hypoxia ECM on healthy stiffness gels produced significant changes in cellular gene expression levels of Bmp2, Col1α1, Col3α1 and Fn1. The signaling and cell morphology observed at low substrate stiffness suggests early changes to the ECM composition can initiate processes associated with disease progression. These data suggest that Sugen-Chronic Hypoxia ECM can be used to investigate cell-ECM interactions relevant to pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

Ischemic stroke is responsible for many deaths and long-term disability world wide. Development of effective therapy has been the target of intense research. Accumulating preclinical literature has shown that substantial functional improvement after stroke can be achieved using subacutely administered cell-based and pharmacological therapies. This review will discuss some of the latest findings on bone marrow-derived mesenchymal stem cells (BMSCs), human umbilical cord blood cells, and off-label use of some pharmacological agents, to promote recovery processes in the sub-acute and chronic phases following stroke. This review paper also focuses on molecular mechanisms underlying the cell-based and pharmacological restorative processes, which enhance angiogenesis, arteriogenesis, neurogenesis, and white matter remodeling following cerebral ischemia as well as an analysis of the interaction/coupling among these restorative events. In addition, the role of microRNAs mediating the intercellular communication between exogenously administered cells and parenchymal cells, and their effects on the regulation of angiogenesis and neuronal progenitor cell proliferation and differentiation, and brain plasticity after stroke are described. [ABSTRACT FROM AUTHOR]

Ischemic stroke is responsible for many deaths and long-term disability world wide. Development of effective therapy has been the target of intense research. Accumulating preclinical literature has shown that substantial functional improvement after stroke can be achieved using subacutely administered cell-based and pharmacological therapies. This review will discuss some of the latest findings on bone marrow-derived mesenchymal stem cells (BMSCs), human umbilical cord blood cells (HUCBCs) and offlabel use of some pharmacological agents, to promote recovery processes in the subacute and chronic phases following stroke. This review paper also focuses on molecular mechanisms underlying the cell-based and pharmacological restorative processes which enhance angiogenesis, arteriogenesis, neurogenesis and white matter remodeling following cerebral ischemia as well as an analysis of the interaction/coupling among these restorative events. In addition, the role of microRNAs (miRNAs) mediating the intercellular communication between exogenously administered cells and parenchymal cells, and their effects on the regulation of angiogenesis and neuronal progenitor cell proliferation and differentiation, and brain plasticity after stroke are described. [ABSTRACT FROM AUTHOR]

The article presents information on pattern separation in the dentate gyrus (DG). It is stated that no study has directly confirmed about a pattern separation mechanism existence at a cell population level in EC-DG-CA3 circuit. It is also stated that the matter must be reassessed to accurately assess papers on pattern separation to the DG.

Introduction: Human Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties on CD4+ effector T cells by a mechanism partially dependent on GZMB. Moreover, these cells may be easily induced in vitro making them interesting for cell therapy. Methods: We characterized this population of in vitro induced GZMB+Bregs using single cell transcriptomics. To investigate their regulatory properties, Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ligand interactions and to reveal gene expression changes in the T cells. Results: We find that Bregs exhibit a unique set of 149 genes differentially expressed and which are implicated in proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation, activation, inflammation and apoptosis compared to total B cells. We identified and validated 5 receptor/ligand interactions between Bregs and T cells. Functional analysis using specific inhibitors was used to test their suppressive properties and we identified Lymphotoxin alpha (LTA) as a new and potent Breg ligand implicated in Breg suppressive properties. Discussion: We report for the first time for a role of LTA in GZMB+Bregs as an enhancer of GZMB expression, and involved in the suppressive properties of GZMB+Bregs in human. The exact mechanism of LTA/GZMB function in this specific subset of Bregs remains to be determined. [ABSTRACT FROM AUTHOR]

The proliferative potential of mast cells after activation for 3-4h was found to be decreased, which suggests that mast cell degranulation and cell proliferation are differentially regulated. ELK4, a member of the ternary complex factor (TCF) subfamily of Ets transcription factors, is one of the downstream effectors of MAPK signaling that is critical for cell proliferation. And Elk4 has been identified to be vital for macrophage activation in response to zymosan and the transcriptional response to 12-O-tetrade canoyl phorbol-13-acetate (TPA) stimulation in fibroblast. However, the effect of ELK4 on the mast cell transcriptional response to Fc?RI and GPCR mediated activation and its potential functional significance in mast cells remain unclear. Here, we showed that ELK4 expression is downregulated in activated mast cells. Elk4 knockout suppresses cell proliferation and impedes the cell cycle in bone marrow-derived mast cells (BMMCs), which is associated with decreased transcription of cell cycle genes. Additionally, the transcriptional activation of cytokines and chemokines is diminished while mast cell degranulation is enhanced in Elk4 knockout BMMCs. Mechanistically, ELK4 might positively modulate Hdc, Ccl3 and Ccl4 transcription by interacting with MITF and negatively regulate the transcription of degranulation-related genes by complexing with SIRT6. Overall, our study identifies a new physiological role of the transcription factor ELK4 in mast cell proliferation and activation. [ABSTRACT FROM AUTHOR]

Introduction: Glucose and glutamine are major carbon and energy sources that promote the rapid proliferation of cancer cells. Metabolic shifts observed on cell lines or mouse models may not reflect the general metabolic shifts in real human cancer tissue. Method: In this study, we conducted a computational characterization of the flux distributionandvariationsof thecentralenergymetabolismandkeybranches inapancancer analysis, including the glycolytic pathway, production of lactate, tricarboxylic acid (TCA) cycle, nucleic acid synthesis, glutaminolysis, glutamate, glutamine, and glutathione metabolism, and amino acid synthesis, in 11 cancer subtypes and nine matched adjacent normal tissue types using TCGA transcriptomics data. Result: Our analysis confirms the increased influx in glucose uptake and glycolysis and decreased upper part of the TCA cycle, i.e., the Warburg effect, in almost all the analyzed cancer. However, increased lactate production and the second half of the TCA cycle were only seen in certain cancer types. More interestingly, we failed to detect significantly altered glutaminolysis in cancer tissuescompared to their adjacent normal tissues. A systemsbiologymodel of metabolic shifts through cancer and tissue types is further developed and analyzed. We observed that (1) normal tissues have distinct metabolic phenotypes; (2) cancer types have drastically different metabolic shifts compared to their adjacent normal controls; and (3) the different shifts in tissuespecific metabolic phenotypes result in a converged metabolic phenotype through cancer types and cancer progression. Discussion: This study strongly suggests the possibility of having a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors. [ABSTRACT FROM AUTHOR]

The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation of the rapidly accelerating fibrosarcoma-extracellular signal-regulated kinase-MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing. [ABSTRACT FROM AUTHOR]

Background: Testosterone plays a critical role in maintaining reproductive functions and well-beings of the males. Adult testicular Leydig cells (LCs) produce testosterone and are generated from stem Leydig cells (SLCs) during puberty through adulthood. In addition, macrophages are critical in the SLC regulatory niche for normal testicular function. Age-related reduction in serum testosterone contributes to a number of metabolic and quality-of-life changes in males, as well as age-related changes in immunological functions. How aging and testicular macrophages may affect SLC function is still unclear. Methods: SLCs and macrophages were purified from adult and aged mice via FACS using CD51 as a marker protein. The sorted cells were first characterized and then co-cultured in vitro to examine how aging and macrophages may affect SLC proliferation and differentiation. To elucidate specific aging effects on both cell types, co-culture of sorted SLCs and macrophages were also carried out across two ages. Results: CD51+ (weakly positive) and CD51++ (strongly positive) cells expressed typical SLC and macrophage markers, respectively. However, with aging, both cell types increased expression of multiple cytokine genes, such as IL-1b, IL-6 and IL-8. Moreover, old CD51+ SLCs reduced their proliferation and differentiation, with a more significant reduction in differentiation (2X) than proliferation (30%). Age matched CD51++ macrophages inhibited CD51+ SLC development, with a more significant reduction in old cells (60%) than young (40%). Crossed-age coculture experiments indicated that the age of CD51+ SLCs plays a more significant role in determining age-related inhibitory effects. In LC lineage formation, CD51+SLC had both reduced LC lineage markers and increased myoid cell lineage markers, suggesting an age-related lineage shift for SLCs. Conclusion: The results suggest that aging affected both SLC function and their regulatory niche cell, macrophages. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma is the most common and fatal form of kidney cancer, accounting for 80% of new cases. Although it has been reported that GTSE1 is highly expressed in a variety of tumors and associated with malignant progression and poor clinical prognosis, its clinical significance, correlations with immune cell infiltration and biological function in ccRCC are still poorly understood. Methods: The gene expression, clinicopathological features, and clinical significance of GTSE1 were analyzed using multiple databases, including TCGA, GEO, TIMER, and UALCAN Kaplan-Meier survival analysis, gene set enrichment analysis gene ontology enrichment Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed. Tumor-infiltrating immune cells and immunomodulators were extracted and analyzed using TCGA-KIRC profiles. Protein-protein interactions were built using the STRING website. The protein level of GTSE1 in ccRCC patients was detected by immunohistochemistry using a ccRCC tissue chip. Finally, MTT assays, colony-formation assays, cell flow cytometry analyses, EdU-staining assays, wound-healing assays, and transwell migration and invasion assays were conducted to assess the biological function of GTSE1 in vitro. Results: GTSE1 was overexpressed in ccRCC tissues and cells, and GTSE1 overexpression was associated with adverse clinical-pathological factors and poor clinical prognosis. Meanwhile, the functional enrichment analysis indicated that GTSE1 and its coexpressed genes were mainly related to the cell cycle, DNA replication, and immunoreaction, such as T-cell activation and innate immune response, through multiple signaling pathways, including the P53 signaling pathway and T-cell receptor signaling pathway. Furthermore, we observed a significant relationship between GTSE1 expression and the levels of infiltrating immune cells in ccRCC. Biological functional studies demonstrated that GTSE1 could promote the malignant progression of ccRCC by promoting cell proliferation, cell cycle transition, migration, and invasion capacity and decreasing the sensitivity of ccRCC cells to cisplatin. Conclusion: Our results indicate that GTSE1, serving as a potential oncogene, can promote malignant progression and cisplatin resistance in ccRCC. Additionally, high GTSE1 expression contributes to an increased level of immune cell infiltration and is associated with a worse prognosis, providing a potential target for tumor therapy in ccRCC. [ABSTRACT FROM AUTHOR]

Background: Cancer, also known as a malignant tumor, is caused by the activation of oncogenes, which leads to the uncontrolled proliferation of cells that results in swelling. According to the World Health Organization (WHO), cancer is one of the main causes of death worldwide. The main variables limiting the efficacy of antitumor treatments are side effects and drug resistance. The search for natural, safe, low toxicity, and efficient chemical compounds in tumor research is essential. Berberine is a pentacyclic isoquinoline quaternary ammonium alkaloid isolated from Berberis and Coptis that has long been used in clinical settings. Studies in recent years have reported the use of berberine in cancer treatment. In this study, we performed a bibliometric analysis of berberine- and tumor-related research. Materials and methods: Relevant articles from January 1, 2002, to December 31, 2021, were identified from the Web of Science Core Collection (WOSCC) of Clarivate Analytics. Microsoft Excel, CiteSpace, VOSviewer, and an online platform were used for the literary metrology analysis. Results: A total of 1368 publications had unique characteristics. Publications from China were the most common (783 articles), and Y. B. Feng (from China) was the most productive author, with the highest total citations. China Medical University (Taiwan) and Sun Yat-sen University (China) were the two organizations with the largest numbers of publications (36 each). Frontiers in Pharmacology was the most commonly occurring journal (29 articles). The present body of research is focused on the mechanism, molecular docking, and oxidative stress of berberine in tumors. Conclusion: Research on berberine and tumors was thoroughly reviewed using knowledge map and bibliometric methods. The results of this study reveal the dynamic evolution of berberine and tumor research and provide a basis for strategic planning in cancer research. [ABSTRACT FROM AUTHOR]

Plant leaves display abundant morphological richness yet grow to characteristic sizes and shapes. Beginning with a small number of undifferentiated founder cells, leaves evolve via a complex interplay of regulatory factors that ultimately influence cell proliferation and subsequent post-mitotic cell enlargement. During their development, a sequence of key events that shape leaves is both robustly executed spatiotemporally following a genomic molecular network and flexibly tuned by a variety of environmental stimuli. Decades of work on Arabidopsis thaliana have revisited the compensatory phenomena that might reflect a general and primary size-regulatory mechanism in leaves. This review focuses on key molecular and cellular events behind the organ-wide scale regulation of compensatory mechanisms. Lastly, emerging novel mechanisms of metabolic and hormonal regulation are discussed, based on recent advances in the field that have provided insights into, among other phenomena, leaf-size regulation. [ABSTRACT FROM AUTHOR]

Background: Stomach adenocarcinoma (STAD) is the most common type of gastric cancer. In this study, the functions and potential mechanisms of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta (HADHB) in STAD were explored. Methods: Different bioinformatics analyses were performed to confirm HADHB expression in STAD. HADHB expression in STAD tissues and cells was also evaluated using western blot, qRT-PCR, and immunohistochemistry. Further, the viability, proliferation, colony formation, cell cycle determination, migration, and wound healing capacity were assessed, and the effects of HADHB on tumour growth, cell apoptosis, and proliferation in nude mice were determined. The upstream effector of HADHB was examined using bioinformatics analysis and dual luciferase reporter assay. GSEA was also employed for pathway enrichment analysis and the expression of Hippo-YAP pathway-related proteins was detected. Results: The expression of HADHB was found to be low in STAD tissues and cells. The upregulation of HADHB distinctly repressed the viability, proliferation, colony formation, cell cycle progression, migration, invasion, and wound healing of HGC27 cells, while knockdown of HADHB led to opposite effects. HADHB upregulation impeded tumour growth and cell proliferation, and enhanced apoptosis in nude mice. KLF4, whose expression was low in STAD, was identified as an upstream regulator of HADHB. KLF4 upregulation abolished the HADHB knockdown-induced tumour promoting effects in AGS cells. Further, HADHB regulates the Hippo-YAP pathway, which was validated using a pathway rescue assay. Low expression of KLF4 led to HADHB downregulation in STAD. Conclusion: HADHB might function as a tumour suppressor gene in STAD by regulation the Hippo-YAP pathway. [ABSTRACT FROM AUTHOR]

Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, “drug-like” mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha- 2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = –1.54; –0.35], and various statins [p < 0.05, 95% CI = –3.17; –0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted. [ABSTRACT FROM AUTHOR]

Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCIH460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of the 131I-labeled high-affinity peptides Caerin 1.1 and Caerin 1.9 for the treatment of A549 human NSCLC cells. Methods: ① 3-[4,5-Dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and plate clone formation assays were performed to confirm the in vitro anti-tumor activity of Caerin 1.1 and Caerin 1.9. ② Chloramine-T was used to label Caerin 1.1 and Caerin 1.9 with 131I, and the Cell Counting Kit 8 assay was performed to analyze the inhibitory effect of unlabeled Caerin 1.1, unlabeled Caerin 1.9, 131I-labeled Caerin 1.1, and 131I-labeled Caerin 1.9 on the proliferation of NSCLC cells. An A549 NSCLC nude mouse model was established to investigate the in vivo anti-tumor activity of unlabeled Caerin 1.1, unlabeled Caerin 1.9, 131I-labeled Caerin 1.1, and 131I-labeled Caerin 1.9. Results: ① Caerin 1.1 and Caerin 1.9 inhibited the proliferation of NSCLC cells in vitro in a concentration-dependent manner. The half-maximal inhibitory concentration was 16.26 µg/ml and 17.46 µg/ml, respectively, with no significant intergroup difference (P>0.05). ② 131I-labeled Caerin 1.1 and 131I-labeled Caerin 1.9 were equally effective and were superior to their unlabeled versions in their ability to inhibit the proliferation and growth of NSCLC cells (P>0.05). Conclusions: 131I-labeled Caerin 1.1 and 131I-labeled Caerin 1.9 inhibit the proliferation and growth of NSCLC cells and may become potential treatments for NSCLC. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a genetically complex disease. The key myelomainitiating genetic events are hyperdiploidy and translocations involving the immunoglobulin heavy chain (IgH) enhancer on chromosome 14, which leads to the activation of oncogenes (e.g., CCND1, CCND3, MAF, and MMSET). The t(11;14) translocation is the most common in MM (15%-20%) and results in cyclin D1 (CCND1) upregulation, which leads to kinase activation and tumor cell proliferation. Notably, t(11;14) occurs at a higher rate in patients with plasma cell leukemia (40%) and light chain amyloidosis (50%). Patients with myeloma who harbor the t(11;14) translocation have high levels of the antiapoptotic protein B-cell lymphoma 2 (BCL2). Multiple studies demonstrated that the presence of t(11;14) was predictive of BCL2 dependency, suggesting that BCL2 could be a target in this subtype of myeloma. Venetoclax, an oral BCL2 inhibitor, has shown remarkable activity in treating relapsed/refractory MMpatients with t(11;14) and BCL2 overexpression, either as monotherapy or in combination with other anti-myeloma agents. In this review, we describe the molecular defects associated with the t(11;14), bring into question the standard cytogenetic risk of myeloma patients harboring t(11;14), summarize current efficacy and safety data of targeted venetoclax-based therapies, and discuss the future of individualized or precision medicine for this unique myeloma subgroup, which will guide optimal treatment. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a special type of endogenous RNAs with extensive roles in multiple human diseases. They are formed by back-splicing of partial sequences of the parental precursor mRNAs. Unlike linear RNAs, their covalently closed loop structure without a 5' cap and a 3' polyadenylated tail confers on them high stability and they are difficult to be digested by RNase R. Increasing evidence has proved that aberrant expressions of many circRNAs are detected and that circRNAs exert essential biological functions in disease development and progression via acting as a molecular sponge of microRNA, interacting with proteins as decoys or scaffolds, or self-encoding small peptides. Circular RNA zinc finger protein 609 (circ-ZNF609) originates from exon2 of ZNF609, which is located at chromosome 15q22.31, and it has recently been proved that it can translate into a protein. Being aberrantly upregulated in various diseases, it could promote malignant progression of human tumors, as well as tumor cell proliferation, migration, and invasion. Here in this review, we concluded the biological functions and potential mechanisms of circ-ZNF609 in multiple diseases, which could be further explored as a targetable molecule in future accurate diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Methods: First, GSEA strategy and WGCNA analysis were used to screen for anti-ovarian cancer drugs and furthern optimal module, respectively. In addition, functional enrichments of module genes were realized by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Kaplan-Meier was then employed to analyze the prognostic impact of USP1 expression on OV patients. Cell proliferation and cell cycle assays were used to confirm biological functions of USP1 in the final. Results: Through the forementioned methods, we obtained five candidate drugs against OV from 353 anticancer drugs, and proposed ML323 as a novel anti-OV drug. As our hypothesized, ML323 significantly inhibited the proliferation of OV cells. Combined with WGCNA and KEGG analysis, the turquoise module was related to ML323, together with cell cycle. USP1 was subsequently identified as a target of ML323 and according to the TCGA database, USP1 negatively correlated with prognosis in OV, and its reduction and ML323-treatment both inhibited the proliferation of OV cells, blocking the S phase of cell cycle in vitro. Conclusion: Taken together, ML323 exerts its inhibitory effect on the proliferation of OV cells by targeting USP1-regulated cell cycle, providing a therapeutical strategy and potential target against OV. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with advanced cervical cancer remains unsatisfactory. A study indicated that transmembrane protein 33 (TMEM33) was implicated in tumor recurrence, while its role in cervical cancer has not been elucidated. Methods: TMEM33 expression in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) was primarily screened in The Cancer Genome Atlas (TCGA), and further validated in Gene Expression Omnibus (GEO) database. The Kaplan–Meier plotter analysis and Cox regression were constructed to evaluate the prognostic value of TMEM33 in CESC. Functional enrichment analysis was performed with GO, KEGG and GSEA tools. CCK-8 assay and colony formation assay were performed to investigate the carcinogenesis role of TMEM33 in cervical cancer cell proliferation. Results: TMEM33 expression was significantly elevated in CESC compared with normal tissues. High expression of TMEM33 was associated with poor prognostic clinical characteristics in CESC patients. KM-plotter analysis revealed that patients with increased TMEM33 had shorter overall survival (OS), progress free interval (PFI), and disease specific survival (DSS). Moreover, Multivariate Cox analysis confirmed that high TMEM33 expression was an independent risk factor for OS in patients with CESC. TMEM33 was associated with immune infiltrates, and its expression was correlated with tumorigenesis-related genes RNF4, OCIAD1, TMED5, DHX15, MED28 and LETM1. More importantly, knockdown of TMEM33 in cervical cancer cells decreased the expression of those genes and inhibited cell proliferation. Conclusion: Increased TMEM33 in cervical cancer can serve as an independent prognostic marker and might play a role in tumorigenesis by promoting cell proliferation. [ABSTRACT FROM AUTHOR]

Phosphatase and tensin homology deleted on chromosome 10 (PTEN) is a tumor suppressor gene. Its encoded protein has phosphatase and lipid phosphatase activities, which regulate the growth, differentiation, migration, and apoptosis of cells. The catalytic activity of PTEN is crucial for controlling cell growth under physiological and pathological conditions. It not only affects the survival and proliferation of tumor cells, but also inhibits a variety of cell regeneration processes. The use of PTEN inhibitors is being explored as a potentially beneficial therapeutic intervention for the repair of injuries to the central nervous system. PTEN influences the proliferation and differentiation of NSCs by regulating the expression and phosphorylation of downstream molecular protein kinase B (Akt) and the mammalian target of rapamycin (mTOR). However, the role of PTEN inhibitors in the Akt/mTOR signaling pathway in NSC proliferation and differentiation is unclear. Dipotassium bisperoxo (picolinoto) oxovanadate (V) [bpv(pic)] is a biologically active vanadium compound that blocks PTEN dephosphorylation and suppresses its activity, and has been used as a PTEN lipid phosphatase inhibitor. Here, bpv(pic) intervention was found to significantly increase the number of rat NSCs, as determined by bromodeoxyuridine staining and the cell counting kit-8, and to increase the percentage of neurons undergoing differentiation, as shown by immunofluorescence staining. Bpv(pic) intervention also significantly increased PTEN and mTOR expression, as shown by real-time PCR analysis and western blotting. In conclusion, PTEN inhibitor bpv(pic) promotes the proliferation and differentiation of NSCs into neurons. [ABSTRACT FROM AUTHOR]