Functional Mechanism Research Articles

Sex-dependent intra-islet structural rearrangements affecting alpha-to-beta cell interactions lead to adaptive enhancements of Ca2+ dynamics in prediabetic beta cells

Aims/hypothesisPrediabetic pancreatic beta cells can adapt their function to maintain normoglycaemia for a limited period of time, after which diabetes mellitus will manifest upon beta cell exhaustion. Understanding sex-specific beta cell compensatory mechanisms and their failure in prediabetes (impaired glucose tolerance) is crucial for early disease diagnosis and individualised treatment. Our aims were as follows: (1) to determine the key time points of the progression from beta cells’ functional adaptations to their failure in vivo; and (2) to mechanistically explain in vivo sex-specific beta cell compensatory mechanisms and their failure in prediabetes.MethodsIslets from male and female transgenic Ins1CreERT2-GCaMP3 mice were transplanted into the anterior chamber of the eye of 10- to 12-week-old sex-matched C57BL/6J mice. Recipient mice were fed either a control diet (CD) or western diet (WD) for a maximum of 4 months. Metabolic variables were evaluated monthly. Beta cell cytoplasmic free calcium concentration ([Ca2+]i) dynamics were monitored in vivo longitudinally by image fluorescence of the GCaMP3 reporter islets. Global islet beta cell [Ca2+]i dynamics in line with single beta cell [Ca2+]i analysis were used for beta cell coordination studies. The glucagon receptor antagonist L-168,049 (4 mmol/l) was applied topically to the transplanted eyes to evaluate in vivo the effect of glucagon on beta cell [Ca2+]idynamics. Human islets from non-diabetic women and men were cultured for 24 h in either a control medium or high-fat/high-glucose medium in the presence or absence of the glucagon receptor antagonist L-168,049. [Ca2+]i dynamics of human islets were evaluated in vitro after 1 h exposure to Fura-10.ResultsMice fed a WD for 1 month displayed increased beta cell [Ca2+]i dynamics linked to enhanced insulin secretion as a functional compensatory mechanism in prediabetes. Recruitment of inactive beta cells in WD-fed mice explained the improved beta cell function adaptation observed in vivo; this occurred in a sex-specific manner. Mechanistically, this was attributable to an intra-islet structural rearrangement involving alpha cells. These sex-dependent cytoarchitecture reorganisations, observed in both mice and humans, induced enhanced paracrine input from adjacent alpha cells, adjusting the glucose setpoint and amplifying the insulin secretion pathway. When WD feeding was prolonged, female mice maintained the adaptive mechanism due to their intrinsically high proportion of alpha cells. In males, [Ca2+]i dynamics progressively declined subsequent to glucose stimulation while insulin secretion continue to increase, suggesting uncoordinated beta cell function as an early sign of diabetes.Conclusions/interpretationWe identified increased coordination of [Ca2+]i dynamics as a beta cell functional adaptation mechanisms in prediabetes. Importantly, we uncovered the mechanisms by which sex-dependent beta cell [Ca2+]i dynamics coordination is orchestrated by an intra-islet structure reorganisation increasing the paracrine input from alpha cells on beta cell function. Moreover, we identified reduced [Ca2+]i dynamics coordination in response to glucose as an early sign of diabetes preceding beta cell secretory dysfunction, with males being more vulnerable. Alterations in coordination capacity of [Ca2+]i dynamics may thus serve as an early marker for beta cell failure in prediabetes.Graphical

Studying quantum effects of fine scaling on the buckling behavior of CNTs under torsional loading using the density functional theory and molecular mechanics approach

In this study, we introduce a comprehensive investigation into the buckling behavior of carbon nanotubes (CNTs) using a combined approach of quantum mechanics and molecular mechanics methods. A novel aspect of our research lies in the exploration of the quantum effects of fine scaling on the buckling behavior of finite‐length nanotubes across various dimensions and chiralities. Specifically, we analyze the critical buckling strain variations in CNTs with distinct lengths, diameters, and chiralities, revealing pronounced differences influenced by atomic arrangement and the type of structure used in nanotube construction. Our findings elucidate that at smaller dimensions, nanotubes exhibit a higher critical buckling strain than other chiralities, while zigzag atomic arrangements demonstrate greater resistance to torsional loading at larger diameters. Additionally, we compare the buckling behavior of nanotubes obtained by wrapping armchair and zigzag nanosheets, highlighting differential resistance trends. This research not only underscores the critical role of quantum effects in determining nanotube buckling but also provides valuable insights into the nuanced influences of atomic arrangement and nanosheet type on the mechanical properties of CNTs. Thus, our work contributes a novel perspective to the field, bridging the gap between quantum mechanics and the mechanical behavior of nanostructures, which has significant implications for the design and application of nanoscale materials

Let-7 microRNA targets BmCentrin to modulate the development and functionality of the middle silk gland in the silkworm, Bombyx mori.

The silk gland of the silkworm Bombyx mori serves as a valuable model for investigating the morphological structure and physiological functions of organs. Previous studies have demonstrated the notable regulatory role of let-7 microRNA in the silk gland, but its specific molecular mechanism remains to be elucidated across different segments of this organ. In this study, we further investigated the functional mechanism of let-7 in the middle silk gland (MSG). The MSG of a let-7 knockout strain was analyzed using a combined proteomic and metabolomic technique, revealing the enrichment of differential proteins and metabolites in the DNA synthesis and energy metabolism pathways. BmCentrin was identified as a novel target gene of let-7 in the MSG, and its downregulation inhibited the proliferation of BmN4-SID1 cells, which is exactly opposite to the role of let-7 in these cells. CRISPR/Cas9 genome editing and transgenic technologies were employed to manipulate BmCentrin in the MSG. Knockout of BmCentrin led to severe MSG atrophy, whereas the overexpression of BmCentrin resulted in beaded MSG. Further measurements of these knockout or overexpression strains revealed significant changes in the expression levels of sericin protein genes, the weight of the cocoon and the mechanical properties of the silk. Investigating the biological role of BmCentrin in the silk gland offers valuable insights for elucidating the molecular mechanisms by which let-7 controls silk gland development and silk protein synthesis in the silkworm.

THE GENESIS OF THE PRINCIPLES OF THE LEGAL STATUS OF AN INDIVIDUAL IN EUROPEAN INTERNATIONAL LEGAL REALITY

Introduction. The article considers historical and legal origins of the foundations of the legal status of an individual in the European system of protection of human rights and freedoms as part of international legal reality of the region. The work examines the phenomenon of the legal status of a person in the European international legal reality in view of its modern normative regulation, protection mechanisms at the regional level and worldview sources of the evolution of its foundations. Summary of the main research results. It was determined that the European international legal reality is a regional phenomenon of international law and includes universal and European regional norms and principles, sub-regional European international legal acts, legal culture and legal consciousness, moral value characteristics and institutions of European international law. The latter is closely related to the phenomenon of the European international legal reality in terms of reflecting the objective legal realm in Europe. The main purpose of the functioning of the European international legal reality is the protection of human rights and freedoms in the region. The regional system of protection of human rights and freedoms is an integral part of the European international legal reality and guarantees the fundamentals of the legal status of a person in Europe. The main principles of the legal status of a person in the European international legal reality are the general principles and standards of law, the moral, value and ideological characteristics of European international law. The genesis of the foundations of the legal status of a person in Europe and European identity in general is ancient Roman law, Christian dogmas and Germanic customs. It was the preservation of the main system-forming components of the Roman legal complex of principles and norms, the influence of Christian spirituality concept on the general European attitude towards the individual and the separation of the Romano-Germanic legal family features on the basis of Germanic phenomenon that became the basis of the modern European legal reality and laid the foundations of the individual's legal position. Conclusions. At the current stage of the European international legal reality development, the legal status of a person is a fundamental category that emerged and evolved on the basis of centuries-old legal traditions of the region. Current regulatory and legal consolidation and functioning of regional mechanisms for the protection of human rights and freedoms is the result of historical and legal evolution of the foundations of the legal status of a person in Europe.

Effective delivery of miR-150-5p with nucleus pulposus cell-specific nanoparticles attenuates intervertebral disc degeneration.

The use of gene therapy to deliver microRNAs (miRNAs) has gradually translated to preclinical application for the treatment of intervertebral disc degeneration (IDD). However, the effects of miRNAs are hindered by the short half-life time and the poor cellular uptake, owing to the lack of efficient delivery systems. Here, we investigated nucleus pulposus cell (NPC) specific aptamer-decorated polymeric nanoparticles that can load miR-150-5p for IDD treatment. The role of miR-150-5p during disc development and degeneration was examined by miR-150-5p knockout (KO) mice. Histological analysis was undertaken in disc specimens. The functional mechanism of miR-150-5p in IDD development was investigated by qRT-PCR assay, Western blot, coimmunoprecipitation and immunofluorescence. NPC specific aptamer-decorated nanoparticles was designed, and its penetration, stability and safety were evaluated. IDD progression was assessed by radiological analysis including X-ray and MRI, after the annulus fibrosus needle puncture surgery with miR-150-5p manipulation by intradiscal injection of nanoparticles. The investigations into the interaction between aptamer and receptor were conducted using mass spectrometry, molecular docking and molecular dynamics simulations. We investigated NPC-specific aptamer-decorated polymeric nanoparticles that can bind to miR-150-5p for IDD treatment. Furthermore, we detected that nanoparticle-loaded miR-150-5p inhibitors alleviated NPC senescence in vitro, and the effects of the nanoparticles were sustained for more than 3months in vivo. The microenvironment of NPCs improves the endo/lysosomal escape of miRNAs, greatly inhibiting the secretion of senescence-associated factors and the subsequent degeneration of NPCs. Importantly, nanoparticles delivering miR-150-5p inhibitors attenuated needle puncture-induced IDD in mouse models by targeting FBXW11 and inhibiting TAK1 ubiquitination, resulting in the downregulation of NF-kB signaling pathway activity. NPC-targeting nanoparticles delivering miR-150-5p show favorable therapeutic efficacy and safety and may constitute a promising treatment for IDD.

FEATURES OF THE USE OF TECHNICAL MEANS IN THE REMEDIAL WORK WITH PERSONS WITH STUTTERING

The scientific and methodological article considers the problem of using technical means to correct stuttering. The existing approaches to speech therapy work using traditional methods were analyzed as well as the peculiarities of the implementation of acoustic devices. The method of rhythmization as an effective means of overcoming stuttering is considered in detail and the features of its use are determined. Based on the results of the research, it was concluded that modern technical devices allow designing fundamentally new pedagogical technologies. Specialists in special education direct these technologies to the activation and effective functioning of compensatory mechanisms, the formation and development of speech activity of persons with stuttering. The purpose of the study is to analyze the existing approaches to speech therapy work using traditional methods and to outline the role of technical acoustic means in the process of speech correction. The use of technical means in remedial work with persons with speech disorders is a challenge of the times, which reflects progressive changes in the scientific and technical sphere and improves the effectiveness of logocorrective work for various mental and physical disorders. Technical means allow for remedial and developmental work to overcome stuttering, and their implementation requires compliance with certain conditions: compliance of the special software with the computer configuration; use of methodically justified and tested technical means and programs; ensuring the optimal load regime; complex influence in the process of correction of group classes and individual consultations; creation of a comfortable psycho-emotional environment; the use of modern remedial technologies and their differentiated use, taking into account the individual characteristics of a patient. We see the prospect of further research in the development of methods of using information and communication technologies in remedial work with persons with severe speech disorders.

Protective effects of Maillard products of skipjack trypsin hydrolysate on uric acid-induced injury of human kidney-2 cell (HK-2)

ABSTRACT The uric acid (UA) induced damage influences human health and deserves attention. The purpose of this study was to investigate the protective effects of Skipjack trypsin hydrolysate (STH) and its Maillard product (STH-M) and the segmentation of STH-M (STH-M-S) against UA-induced HK-2 cells. The CCK8 assay was used to detect cell viability and flow cytometry was performed to check cell apoptosis and cell cycle and the functional mechanism was analyzed via transcriptome. The results showed STH-M-S could significantly improve the cell viability and inhibit cell apoptosis. Meanwhile, STH-M-S could influence the membrane and protein binding and regulate metabolic-related and immune-related pathways to deal with UA stress. Functional genes contained NEBL, KCNJ16, ABCA12, CLDN2, FLRT3, PRODH, KLHL14, VEPH1, HPGD (down regulated) and FOXL1, SCG5 (up regulated). Collectively, our results suggested that STH-M-S can alleviate cell injury induced by UA. STH-M-S could be an alternative to be applied for the treatment of hyperuricemia.

The axes of biology: a novel axes-based network embedding paradigm to decipher the functional mechanisms of the cell.

Common approaches for deciphering biological networks involve network embedding algorithms. These approaches strictly focus on clustering the genes' embedding vectors and interpreting such clusters to reveal the hidden information of the networks. However, the difficulty in interpreting the genes' clusters and the limitations of the functional annotations' resources hinder the identification of the currently unknown cell's functioning mechanisms. We propose a new approach that shifts this functional exploration from the embedding vectors of genes in space to the axes of the space itself. Our methodology better disentangles biological information from the embedding space than the classic gene-centric approach. Moreover, it uncovers new data-driven functional interactions that are unregistered in the functional ontologies, but biologically coherent. Furthermore, we exploit these interactions to define new higher-level annotations that we term Axes-Specific Functional Annotations and validate them through literature curation. Finally, we leverage our methodology to discover evolutionary connections between cellular functions and the evolution of species. Data and source code can be accessed at https://gitlab.bsc.es/sdoria/axes-of-biology.git.

Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain.

To determine if a 4-week manual therapy treatment restores normal functioning of central pain processing mechanisms in non-specific chronic neck pain (NSCNP), as well as the existence of a possible relationship between changes in pain processing mechanisms and clinical outcome. Cohort study. Sixty-three patients with NSCNP, comprising 79% female, with a mean age of 45.8 years (standard deviation: 14.3), received four treatment sessions (once a week) of manual therapy including articular passive mobilizations, soft tissue mobilization and trigger point treatment. Pressure pain thresholds (PPTs), conditioned pain modulation (CPM) and temporal summation of pain (TSP) were evaluated at baseline and after treatment completion. Therapy outcome was measured using the Global Rating of Change Scale (GROC), the Neck disability Index (NDI), intensity of pain during the last 24 hours, Tampa Scale of Kinesiophobia (TSK) and Pain Catastrophizing Scale (PCS). Two sets of generalized linear mixed models with Gaussian response and the identity link were employed to evaluate the effect of the intervention on clinical, psychological and psychophysical measures and the association between psychophysical and clinical outcomes. Following treatment, an increased CPM response (Coefficient: 0.89; 95% credibility interval = 0.14 to 1.65; P = .99) and attenuated TSP (Coefficient: -0.63; 95% credibility interval = -0.82 to -0.43; P = 1.00) were found, along with amelioration of pain and improved clinical status. PPTs at trapezius muscle on the side of neck pain were increased after therapy (Coefficient: 0.22; 95% credibility interval = 0.03 to 0.42; P = .98), but not those on the contralateral trapezius and tibialis anterior muscles. Only minor associations were found between normalization of TSP/CPM and measures of clinical outcome. Clinical improvement after manual therapy is accompanied by restoration of CPM and TSP responses to normal levels in NSCNP patients. The existence of only minor associations between changes in central pain processing and clinical outcome suggests multiple mechanisms of action of manual therapy in NSCNP.

The mechanism of phonetic information in voice identity discrimination: a comparative study based on sighted and blind people

PurposeThe purpose of this study is to examine whether phonetic information functions and how phonetic information affects voice identity processing in blind people.MethodTo address the first inquiry, 25 normal sighted participants and 30 blind participants discriminated voice identity, when listening forward speech and backward speech from their own native language and another unfamiliar language. To address the second inquiry, combining articulatory suppression paradigm, 26 normal sighted participants and 26 blind participants discriminated voice identity, when listening forward speech from their own native language and another unfamiliar language.ResultsIn Experiment 1, not only in the voice identity discrimination task with forward speech, but also in the discrimination task with backward speech, both the sighted and blind groups showed the superiority of the native language. This finding supports the view that backward speech still retains some phonetic information, and indicates that phonetic information can affect voice identity processing in sighted and blind people. In addition, only the superiority of the native language of sighted people was regulated by the speech manner, which is related to articulatory rehearsal. In Experiment 2, only the superiority of the native language of sighted people was regulated by articulatory suppression. This indicates that phonetic information may act in different ways on voice identity processing in sighted and blind people.ConclusionThe heightened dependence on voice source information in blind people appears not to undermine the function of phonetic information, but it appears to change the functional mechanism of phonetic information. These findings suggest that the present phonetic familiarity model needs to be improved with respect to the mechanism of phonetic information.

Analysis of prognostic value of lactate metabolism-related genes in ovarian cancer based on bioinformatics

BackgroundRecent studies have provided evidence supporting the functional role and mechanism of lactate in suppressing anticancer immunity. However, there is no systematic analysis of lactate metabolism-related genes (LMRGs) and ovarian cancer (OV) prognosis.ResultsSix genes (CCL18, CCND1, MXRA5, NRBP2, OLFML2B and THY1) were selected as prognostic genes and a prognostic model was utilized. Kaplan-Meier (K-M) and Receiver Operating Characteristic (ROC) analyses were further performed and indicated that the prognostic model was effective. Subsequently, the neoplasm_cancer_status and RiskScore were determined as independent prognostic factors, and a nomogram was established with relatively accurate forecasting ability. Additionally, 2 types of immune cells (Central memory CD8 T cell and Immature B cell), 4 types of immune functions (APC co inhibition, DCs, Tfh and Th1 cells), 9 immune checkpoints (BTLA, CTLA4, IDO1, LAG3, VTCN1, CXCL10, CXCL9, IFNG, CD27) and tumor immune dysfunction and exclusion (TIDE) scores were significantly different between risk groups. The expression of 6 genes were verified by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and the expression of 6 genes were higher in the high-grade serous carcinoma (HGSC) samples.ConclusionA prognostic model related to lactate metabolism was established for OV based on six genes (CCL18, CCND1, MXRA5, NRBP2, OLFML2B and THY1) that could provide new insights into therapy.

Functional Property and Regulatory Mechanism of Macrophages in Complementary and Alternative Medicine: From Bench to Clinic.

Complementary and alternative medicine (CAM) includes a wide range of treatments that are gaining acceptance among the public. It is increasingly being recognized as a viable option for treating various diseases with minimal side effects. Common avenues of this therapy include herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy, and homeopathy etc. Macrophages are highly heterogeneous cells that play multiple regulatory roles. Practices such as herbal medicine, acupuncture, physical exercise, aromatherapy and dietary therapy exert curative effects by modulating the polarization status and the secretory phenotype of macrophages directly. Furthermore, herbal medicine, acupuncture, and physical exercise influence the crosstalk between macrophages and other types of cells, including cancer cells and T cells. Mechanistically, herbal medicine and acupuncture produce curative effects in diverse diseases, including inflammatory diseases and tumors, mainly by influencing the phosphorylation of signaling proteins in macrophages. Therefore, targeting macrophages offers theoretical support for advancing the scientific understanding of this therapy and aids in identifying potential therapeutic options. Hence, in this review, we systematically summarize the different regulations of macrophages in herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy and homeopathy, and further highlight the therapeutic potential of targeting macrophages in complementary and alternative medicine.

Characteristics and Trends of Urban Waterfront Human Settlements Based on CiteSpace

Urban waterfront human settlements have gradually become a hot topic for research in recent years. Using CiteSpace, 597 publications from 2017 to 2023 that were retrieved from the Web of Science were analyzed and sorted out, and the following characteristics were found: (1) The research hotspots transitioned from thermal comfort evaluation to the functional mechanism of water bodies, and then to the impact on the environment and residents’ behavior. (2) The integration of disciplines has promoted the diversification of perspectives on urban waterfront human settlements, and the content has become more concentrated in interdisciplinary fields. Research on corresponding technology and methods of urban waterfront human settlement has improved, and so has the extensiveness of the experiments. (3) The research on urban waterfront human settlement from the perspective of ecology has been improving. The research focuses more on the harmonious coexistence of ecological and cultural values and human beings.

FYN as an emerging biological biomarker for prognosis and potential therapeutic target in LGG

ABSTRACT Objectives This study aimed to explore the expression, clinical significance, and functional mechanism of FYN in lower-grade gliomas (LGG). Methods The mRNA and protein expression of FYN in LGG tissues were detected using databases including OncoLnc, GEPIA, and Human protein atlas (HPA). The UCSC Xena browser, TIMER, STRING and Metascape databases were used to investigate Kaplan–Meier survival curves, correlations between FYN expression and various types of immune cell infiltration, protein interaction network and possible functional mechanism. Results FYN expression in LGG, IDH mutation or 1p19q co-deletion subgroup was significantly higher than in corresponding control groups (p < 0.05). Patients with higher FYN expression had longer overall survival (p < 0.05). Male or no 1p19q co-deletion groups with higher FYN expression also had longer overall survival (p < 0.05). FYN expression had close correlation with infiltrating levels of cell purity, CD4+T cells, macrophages, and CD8+T cells (p < 0.05). Protein interaction network result showed correlation among FYN, SH2D1A, LCK, CAV1, SRC, CBL and PTK2. Functional enrichment analysis revealed that FYN and its related genes mainly participated in bacterial invasion of epithelial cells and natural killer cell mediated cytotoxicity. Peptidyl-tyrosine phosphorylation, negative regulation of anoikis, immune effector process, transmembrane receptor protein tyrosine kinase signaling pathway, epidermal growth factor receptor signaling pathway, and negative regulation of protein modification process may be the critical biological process. Conclusions FYN is up-expressed in LGG and related to its good prognosis. It participated in tumor pathophysiological processes and may be a therapeutic target for LGG.

Space in the “DAU” project (dir. Ilya Khrzhanovsky). Contexts

The article is devoted to the analysis of space in the “DAU” project, directed by Ilya Khrzhanovsky in cooperation with Yekaterina Oertel, Alexei Slyusarchuk and Ilya Permakov, among others. Feature films and documentaries that constitute the project were shot in the years 2009–2012, mainly in Kharkiv, in a closed scientific institute, built exclusively for this purpose. The aim of the article is to examine selected spatial solutions in the project, to contextualize them, and, consequently, to link the film architecture with the behavioral sphere and the corporeality of the characters. The methodological tool, supporting the research of the text, is the category of the underground, embedded in the work Notes from the Underground by Fyodor Dostoyevsky. In the process of interpretation, the author draws attention to the connections between the mechanisms of oppression functioning in the totalitarian system and the symbolic language of the body and architecture.

Legal regulation of the activities of cooperative societies in Eastern Galicia in the interwar period at the beginning of the ХХ century

Based on archival materials, legislative acts, and studies of contemporaries, the article attempts to highlight the role of legal regulation in the formation and development of the cooperative movement in the region. The study helps to better understand the complex interaction between political authorities and public initiatives in the context of socio-economic transformations of the interwar period in Eastern Galicia. The problem of legal regulation of the activities of cooperative societies in Eastern Galicia in the early twentieth century, in particular in the interwar period, is relevant and important for understanding the socio-economic processes of that time. A study of this issue will allow us to better understand the role and impact of the cooperative movement on the development of economic sectors and the lives of the local population. This article examines the legal environment in which cooperative societies operated in Eastern Galicia in the interwar period. The article analyses the legal acts regulating the status, rights and obligations of cooperative organisations and assesses their effectiveness and impact on the development of the cooperative movement (the Trade Law, the Law on Companies, the Ministry of Internal Affairs’ Order). However, the legal regulation of the activities of cooperative societies during this period remains poorly understood, especially in terms of their impact on community development and economic well-being of the region. The development of the Ukrainian cooperative movement in the nineteenth century coincided with the beginning of the capitalist industrialisation of Ukrainian lands. The Austrian government took this movement seriously, which was reflected in a large number of legislative initiatives of the Austrian Reichsrat. The government adopted various legal acts aimed at regulating the activities of voluntary associations, organisations and societies. Coverage of this topic will help to understand the mechanisms of functioning of cooperatives in the fields of production, trade and services, as well as their interaction with government agencies and other sectors of the economy. Further research on this topic could serve as a basis for developing recommendations for improving the legal environment for the development of the cooperative sector in modern Ukraine.

Decreased expression of KLF6 in ectopic endometrial stromal cells contributes to endometriosis progression by targeting CTNNB1

Despite decades of research, endometriosis remains a mysterious gynecological disease with unknown etiology and pathogenesis. Krüppel-like Factor 6 (KLF6), a transcription factor, has a wide expression profile and regulates a variety of biological processes. Here, we investigated the expression and function of KLF6 and its possible regulatory mechanisms in endometriosis. To determine the function of KLF6, knockdown and overexpression experiments were performed in eutopic endometrial stromal cells (EU-ESCs) and ectopic endometrial stromal cells (EC-ESCs), respectively. Cell viability, apoptosis, migration, invasion, and angiogenesis assays were conducted in ESCs. ChIP-sequencing and mRNA-sequencing were performed to investigate the functional mechanism of KLF6 in regulating ESCs. We found that KLF6 was highly expressed in eutopic endometrium of endometriosis patients, compared with ectopic endometrium. Similarly, the same was true in EU-ESCs, which was compared with EC-ESCs. Overexpression of KLF6 significantly suppressed EC-ESC proliferation, migration and invasion and induced cell apoptosis, while knockdown of KLF6 resulted in the opposite effects on EU-ESCs. Overexpression of KLF6 significantly inhibited EC-ESC angiogenesis. Mechanistically, the results of ChIP sequencing and mRNA sequencing revealed that CTNNB1 may be a transcriptional target regulated by KLF6. Reintroduction of KLF6 reversed the effects of KLF6 knockdown on EU-ESCs. KLF6 inhibited the proliferation, migration and angiogenesis of EC-ESCs by inhibiting the expression of CTNNB1. Our findings provided a new perspective on the role of KLF6 in endometriosis progression and inspire potential targeted therapeutic strategies.

Luteolin attenuates CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11.

Luteolin (3,4,5,7-tetrahydroxy flavone) is reported to strongly protect from acute carbon tetrachloride (CCl4) -induced liver injury or fibrosis. Ferroptosis can be induced by hepatic injury, and contributes to liver fibrosis development. The exact functional mechanism underlying luteolin inhibition of hepatic injury and whether ferroptosis is involved are unclear. Mice model and cell model of liver injury were constructed or induced to explore the effect and molecular mechanisms of Luteolin in the treatment of hepatic injury using CCl4. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to evaluate HepG2 cell viability and apoptosis. The differential expressed genes involved in liver injury were scanned using RNA-seq and confirmed using functional study. Western blot was used to detect the indicators related to ferroptosis. Luteolin attenuated hepatic injury by alleviating cell morphology and decreasing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels in vivo mice models, and increasing cell viability, downregulating arachidonate 12-lipoxygenase (ALOX12), cyclooxygenase-2 (COX-2) and P21 protein expression, suppressing apoptosis in vitro cell models. Luteolin also inhibited ferroptosis by stimulating glutathione peroxidase 4 (GPX4) and mitochondrial ferritin (FTMT) protein expression, increasing glutathione (GSH) content, and minimizing Fe2+ and malondialdehyde (MDA) levels. Solute carrier family 7a member 11 (SLC7A11) was identified to be a key regulatory gene that participated in luteolin attenuation of CCl4-induced hepatic injuries in HepG2 cells using Microarray assay. Functional study showed that SLC7A11 can alleviate hepatic injury and ferroptosis. Luteolin attenuated CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11. SLC7A11 may serve as a novel alternative therapeutic target for hepatic injury.

CLOCK evolved in cnidaria to synchronize internal rhythms with diel environmental cues

CLOCK evolved in cnidaria to synchronize internal rhythms with diel environmental cues

CLOCK evolved in cnidaria to synchronize internal rhythms with diel environmental cues.

The circadian clock enables anticipation of the day/night cycle in animals ranging from cnidarians to mammals. Circadian rhythms are generated through a transcription-translation feedback loop (TTFL or pacemaker) with CLOCK as a conserved positive factor in animals. However, CLOCK's functional evolutionary origin and mechanism of action in basal animals are unknown. In the cnidarian Nematostella vectensis, pacemaker gene transcript levels, including NvClk (the Clock ortholog), appear arrhythmic under constant darkness, questioning the role of NvCLK. Utilizing CRISPR/Cas9, we generated a NvClk allele mutant (NvClkΔ), revealing circadian behavior loss under constant dark (DD) or light (LL), while maintaining a 24 hr rhythm under light-dark condition (LD). Transcriptomics analysis revealed distinct rhythmic genes in wild-type (WT) polypsunder LD compared to DD conditions. In LD, NvClkΔ/Δ polyps exhibited comparable numbers of rhythmic genes, but were reduced in DD. Furthermore, under LD, the NvClkΔ/Δ polyps showed alterations in temporal pacemaker gene expression, impacting their potential interactions. Additionally, differential expression of non-rhythmic genes associated with cell division and neuronal differentiation was observed. These findings revealed that a light-responsive pathway can partially compensate for circadian clock disruption, and that the Clock gene has evolved in cnidarians to synchronize rhythmic physiology and behavior with the diel rhythm of the earth's biosphere.