Cell Contraction Research Articles

Glucose Upregulates ChREBP via Phosphorylation of AKT and AMPK to Modulate MALT1 and WISP1 Expression.

Glucose can activate the carbohydrate response element binding protein (ChREBP) transcription factor to control gene expressions in the metabolic pathways. The way of ChREBP involvement in human prostate cancer development remains undetermined. This study examined the interactions between prostate fibroblasts and cancer cells under the influences of ChREBP. Results showed that high glucose (30 mM) increased the phosphorylation of AKT at S473 and AMP-activated protein kinase (AMPK) at S485 in human prostate fibroblast (HPrF) cells and prostate cancer PC-3 cells. High glucose enhanced the expression of ChREBP, which increased the expressions of fibronectin, alpha-smooth muscle actin (α-SMA), and WNT1 inducible signaling pathway protein 1 (WISP1), magnifying the cell growth and contraction in HPrF cells in vitro. The cell proliferation, invasion, and tumor growth in prostate cancer PC-3 cells were enhanced by inducing the expressions of ChREBP, mucosa-associated lymphoid tissue 1 (MALT1), and epithelial-mesenchymal transition markers with high glucose treatment. Moreover, ectopic ChREBP overexpression induced NF-κB signaling activities via upregulating MALT1 expression in PC-3 cells. Our findings illustrated that ChREBP is an oncogene in the human prostate. High glucose condition induces a glucose/ChREBP/MALT1/NF-κB axis which links the glucose metabolism to the NF-κB activation in prostate cancer cells, and a glucose/ChREBP/WISP1 axis mediating autocrine and paracrine signaling between fibroblasts and cancer cells to promote cell migration, contraction, growth, and invasion of the human prostate.

CSIG-24. BRAIN MICROENVIRONMENT-DEPENDENT NEURODEVELOPMENTAL LINEAGE PLASTICITY PROMOTES ADAPTATION TO ONCOGENE INHIBITION IN MALIGNANT GLIOMAS

Abstract Phenotypic plasticity drives non-genetic tumor adaptation in response to various microenvironmental and therapeutic pressures, consequently promoting tumor heterogeneity and progression. In malignant gliomas, the intrinsic and extrinsic mechanisms underlying phenotypic lineage plasticity and its contribution to drug resistance remain unclear. The epidermal growth factor receptor (EGFR) is frequently altered in glioma and serves as a critical regulator of normal radial glia (RG) cells – multipotent progenitors that give rise to cortical neurons and glia in the developing brain. Here, through interrogation of a large panel of diverse glioblastoma (GBM) patient-derived gliomaspheres and orthotopic xenografts, we find that enrichment of RG-like cells is significantly correlated with responses to pharmacological ablation of EGFR, highlighting EGFR as a crucial lineage survival factor for a population of malignant RG-like cells in GBM. Single-cell RNA sequencing and quantitative proteomics reveal that adaptation to EGFR inhibition is linked to a temporal contraction in RG-like cells and concomitant increase in lineage-restricted neuronal and oligodendrocyte progenitor (NPC/OPC)-like states exclusively in the orthotopic brain environment. This lineage transition is coupled to heightened RAS signaling gene expression programs and sustained activation of MAPK signaling, despite robust and durable inhibition of EGFR activation. Furthermore, constitutively active MEK – but not AKT – is sufficient to rescue tumor proliferation under EGFRi, suggesting that the brain microenvironment modulates RAS-MAPK oncogenic signaling to drive lineage transitions following EGFR blockade. Collectively, these results highlight a critical link between oncogenic signaling and neurodevelopmental lineage plasticity in malignant gliomas, presenting a compelling therapeutic opportunity to block tumor cell state transitions for more durable tumor responses in the native glioma tumor microenvironment.

Anthrax lethal toxin exerts potent metabolic inhibition of the cardiovascular system.

Bacillus anthracis causes anthrax through a combination of bacterial infection and toxemia. As a major virulence factor of B. anthracis, anthrax lethal toxin (LT) is a zinc-dependent metalloproteinase, exerting its cytotoxicity through proteolytic cleavage of the mitogen-activated protein kinase kinases, thereby shutting down the MAPK pathways. Anthrax lethal toxin induces host lethality mostly by targeting the cardiovascular system. Although the enzymatic activity and the molecular targets of LT have long been known, the detailed mechanisms underlying cellular/tissue/organ toxicity are still poorly understood. In this work, we sought to investigate the mechanism of LT-induced cellular damage in the cardiovascular system. We demonstrate for the first time that anthrax lethal toxin has potent inhibitory effects on the central metabolism of cardiomyocytes and endothelial cells. This is likely due to the observed downregulating of c-Myc expression through the toxin-induced inhibition of the ERK pathway. Since c-Myc is a master transcription factor controlling the expression of many rate-limiting metabolic enzymes in glycolysis and the tricarboxylic acid cycle, LT's downregulation of c-Myc may lead to the observed bioenergetic collapse, particularly, in cardiomyocytes. Since cardiac cell contraction requires continuous production of large amounts of ATP, potent inhibition of the bioenergetics of cardiomyocytes would be incompatible with life. Thus, LT-induced lethality through targeting cardiomyocytes and endothelial cells appears to be a consequence of a bioenergetic collapse, likely due to the toxin's potent inhibitory activity on the MEK-ERK-c-Myc-metabolic/bioenergetic axis within these target cells of cardiovascular system.IMPORTANCEAnthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis, the causative pathogen of anthrax disease. Anthrax lethal toxin is a metalloproteinase that cleaves and inactivates MEKs, thereby shutting down MAPK pathways, leading to host mortality primarily through targeting of the cardiovascular system. However, the detailed mechanisms underlying the toxin's cellular and tissue toxicity are still poorly understood. Here, we found that anthrax lethal toxin has potent inhibitory activity on glycolysis and oxidative phosphorylation of cardiomyocytes and endothelial cells. These effects appear to be the consequence of downregulation of c-Myc, a master transcription factor that controls many rate-limiting enzymes of glycolysis and the tricarboxylic acid cycle. With the high demand on energy for cardiac contraction, the potent inhibition of cardiomyocyte metabolism by LT would be incompatible with life. This work provides critical insights into why the cardiovascular system is the major in vivo target of LT-induced lethality.

Metabolomics and proteomics insights into hepatic responses of weaned piglets to dietary Spirulina inclusion and lysozyme supplementation

BackgroundStudying the effect of dietary Spirulina and lysozyme supplementation on the metabolome and proteome of liver tissue contributes to understanding potential hepatic adaptations of piglets to these novel diets. This study aimed to understand the influence of including 10% Spirulina on the metabolome and proteome of piglet liver tissue. Three groups of 10 post-weaned piglets, housed in pairs, were fed for 28 days with one of three experimental diets: a cereal and soybean meal-based diet (Control), a base diet with 10% Spirulina (SP), and an SP diet supplemented with 0.01% lysozyme (SP + L). At the end of the trial, animals were sacrificed and liver tissue was collected. Metabolomics analysis (n = 10) was performed using NMR data analysed with PCA and PLS-DA. Proteomics analysis (n = 5) was conducted using a filter aided sample preparation (FASP) protocol and Tandem Mass Tag (TMT)-based quantitative approach with an Orbitrap mass spectrometer.ResultsGrowth performance showed an average daily gain reduction of 9.5% and a feed conversion ratio increase of 10.6% in groups fed Spirulina compared to the control group. Metabolomic analysis revealed no significant differences among the groups and identified 60 metabolites in the liver tissue. Proteomics analysis identified 2,560 proteins, with 132, 11, and 52 differentially expressed in the Control vs. SP, Control vs. SP + L and SP vs. SP + L comparisons, respectively. This study demonstrated that Spirulina enhances liver energy conversion efficiency, detoxification and cellular secretion. It improves hepatic metabolic efficiency through alterations in fatty acid oxidation (e.g., upregulation of enzymes like fatty acid synthase and increased acetyl-CoA levels), carbohydrate catabolism (e.g., increased glucose and glucose-6-phosphate), pyruvate metabolism (e.g., higher levels of pyruvate and phosphoenolpyruvate carboxykinase), and cellular defence mechanisms (e.g., upregulation of glutathione and metallothionein). Lysozyme supplementation mitigates some adverse effects of Spirulina, bringing physiological responses closer to control levels. This includes fewer differentially expressed proteins and improved dry matter, organic matter and energy digestibility. Lysozyme also enhances coenzyme availability, skeletal myofibril assembly, actin-mediated cell contraction, tissue regeneration and development through mesenchymal migration and nucleic acid synthesis pathways.ConclusionsWhile Spirulina inclusion had some adverse effects on growth performance, it also enhanced hepatic metabolic efficiency by improving fatty acid oxidation, carbohydrate catabolism and cellular defence mechanisms. The addition of lysozyme further improved these benefits by reducing some of the negative impacts on growth and enhancing nutrient digestibility, tissue regeneration, and overall metabolic balance. Together, Spirulina and lysozyme demonstrate potential as functional dietary components, but further optimization is needed to fully realize their benefits without compromising growth performance.

Ca2+ Signaling in Cardiovascular Fibroblasts

Fibrogenesis is a physiological process required for wound healing and tissue repair. It is induced by activation of quiescent fibroblasts, which first proliferate and then change their phenotype into migratory, contractile myofibroblasts. Myofibroblasts secrete extracellular matrix proteins, such as collagen, to form a scar. Once the healing process is terminated, most myofibroblasts undergo apoptosis. However, in some tissues, such as the heart, myofibroblasts remain active and sensitive to neurohumoral factors and inflammatory mediators, which lead eventually to excessive organ fibrosis. Many cellular processes involved in fibroblast activation, including cell proliferation, protein secretion and cell contraction, are highly regulated by intracellular Ca2+ signals. This review summarizes current research on Ca2+ signaling pathways underlying fibroblast activation. We present receptor- and ion channel-mediated Ca2+ signaling pathways, discuss how localized Ca2+ signals of the cell nucleus may be involved in fibroblast activation and present Ca2+-sensitive transcription pathways relevant for fibroblast biology. When investigated, we highlight how the function of Ca2+-handling proteins changes during cardiac and pulmonary fibrosis. Many aspects of Ca2+ signaling remain unexplored in different types of cardiovascular fibroblasts in relation to pathologies, and a better understanding of Ca2+ signaling in fibroblasts will help to design targeted therapies against fibrosis.

I-mfa, Mesangial Cell TRPC1 Channel, and Regulation of Glomerular Filtration Rate.

Inhibitor of MyoD family A (I-mfa) is a cytosolic protein. Its function in kidney is unknown. The aim of the present study was to examine the regulatory role of I-mfa on glomerular filtration rate (GFR). GFR was measured by transdermal measurement of FITC-sinitrin clearance in conscious wild type (WT) and I-mfa knockout (KO) mice. Cell contractility was assessed in a single human or mouse mesangial cell. Single cell RNA sequence (scRNA-seq), Western blot, and Ca2+ imaging were used to evaluate the effects of I-mfa on TRPCs at messenger, protein and functional levels in MCs. In KO mice, GFR was significantly lower than that in WT mice. In WT mice, knocking down I-mfa selectively in mesangial cells using targeted nanoparticle/siRNA delivery system significantly decreased GFR. In human mesangial cells, overexpression of I-mfa significantly blunted the Ang II-stimulated contraction, and knockdown of I-mfa significantly enhanced the contractile response. Consistently, the Ang II-induced contraction was significantly augmented in primary mesangial cells isolated from KO mice. The exaggerated response was restored by re-introducing I-mfa. Furthermore, scRNA-seq showed an increase in trpc1 messenger and Western blot showed an increase in TRPC1 protein abundance in I-mfa KO mouse mesangial cells. TRPC1 protein abundance was decreased in HEK cells overexpressing I-mfa. Ca2+ imaging experiments showed that downregulation of I-mfa significantly enhanced Ang II-stimulated Ca2+ entry in human mesangial cells. Finally, TRPC1 inhibitor, Pico145 significantly blunted Ang II-induced mesangial cell contraction. I-mfa positively regulated GFR by decreasing mesangial cell contractile function through inhibition of TRPC1-mediated Ca2+ signaling.

Regulation of vascular smooth muscle cell contraction during early postnatal ontogenesis

Growth of the body in early postnatal ontogenesis is associated with changes in the functioning of many organ systems, including the cardiovascular system. The circulatory system of newborns is characterized by numerous structural and functional features, which at the systemic level is manifested in a significantly lower level of blood pressure. This review describes the differences in the mechanisms of regulation of vascular smooth muscle cell contraction in early postnatal ontogenesis and in adulthood, including age-related changes in the functioning of ion channels, which activity affects membrane potential level and intracellular concentration of calcium ions, as well as changes in calcium sensitivity of the contractile apparatus. The final section of the review discusses the connection between the mechanisms regulating contraction and differentiation of vascular smooth muscle cells during maturation.

Pink1-Dependent Mitophagy in Vascular Smooth Muscle Cells: Implications for Arterial Constriction

Hypertension is a major global health issue, contributing to significant cardiovascular morbidity and mortality. Mitochondrial dysfunction, particularly through dysregulated mitophagy, has been implicated in the pathogenesis of hypertension. We wanted to find out the relationship between mitochondrial autophagy and changes in arterial smooth muscle cell tension and the molecular mechanism. Using RNA-seq analysis, we identified significant upregulation of autophagy-related genes, including Pink1, in the aortas of spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. Further in vivo and in vitro studies revealed enhanced mitophagy, characterized by increased expression of Pink1 protein. Our experiments showed that knockdown of Pink1 expression by shRNA attenuated KPSS-induced vascular smooth muscle cells (VSMCs) contraction, suggesting that excessive mitophagy contributes to vascular dysfunction in hypertension. These findings highlight Pink1-mediated mitophagy as a crucial player in hypertensive vascular remodeling and present a potential therapeutic target for managing hypertension.

Actomyosin contraction in the follicular epithelium provides the major mechanical force for follicle rupture during Drosophila ovulation

Ovulation is critical for sexual reproduction and consists of the process of liberating fertilizable oocytes from their somatic follicle capsules, also known as follicle rupture. The mechanical force for oocyte expulsion is largely unknown in many species. Our previous work demonstrated that Drosophila ovulation, as in mammals, requires the proteolytic degradation of the posterior follicle wall and follicle rupture to release the mature oocyte from a layer of somatic follicle cells. Here, we identified actomyosin contraction in somatic follicle cells as the major mechanical force for follicle rupture. Filamentous actin (F-actin) and nonmuscle myosin II (NMII) are highly enriched in the cortex of follicle cells upon stimulation with octopamine (OA), a monoamine critical for Drosophila ovulation. Pharmacological disruption of F-actin polymerization prevented follicle rupture without interfering with the follicle wall breakdown. In addition, we demonstrated that OA induces Rho1 guanosine triphosphate (GTP)ase activation in the follicle cell cortex, which activates Ras homolog (Rho) kinase to promote actomyosin contraction and follicle rupture. All these results led us to conclude that OA signaling induces actomyosin cortex enrichment and contractility, which generates the mechanical force for follicle rupture during Drosophila ovulation. Due to the conserved nature of actomyosin contraction, this work could shed light on the mechanical force required for follicle rupture in other species including humans.

Relaxin Modulates the Genomic Actions and Biological Effects of Estrogen in the Myometrium.

Estradiol (E2) and relaxin (Rln) are steroid and polypeptide hormones, respectively, with important roles in the female reproductive tract, including myometrium. Some actions of Rln, which are mediated by its membrane receptor RXFP1, require or are augmented by E2 signaling through its cognate nuclear steroid receptor, estrogen receptor alpha (ERα). In contrast, other actions of Rln act in opposition to the effects of E2. Here we explored the molecular and genomic mechanisms that underlie the functional interplay between E2 and Rln in the myometrium. We used both ovariectomized female mice and immortalized human myometrial cells expressing wild-type or mutant ERα (hTERT-HM-ERα cells). Our results indicate that Rln modulates the genomic actions and biological effects of estrogen in the myometrium and myometrial cells by reducing phosphorylation of ERα on serine 118 (S118), as well as by reducing the E2-dependent binding of ERα across the genome. These effects were associated with changes in the hormone-regulated transcriptome, including a decrease in the E2-dependent expression of some genes and enhanced expression of others. The inhibitory effects of Rln cotreatment on the E2-dependent phosphorylation of ERα required the nuclear dual-specificity phosphatases DUSP1 and DUSP5. Moreover, the inhibitory effects of Rln were reflected in a concomitant inhibition of the E2-dependent contraction of myometrial cells. Collectively, our results identify a pathway that integrates Rln/RXFP1 and E2/ERα signaling, resulting in a convergence of membrane and nuclear signaling pathways to control genomic and biological outcomes.

PIP5K-Ras bistability initiates plasma membrane symmetry breaking to regulate cell polarity and migration.

Symmetry breaking, polarity establishment, and spontaneous cell protrusion formation are fundamental but poorly explained cell behaviors. Here, we demonstrate that a biochemical network, where the mutually inhibitory localization of PIP5K and Ras activities plays a central role, governs these processes. First, in resting cells devoid of cytoskeletal activity, PIP5K is uniformly elevated on the plasma membrane, while Ras activity remains minimal. Symmetry is broken by spontaneous local displacements of PIP5K, coupled with simultaneous activations of Ras and downstream signaling events, including PI3K activation. Second, knockout of PIP5K dramatically increases both the incidence and size of Ras-PI3K activation patches, accompanied by branched F-actin assembly. This leads to enhanced cortical wave formation, increased protrusive activity, and a shift in migration mode. Third, high inducible overexpression of PIP5K virtually eliminates Ras-PI3K signaling, cytoskeletal activity, and cell migration, while acute recruitment of cytosolic PIP5K to the membrane induces contraction and blebs in cancer cells. These arrested phenotypes are reversed by reducing myosin II activity, indicating myosin's involvement in the PIP5K-Ras-centered regulatory network. Remarkably, low inducible overexpression of PIP5K unexpectedly facilitates polarity establishment, highlighting PIP5K as a highly sensitive master regulator of these processes. Simulations of a computational model combining an excitable system, cytoskeletal loops, and dynamic partitioning of PIP5K recreates the experimental observations. Taken together, our results reveal that a bistable, mutually exclusive localization of PIP5K and active Ras on the plasma membrane triggers the initial symmetry breaking. Coupled actomyosin reduction and increased actin polymerization lead to intermittently extended protrusions and, with feedback from the cytoskeleton, self-organizing, complementary gradients of PIP5K versus Ras steepen, raising the threshold of the networks at the rear and lowering it at the front to generate polarity for cell migration.

The Function of RhoA/ROCK Pathway and MYOCD in Airway Remodeling in Asthma

Plain Language SummaryAsthma is a common chronic respiratory disease characterized by chronic airway inflammation and abnormal airway remodeling. The regulation process of RhoA/ROCK signaling pathway and downstream MRTF-A gene is well studied and exhibits significant associations with cell contraction and cell proliferation, which correlates tightly with airway remodeling. While most studies focusing on the MRTF-A to clarify the mechanism of cell growth, we paid close attention to MYOCD gene, which shares homology with MRTF-A but expressed specifically in smooth muscle cells. Through the series cell experiments, molecular assays, and literature review, we firstly illustrated the potential function of MYOCD underlying the regulation of RhoA/ROCK activated cell proliferation and subsequent airway remodeling in airway smooth muscle cells. This novel sight provides therapeutic targets for asthma.

Unveiling the Bioactive Potential of Bacterial Isolates from Extreme Environments of Pakistan by In Vitro and In Silico Approaches.

The soil hosts a wide array of bacterial species capable of producing diverse bioactive compounds. This research aimed to screen bacterial isolates for their bioactive potential from extreme environments in Pakistan. Out of the 69 isolates examined, only 7 exhibited antagonistic activity against Bacillus sp. and Escherichia coli test strains. Notably, the B. cereus DS-2 strain demonstrated the highest antibacterial potential (31mm and 15mm) against the Bacillus and E. coli test strains, respectively. Mode-of-action studies suggested that the crude extract might have induced morphological abnormalities in the Bacillus sp. (test strain), causing cell contraction, chain breakage, and deformation. Furthermore, the B. cereus DS-2 strain displayed significant antioxidant potential (64.8%) as revealed by the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Thin-layer chromatography (TLC) of the DS-2crude extract led to the separation of six components, with only spots 3 and 4 exhibiting the antibacterial potential (3mm and 5mm, respectively). Subsequently, gas chromatography-mass spectrometry (GC-MS) analysis of the bioactive fraction extracted from TLC revealed the presence of diisooctyl phthalate, dibutyl phthalate, hexadecanoic acid methyl ester, and octadecanoic acid methyl ester. Molecular docking analysis of diisooctyl phthalate and dibutyl phthalate revealed their binding affinity against E. coli and Bacillus sp. targets. ADMET analysis confirmed the solubility, toxicity, and drug-like properties of the ligands based on Lipinski's rule of five. Current findings suggest that these compounds hold promise as antibacterial agents in drug development. This study underscores the diverse microbial community present in extreme environments and highlights the versatile applications of natural products derived from these strains.

Silencing the long noncoding RNA MALAT1 inhibits vitreous-induced epithelial-mesenchymal transition in RPE cells by regulating the PDGFRs/AKT axis.

Epithelial-mesenchymal transition (EMT) is a crucial pathological process that contributes to proliferative vitreoretinopathy (PVR), and research indicates that factors present in the vitreous that target cells play pivotal roles in regulating EMT. Experimental studies have confirmed that rabbit vitreous (RV) promotes EMT in human retinal pigment epithelial (RPE) cells. The long noncoding RNA (lncRNA) MALAT1 has been implicated in EMT in various diseases. Thus, this study aimed to investigate the involvement of lncRNA MALAT1 in vitreous-induced EMT in RPE cells. MALAT1 was knocked down in ARPE-19 cells by short hairpin RNA (shRNA) transfection. Reverse transcription PCR (RT‒PCR) was used to evaluate MALAT1 expression, and Western blotting analysis was used to measure the expression of EMT-related proteins. Wound-healing, Transwell, and cell contraction assays were conducted to assess cell migration, invasion, and contraction, respectively. Additionally, cell proliferation was assessed using the CCK-8 assay, and cytoskeletal changes were examined by immunofluorescence. MALAT1 expression was significantly increased in ARPE-19 cells cultured with RV. Silencing MALAT1 effectively suppressed EMT and downregulated the associated factors snail1 and E-cadherin. Furthermore, silencing MALAT1 inhibited the RV-induced migration, invasion, proliferation, and contraction of ARPE-19 cells. Silencing MALAT1 also decreased RV-induced AKT and P53 phosphorylation. In conclusion, lncRNA MALAT1 participates in regulating vitreous-induced EMT in human RPE cells; these results provide new insight into the pathogenesis of PVR and offer a potential direction for the development of antiproliferative drugs.

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Relaxin Modulates the Genomic Actions and Biological Effects of Estrogen in the Myometrium.

Estradiol (E2) and relaxin (Rln) are steroid and polypeptide hormones, respectively, with important roles in the female reproductive tract, including myometrium. Some actions of Rln, which are mediated by its membrane receptor RXFP1, require or are augmented by E2 signaling through its cognate nuclear steroid receptor, estrogen receptor alpha (ERα). In contrast, other actions of Rln act in opposition to the effects of E2. Here we explored the molecular and genomic mechanisms that underlie the functional interplay between E2 and Rln in the myometrium. We used both ovariectomized female mice and immortalized human myometrial cells expressing wild-type or mutant ERα (hTERT-HM-ERα cells). Our results indicate that Rln modulates the genomic actions and biological effects of estrogen in the myometrium and myometrial cells by reducing phosphorylation of ERα on serine 118 (S118), as well as by reducing the E2-dependent binding of ERα across the genome. These effects were associated with changes in the hormone-regulated transcriptome, including a decrease in the E2-dependent expression of some genes and enhanced expression of others. The inhibitory effects of Rln cotreatment on the E2-dependent phosphorylation of ERα required the nuclear dual-specificity phosphatases DUSP1 and DUSP5. Moreover, the inhibitory effects of Rln were reflected in a concomitant inhibition of the E2-dependent contraction of myometrial cells. Collectively, our results identify a pathway that integrates Rln/RXFP1 and E2/ERα signaling, resulting in a convergence of membrane and nuclear signaling pathways to control genomic and biological outcomes.

Effect of Mn2+ doping and DDAB-assisted postpassivation on the structural and optical properties of CsPb(Cl/Br)3 halide perovskite nanocrystals

Cesium lead halide perovskite (CsPbX3; X = Cl, Br, I) nanocrystals showing intense band-edge emission and high photoluminescence quantum yield are known to be a potential candidate for application in optoelectronic devices. However, controlling toxicity due to the presence of Pb2+ in lead-based halide perovskites is a major challenge for the environment that needs to be tackled cautiously. In this work, we have partially replaced Pb2+ with Mn2+ ions in the CsPb(Cl/Br)3 nanocrystals and investigated their impact on the structural and optical properties. The Rietveld refinement shows that CsPbCl2Br nanocrystals possess a cubic crystal structure with Pm 3̅ m space group, the Mn2+ doping results in the contraction of the unit cell. The CsPb(Cl/Br)3: Mn nanocrystals show a substantial change in the optical properties with an additional emission band at ∼588 nm through a d-d transition, changing the emission color from blue to pink. Here, a didodecyldimethylammonium bromide (DDAB) ligand that triggers both anion and ligand exchange in the CsPb(Cl/Br)3: Mn nanocrystals have been used to regulate the exchange reaction and tune the emission color of halide perovskites by changing the peak position and the PL intensities of band-edge and Mn2+ defect states. We have also shown that oleic acid helps in the desorption of oleylamine capping from the CsPb(Cl/Br)3: Mn nanocrystal surfaces and DDAB, resulting in the substitution of Cl− with Br− as well as provides capping with shorter branched length ligand which led to increase in the overall PL intensity by many folds.

Enhanced Piezoelectric Performance of PVDF-TrFE Nanofibers through Annealing for Tissue Engineering Applications.

This study investigates bioelectric stimulation's role in tissue regeneration by enhancing the piezoelectric properties of tissue-engineered grafts using annealed poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE) scaffolds. Annealing at temperatures of 80°C, 100°C, 120°C, and 140°C was assessed for its impact on material properties and physiological utility. Analytical techniques such as Differential Scanning Calorimetry (DSC), Fourier-Transform Infrared Spectroscopy (FTIR), and X-ray Diffraction (XRD) revealed increased crystallinity with higher annealing temperatures, peaking in β-phase content and crystallinity at 140°C. Scanning Electron Microscopy (SEM) showed that 140°C annealed scaffolds had enhanced lamellar structures, increased porosity, and maximum piezoelectric response. Mechanical tests indicated that 140°C annealing improved elastic modulus, tensile strength, and substrate stiffness, aligning these properties with physiological soft tissues. In vitro assessments in Schwann cells demonstrated favorable responses, with increased cell proliferation, contraction, and extracellular matrix attachment. Additionally, genes linked to extracellular matrix production, vascularization, and calcium signaling were upregulated. The foreign body response in C57BL/6 mice, evaluated through Hematoxylin and Eosin (H&E) and Picrosirius Red staining, showed no differences between scaffold groups, supporting the potential for future functional evaluation of the annealed group in tissue repair.

Hemal sinus basal laminae contact sites: a possible route between gonadal lumen and myoepithelial cells in the gonad of the sea star Patiria pectinifera.

Sea stars are a group of marine invertebrates suitable for studying the hormonal regulation of reproduction and spawning. In spite of substantial progress in understanding how various substances such as 1-methyladenine act in their gonads, there are still many gaps concerning the fine details of their action. One such gap is how the gonadal wall contraction is induced. Recent literature data suggest that, upon 1-methyladenine stimulation, some cells within the gonadal lumen produce non-neuronal acetylcholine that, upon contact with the gonadal wall, induces contraction of myoepithelial cells. Our ultrastructural study of the gonads in the sea star Patiria pectinifera has shown, for the first time, that there are sites where the basal laminae bordering the hemal sinus directly contact one another and appear at this contact site as a single entity. These contact sites are often associated with hemidesmosome-like junctions that anchor male accessory cells or female follicle cells on one side of the site and myoepithelial cells on the opposite. We suggest that contraction-inducing substance is secreted from an accessory or follicle cell, passes through a basal lamina contact site, and on the opposite side of the contact site acts on a myoepithelial cell to induce its contraction.

Structural and Electronic Properties of the Magnetic and Nonmagnetic X0.125Mg0.875B2 (X = Nb, Ni, Fe) Materials: A DFT/HSE06 Approach to Investigate Superconductor Behavior.

MgB2 material has a simple composition and structure that is well-reported and characterized. This material has been widely studied and applied in the last 20 years as a superconductor in wire devices and storage material for H in the hydride form. MgB2 doped with transition metals improves the superconductor behavior, such as the critical temperature (T cs) or critical current (J sc) for the superconducting state. The results obtained in this manuscript indicate that Nb-, Fe-, and Ni-doping in the Mg site leads to a contraction of the unit cell through the spin polarization on the electronic resonance of the boron layer. Fe and Ni transition metals doping perturb the electronic resonance because of stronger dopant-boron bonds. The unpaired electrons are transferred from 3d orbitals to the empty 2p z orbitals of the boron atoms, locating α electrons in the σ bonds and β electrons in the π orbitals. The observed influence of magnetic dopants on MgB2 enables the proposal of an electronic mechanism to explain the spin polarization of boron hexagonal rings.