The most prevalent Ca2+-buffer proteins (CaBPs: parvalbumin—PV; calbindin—CaB; calretinin—CaR) are widely expressed by various neurons throughout the brain, including the retinal ganglion cells (RGCs). Even though their retinal expression has been extensively studied, a coherent assessment of topographical variations is missing. To examine this, we performed immunohistochemistry (IHC) in the mouse retina. We found variability in the expression levels and cell numbers for CaR, with stronger and more numerous labels in the dorso-central area. CaBP+ cells contributed to RGCs with all soma sizes, indicating heterogeneity. We separated 4-9 RGC clusters in each area based on expression levels and soma sizes. Besides the overall high variety in cluster number and size, the peripheral half of the temporal retina showed the greatest cluster number, indicating a better separation of RGC subtypes there. Multiple labels showed that 39% of the RGCs showed positivity for a single CaBP, 30% expressed two CaBPs, 25% showed no CaBP expression and 6% expressed all three proteins. Finally, we observed an inverse relation between CaB and CaR expression levels in CaB/CaR dually- and CaB/CaR/PV triple labeled RGCs, suggesting a mutual complementary function.

The total, soluble and insoluble oxalate contents of fresh and wok-fried fat hen (Chenopodium album) leaves were extracted and measured using HPLC chromatography. The total oxalate content of the raw leaves was 1112.4 mg/100 g dry matter (DM), and the levels were significantly reduced by boiling (682.8 mg/100 g DM) or cooking the leaves in a wok (883.6 mg/100 g DM). The percentages of soluble oxalate contents in the total oxalates of the raw and boiled leaves were similar (mean 75%), while the proportion of soluble oxalate content in the wok-fried leaves were reduced to 53.4% of the total, giving a significant increase in the insoluble oxalate content of the wok-fried leaves. The percentage of insoluble calcium in the total calcium was significantly reduced (P < 0.05) when the leaves were boiled but the insoluble oxalate content significantly increased (67.2%) in the wok-fried leaves when compared to the content of the original raw leaves. Processing the cooked leaves into pesto or extracting the juice gave final products that contained significantly reduced total and soluble oxalate contents. The addition of calcium chloride to the juice made a very small reduction in the soluble oxalate content in the juice.

This paper addresses the effect of both microstructure and relative humidity on the long-term creep properties of sustainable calcium carbonate (CaCO₃) cements. Those can be prepared by mixing amorphous calcium carbonate and vaterite with water. A larger starting amount of vaterite, X_V, within the mixture design gives a higher elasticity and resistance to the specimens due to the larger overall bridging area within the newly formed calcite crystals. Regarding creep properties for a given relative humidity, the amplitude of creep strain decreases with X_V, and makes the relation between the elastic modulus, E, and hardness, H, of the samples to be linear with the contact creep modulus, C. On the other hand, for a given composition, the amplitude of creep increases with the relative humidity, making the contact creep modulus, Ci, to rise exponentially with the elastic modulus, E, and hardness, H, of the specimens. The most probable creep mechanisms for this kind of cement seem to be a combination of microcraking in the early stages and dissolution and reprecipitation of calcite in the long-term (also known as pressure solution theory). The presence of water in pores with increasing relative humidity might enhance the local dissolution of calcite, and hence the creep amplitude.

Acid proteins capable of nucleating Ca2+ and displaying aggregation capacity play key roles in the formation of calcium carbonate biominerals. EF-hands are among the largest Ca2+-binding motif in proteins. Gad m 1, an Atlantic cod β-parvalbumin isoform, is a monomeric EF-hand protein that acts as a Ca2+ buffer in fish muscle and is able to form amyloids under acidic conditions. Since nucleating Ca2+ protein have a propensity to form extended β-strand structures, we wondered whether amyloid assemblies of a protein containing refolded EF-hand motifs were able to influence the in vitro calcium carbonate crystallization. Here we have used the Gad m 1 chain as model to generate monomeric and amyloid assemblies and analyze their effect on in vitro calcite formation. We found that only amyloid assemblies alter calcite morphology.

Non-Vitamin K Oral Anticoagulants (NOACs) have revolutionized anticoagulant therapy, offering improved safety and efficacy over traditional agents like warfarin. This review comprehensively examines the dual roles of NOACs—Apixaban, Rivaroxaban, Edoxaban, and Dabigatran—not only as anticoagulants but also as modulators of inflammation via Protease-Activated Receptor (PAR) signaling. We highlight the unique pharmacotherapeutic properties of each NOAC, supported by key clinical trials demonstrating their effectiveness in preventing thromboembolic events. Beyond their established anticoagulant roles, emerging research suggests that NOACs influence inflammation through PAR signaling pathways, implicating factors such as FXa and Thrombin in the modulation of inflammatory responses. This review synthesizes current evidence on the anti-inflammatory potential of NOACs, exploring their impact on inflammatory markers and conditions like atherosclerosis and diabetes. By delineating the mechanisms by which NOACs mediate anti-inflammatory effects, this work aims to expand their therapeutic utility, offering new perspectives for managing inflammatory diseases. Our findings underscore the broader clinical implications of NOACs, advocating for their consideration in therapeutic strategies aimed at addressing inflammation-related pathologies. This comprehensive synthesis not only enhances understanding of NOACs' multifaceted roles but also paves the way for future research and clinical applications in inflammation and cardiovascular health

Phosphorus (P) and iron (Fe) deficiency are major limiting factors for plant productivity worldwide. White lupin (Lupinus albus L.) has become a model plant for understanding plant adaptations to P and Fe deficiency, because of its ability to form cluster roots, bottle-brush-like root structures that play an important role in the uptake of P and Fe from soil. However, little is known about the signaling pathways involved in sensing and responding to P and Fe deficiency. Sucrose, sent in increased concentrations from the shoot to the root, has been identified as a long-distance signal of both P and Fe deficiency. To unravel responses to sucrose as signal, we performed Oxford Nanopore cDNA sequencing of white lupin roots treated with sucrose for 10 min, 15 min, and 20 min, compared to untreated controls. We identified a set of 17 genes, including two bHLH transcription factors, that were up-regulated at all three time points of sucrose treatment. GO (gene ontology) analysis revealed enrichment of auxin- and gibberellin-responses as early as 10 min after sucrose addition, and the emerging of ethanol-responses at 20 min of sucrose treatment, indicating a sequential involvement of these hormones in plant responses to sucrose.

Myocardial hypertrophy is the most common condition that accompanies heart changings in children. Transcriptional pathways regulating gene expression playing a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pump and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs makes combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.

PIEZO1 plays a crucial role in the human body as a mechanosensory ion channel. It has been demonstrated that PIEZO1 is important in tissue development and regulating many essential physiological processes. Studies have suggested that the PIEZO1 ion channel plays a role in invasion and progression in cancer; elevated levels of PIEZO1 have been correlated with increased migration in breast cancer cells, chemo-resistance and invasion in gastric cancer cells, and increased invasion of osteosarcoma cells. In addition, high PIEZO1 expression levels were correlated with a worse prognosis in glioma patients. On the other hand, studies in lung cancer have attributed high PIEZO1 levels to better patient outcomes. However, the clinical impact of PIEZO1 in breast cancer is not well characterized. Therefore, our goal was to determine the clinical relevance of PIEZO1 in breast cancer. Analysis of breast cancer data from The Cancer Genome Atlas (TCGA) was conducted to investigate PIEZO1 expression levels and correlation to survival, followed by validation in an independent dataset, GSE3494. We also performed gene set enrichment analysis (GSEA) and analyzed immune cell levels in breast tumors from TCGA through a CIBERSORT algorithm. Our results demonstrated that PIEZO1 expression levels are higher in hormone receptor (HR) negative than HR positive cohorts. High PIEZO1 expression is correlated with a significant decrease in survival in HR negative cohorts, suggesting that PIEZO1 could be utilized as a prognostic biomarker in HR negative breast cancer. GSEA showed that various signaling pathways associated with more invasive phenotypes and resistance to treatments, including epithelial-mesenchymal transition (EMT), hypoxia, and multiple signaling pathways, are enriched in high PIEZO1 HR negative tumors. Our results also demonstrated a decrease in CD8+ and CD4+ T cell infiltration in high PIEZO1 HR negative tumors. Further investigations are necessary to elucidate the mechanistic roles of PIEZO1 in HR negative breast cancer.

Background: The molecular domestication of the gag gene of retrotransposons and retroviruses gave rise to the Gagr gene in the genome of Drosophila. The Gagr protein has a conservative structure in all Drosophila species, suggesting an essential function. As we previously shown, the Gagr gene may play a part in immune response and processes linked to stress reactions. Methods: Tub-GAL4&gt;UAS-Gagr flies, which had the Gagr gene knockdown in all tissues, were compared with the control hybrid Tub-GAL4&gt;w1118. Gagr gene function was verified by RNA-sequencing followed by RT-PCR and physiological tests. Results: In contrast to the control strain, we observed that flies with the Gagr gene knockdown had a shorter lifespan, but the mutant strain was more resistant to heat stress. Also, the Gagr knockdown strain had higher level of transcription of the immune response genes, according to a transcriptome analysis. It has been shown that the ammonium persulfate used to induce stress causes the Toll, Jal-STAT, and Jnk/MAPK signaling pathways to become activated, which results in a systemic response in numerus tissues in the control strain. Conversely, the Gagr gene mutant strain exhibits low expression of the stress response. Enrichment of the molecular function of genes overexpressed under ammonium persulfate stress in the control strain, but not in the Gagr knockdown mutant, revealed a category with 19 transcription factors involved in the control of organism development, morphogenesis and the functioning of the central nervous system. Their expression pattern and the Gagr gene's expression pattern match. The data obtained demonstrates the importance Gagr is to maintaining both the body's immune system and homeostasis.

The evolutionary conserved STING-cGAS pathway represents one of the most important cytosolic DNA sensing systems that is activated in response to viral invasion and/or damaged integrity of the nuclear envelope. The key outcome of this pathway is the production of IFN, which subsequently stimulates hundreds of genes. In oncology, the situation is a complex one since this pathway may serve either anti- or pro-oncogenic roles in a context-dependent fashion. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as from ruptured micronuclei, it results in the production of interferon which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression. In these cells, the pathway initiates a non-canonical nuclear factor κB transcriptional response, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in conjunction with cancer progression and development of new treatment modalities.

Native reactive electrophile species (RES) are long-recognized regulators of pathophysiology; yet, knowledge surrounding how RES regulate context-specific biology remains limited. The latest technological advances in profiling and precision decoding of RES sensing and signaling have begun to bring about improved understanding of localized RES regulatory paradigms. However, studies in purified systems—prerequisites for gaining structure/function insights—prove challenging. We here introduce emerging chemical biology tools available to probe RES signaling, and the new knowledge that these tools have brought to the field. We next discuss existing structural data of RES-sensor proteins complexed with electrophilic metabolites or small molecule drugs (limited to < 300 Da), including challenges faced in acquiring homogenous RES-bound proteins. We further offer considerations that could promote enhanced understanding of RES regulation derived from three-dimensional structures of RES-modified proteins.

Plants are constantly exposed to a variety of different environmental stresses, including drought, salinity, and elevated temperatures. These stress cues are assumed to aggravate in the future driven by the global climate change scenario which we are currently experiencing. These stressors have largely detrimental effects on plant growth and development and, therefore, put global food security in jeopardy. For this reason, it is necessary to expand our understanding of the underlying mechanisms by which plants respond to abiotic stresses. Especially boosting our insight into the ways by which plants balance their growth and their defense programs appears to be of paramount importance, as this may lead to novel perspectives that can pave the way to increase agricultural productivity in a sustainable manner. In this review, our aim was to present a detailed overview of different factettes of the crosstalk between the antagonistic plant hormones abscisic acid (ABA) and auxin, two phytohormones that are the main drivers of plant stress responses, on the one hand, and plant growth, on the other.

The fate of a viral infection in the host begins with various types of cellular responses, such as abortive, productive, latent, and destructive infections. Apoptosis, necroptosis, and pyroptosis are the three major types of regulated cell death mechanisms that play critical roles in viral infection response. Cell shrinkage, nuclear condensation, bleb formation, and retained membrane integrity are all signs of osmotic imbalance-driven cytoplasmic swelling and early membrane damage in necroptosis and pyroptosis. Caspase-driven apoptotic cell demise is considered in many circum-stances as an anti-inflammatory, and some pathogens hijack the cell death signaling routes to initiate a targeted attack against the host. In this review, we selected mechanisms by which viruses interfere with cell death are discussed in-depth and are used to illustrate the general principles and cellular signaling mechanisms of virus-host specific molecule interactions.

If one considers chemical-biology toolsets that have had the greatest impact on numerous fields of life sciences over the most recent years, proximity-labeling tools, such as APEX, and Bio-ID arguably lead the way. This article reflects upon the current state-of-the-art and discusses key limitations underlying these emerging approaches, in particular, the limited functional knowledge they provide in understanding local proteomes / interactomes. This limitation is directly linked to the use of non-biologically- or non-pharmaceutically-relevant reactive intermediates in the course of covalently labeling the local proteomes. As such, these methods cannot report on specific functions of localized protein players, nor can they scrutinize whether the specific functions of such proteins/interactomes can be directly manipulated by pharmacologically-relevant small-molecule ligands. The latest data hint that precision localized electrophile delivery concept ushers a means to address this limitation with high spatiotemporal resolution, and ultimately, in relevant live animals.

Microglia activation causes neuroinflammation, which is a hallmark of neurodegenerative disorders, brain injury, and aging. Ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, reduced microglial activation and enhanced brain functioning in elderly rats. In this study, we studied SH-SY5Y, a human neuroblastoma cell line, and tested viability in the presence of hydrogen peroxide and Sin1 (3-morpholinosydnonimine), which generates reactive oxygen and nitrogen species (ROS/RNS). Both stressors caused significant apoptosis and necrotic cell death that was attenuated by ladostigil. Our results from RNA-seq experiments show that long non-coding RNAs (lncRNAs) account for 30% of all transcripts in SH-SY5Y cells treated with Sin1 for 24 hours. Altogether, we identify 94 differently expressed lncRNAs in the presence of Sin1, including MALAT1, a highly expressed lncRNA with anti-inflammatory and anti-apoptotic functions. Additional activities of Sin-1 upregulated lncRNAs include redox homeostasis (e.g., MIAT, GABPB1-AS1), energy metabolism (HAND2-AS1), and neurodegeneration (e.g., MIAT, GABPB1-AS1, NEAT1). Four lncRNAs implicated as enhancers were significantly upregulated in cells exposed to Sin1 and ladostigil. Finally, we show that H2O2 and Sin1 increased the expression of DJ-1, a redox sensor and modulator of Nrf2 (nuclear factor erythroid 2–related factor 2). Nrf2 (NFE2L2 gene) is a major transcription factor regulating antioxidant genes. In the presence of ladostigil, DJ-1 expression is restored to its baseline. The mechanisms governing SH-SY5Y cell survival and homeostasis are highlighted by the beneficial role of ladostigil in the crosstalk involving Nrf2, antioxidant transcription factor DJ-1, and lncRNAs. Stress-dependent induction of lncRNAs represents an underappreciated regulatory level that contributes to cellular homeostasis and the capacity of SH-SY5Y to cope with oxidative stress.

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their anti-tumor activity were evaluated in vitro both for activity optimization and structure-activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved anti-tumor activity, especially for compound 6e. The compound 6e contains an isothiouronium linked by an alkyl chain consisting of 6 carbon atoms with IC50 ranging from 1.11 to 2.80 μM on various cancer cell lines. Consistently, 6e dose dependently induced the apoptosis of A549 and DU145 cells, in which STAT3 are constitutively active. Western blotting assays indicated that the phosphorylation levels of JAK1, JAK2 and STAT3 were inhibited by 6e at 5 μM without significant change in total STAT3 level. Moreover, 6e also suppressed the expressions of STAT3 downstream genes, including c-Myc, Cyclin D1 and Bcl-XL at 10 μM. An additional in vivo study revealed that 6e at the dose of 10 mg/kg could potently inhibit the DU145 xenograft tumor without obvious body-weight loss. These results clearly indicate that 6e could be a potential anti-tumor agent by targeting JAK/STAT3 signaling pathway.

Pancreatitis and alcoholic pancreatitis are serious health concerns, and there is an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR for developing novel therapeutic strategies for the disease.

Heart regeneration after myocardial infarction remains challenging in reconstruction of blood resupply system. Here, we find that in zebrafish heart after resection of the ventricular apex, the local myocardial cells and the clotted blood cells undergo cell remodeling process via cytoplasmic exocytosis and nuclear reorganization within revascularization-based blastema. The regenerative processes are visualized by spatiotemporal expression of three blastema representative factors (alpha-SMA- which marks for fibrogenesis, Flk1for angiogenesis/hematopoiesis, and Pax3a for remusculogensis)，and two histone modifications (H3K9Ac and H3K9Me3 mark for chromatin remodeling). Using the cultured zebrafish embryonic fibroblasts we identify blastema fraction components and show that Krt5 peptide could link cytoskeleton network and BMP4 signaling pathway to regulate the transcription and chromatin accessibility at the blastema representative genes and bmp4 genes. Our study provides new mechanistic insights into the epithelial-dependent and revascularization-based blastema regeneration for potential myocardial infarction therapy.

Emerging viruses description have grown at an unprecedented rate since the beginning of the 21^st century. The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its related illness, Coronavirus Disease 2019 (COVID-19) has been reported as the third highly pathogenic coronavirus introducing itself into human population in the current era after the SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV). Molecular and cellular studies considering the pathogenesis of this novel coronavirus are still in the early stages of research, however, regarding the similarity of SARS-CoV-2 and other coronaviruses, it could be hypothesized that the NF-κB, Cytokine regulation, ERK, and TNF-α signaling pathways are the more likely causes of inflammation upon onset of COVID-19. There are several drugs prescribed and used to alleviate the activity of these inflammatory cellular signaling pathways which might be beneficial for developing novel therapeutic modalities against COVID-19. In this review, we briefly summarized the alteration of cellular signaling pathways affected by coronavirus infection, particularly SARS-CoV and MERS-CoV and tabulated the current therapeutic agents approved for previous human diseases.

Computational simulation using mathematical models is a useful method for understanding the complex behavior of a living system. The majority of studies using mathematical models to reveal biological mechanisms uses one of the two main approaches: the bottom-up or the top-down approach. When we aim to analyze a large-scale network, such as a comprehensive knowledge-integrated model of a target phenomenon, for example a whole-cell model, the variation of analyses is limited to particular kind of analysis because of the size and complexity of the model. To analyze a large-scale regulatory network of neural differentiation, we developed a hybrid method that combines both approaches. To construct a mathematical model, we extracted network motifs, subgraph structures that recur more often in a metabolic network or gene regulatory network than in a random network, from a large-scale regulatory network, detected regulatory motifs among them, and combined these motifs. We confirmed that the model reproduced the known dynamics of HES1 and ASCL1 before and after differentiation, including oscillation and equilibrium of their concentrations. The model also reproduced the effects of overexpression and knockdown of the Id2 gene. Our model suggests that the characteristic change in HES1 and ASCL1 expression in the large-scale regulatory network is controlled by a combination of four feedback loops, including a large loop which has not been focused on. The model extracted by our hybrid method has the potential to reveal the critical mechanisms of neural differentiation. The hybrid method is applicable to other biological events.

Strigolactones (SLs) are a novel emerging plant hormones, which play important roles in regulating plant organ development and environmental stress tolerance. Even though the SL related genes have been identified and well characterized in some plants. The information of SL related genes in soybean is not fully established yet, especially in response to salt stress. In this study, we identified nine SL biosynthesis genes: two D27, two CCD7, two CCD8, and three MAX1, and seven SL signaling genes: two D14, two MAX2 and three D53 in soybean genome. We found that SL biosynthesis and signaling genes are conserved during evolution in different species. Syntenic analysis of these genes revealed their location on nine chromosomes as well as existence of ten pairs of duplication genes. Moreover, plant hormone and stress-responsive elements were identified in the promoter regions of SL biosynthesis and signaling genes. By using quantitative real-time PCR (qRT-PCR), we confirmed that SL genes have different tissue expression in roots, stems and leaves. Further, we also explored the expression profiles of SL biosynthesis and signaling genes under salt stress. These results suggested that SL signaling genes may play important regulatory roles in response to salt stress. In conclusion, we identified and provided valuable information on the soybean SL biosynthesis and signaling genes, and established a foundation for further functional analysis of soybean SL related genes in response to salt stress.

Suppressors of cytokine signaling (SOCS) influence cytokine and growth factor signaling by negatively regulating the JAK-STAT pathway. This maintains homeostasis during host immune response. However, functional characterization of SOCS family members in invertebrates is limited. In this study, we discovered the Type-I subfamily of the SOCS genes in the mealworm beetle, T. molitor. The full-length ORFs of TmSOCS5, TmSOCS6, and TmSOCS7 consisted of 1,389, 897 and 1,458 nucleotides, encoding polypeptides of 462, 297 and 485 amino acids, respectively, The C-terminal region of TmSOCS was highly conserved in the SH2 and SOCS box domains. Phylogenetic analysis revealed that the three SOCS genes clustered within the same sub-family and the highest amino acid identity was with the Tribolium castaneum SOCS genes (TcSOCS). While the expression of TmSOCS5 and TmSOCS6 was low in larval, pupal, and adult stages of the insect, TmSOCS7 showed higher expression. The expression of TmSOCS5 and TmSOCS6 was higher in larval hemocytes and adult ovary. The microbes expressed the three TmSOCS genes to varying degrees. C. albicans elicited the strongest response in the host with highest 15-fold expression in TmSOCS7 3 h post-inoculation. Collectively, these data suggest that the Type I TmSOCS could play a role in eliciting host immunity.

The organic extract of the Caribbean sponge Smenospongia aurea has been shown to contain an array of novel chlorinated secondary metabolites derived from a mixed PKS-NRPS biogenetic route, such as the smenamides. Here we report the presence of a biogenetically different compound, smenopyrone (1), a polypropionate containing two -pyrone rings. The structure of smenopyrone, including its relative and absolute stereochemistry, was determined by spectroscopic analysis (NMR, MS, ECD) supported by comparison with model compounds from the literature. Pyrone polypropionates are unprecedented in marine sponges, but are commonly found in marine mollusks, where their biosynthesis by symbiotic bacteria has been hypothesized and at least in one case demonstrated. As pyrones have recently been recognized as bacterial signaling molecules, we speculate that smenopyrone could mediate inter-kingdom chemical communication between S. aurea and its symbiotic bacteria.

We evaluated oleanolic acid (OA)-induced anti-cancer activity, apoptotic mechanism, cell cycle status, and MAPK kinase signaling in DU145 (prostate cancer), MCF-7 (breast cancer), and U87 (human glioblastoma) cells. The IC50 values for OA-induced cytotoxicity were 112.57 in DU145, 132.29 in MCF-7, and 163.60 in U87 cells, respectively. OA (at 100 µg/mL) increased the number of apoptotic cells to 27.0% in DU145, 27.0% in MCF-7, and 15.7% in U87 cells, when compared to control cells. This enhanced apoptosis was due to increases in p53, cytochrome c, and Bax expression. OA-treated DU145 cells were arrested in G2 because of the activation of p-ERK and p21, and the decrease in cyclin B1 and cyclin E expression. Furthermore, OA-treated MCF-7 cells were arrested in G1 owing to the activation of p-JNK, p-ERK, p21, and p27, and the decrease in p-AKT, cyclin E, and CDK2. U87 cells also exhibited G1 phase arrest caused by the increase in p-ERK, p-JNK, p21, and p27, and the decrease in CDK2. Thus, OA arrests the cell cycle in different phases, and increases apoptosis in cancer cells. These results suggest that OA may alter the expression of cell cycle regulatory proteins in a cancer type-dependent manner.

Transient receptor potential canonical (TRPC) channels are calcium channels with diverse expression profiles and physiological implications in the retina. Neurons and glial cells of rat retinas with photoreceptor degeneration caused by retinitis pigmentosa (RP) exhibit basal calcium levels that are above those detected in healthy retinas. Inner retinal cells are the last to degenerate and are responsible for maintaining the activity of the visual cortex even after complete loss of photoreceptors. We considered the possibility that TRPC1 and TRPC5 channels might be associated with both the high calcium levels and the delay in inner retinal degeneration. TRPC1 is known to mediate protective effects in neurodegenerative processes, while TRPC5 promotes cell death. In order to comprehend the implications of these channels in RP, the co-localization and subsequent physical interaction between TRPC1 and TRPC5 in healthy retina (Sprague-Dawley rats) and degenerating (P23H-1, a model of RP) retina were detected by immunofluorescence and proximity ligation assays. There was an overlapping signal in the innermost retina of all animals where TRPC1 and TRPC5 physically interacted. This interaction increased significantly as photoreceptor loss progressed. Both channels function as TRPC1/5 heteromers in the healthy and damaged retina, with a marked function of TRPC1 in response to retinal degenerative mechanisms. Furthermore, our findings support that TRPC5 channels also function in partnership with STIM1 in Müller and retinal ganglion cells. These results suggest that increase in TRPC1/5 heteromers may contribute to slowing of the degeneration of the inner retina during the outer retinal degeneration.

This study explored the feasibility of fluoride removal from simulated semiconductor industry wastewater and its recovery as calcium fluoride using fluidized bed crystallization. The continuous reactor showed best performance (>90% fluoride removal and >95% crystallization efficiency) at a calcium to fluoride ratio of 0.6 within first 40 days of continuous operation. The resulting particle size increased by more than double during this time along with a 36% increase in the seed bed height indicating deposition of CaF2 onto the silica seed. The SEM-EDX analysis showed the size and shape of the crystals formed along with high amount of Ca-F ions presence. The purity of the CaF2 crystals were determined to be 91.1% though ICP-OES analysis. Following the continuous experiment, different process improvement strategies are explored. The addition of excess amount of calcium resulted in an additional 6% fluoride removal, however, compared to this single stage process, a two-stage approach was found to be better strategy to achieve a low effluent fluoride concentration. The fluoride removal reached 94% with this two-stage approach under optimum condition of 4 + 1 h HRT combinations and a [Ca2+]/[F-] ratio of 0.55 and 0.7 for the two reactors, respectively. CFD simulation showed the impact of inlet diameter, bottom-angle shape and width and height ratio of the reactor on mixing inside reactor and possibility of further improvement in reactor performance by optimizing the FBR configuration.

With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as a potential therapeutic strategy. The potential role of the mannose-modified lipid calcium phosphate nanoparticle vaccine in enhancing the anti-tumor immune response was investigated. The aim of this study was to investigate the effect of mannose modification on the immune response of nanoparticles in regulating the tumor microenvironment through systematic review and analysis and to explore its potential clinical application in tumor therapy. Currently, despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and overexpression of immunosuppressive factors limit its clinical application. Therefore, this study will explore how to intervene in the immunosuppressive mechanism in the tumor microenvironment through mannose-modified lipid calcium phosphate nanoparticle vaccines so as to improve the immunotherapy effect of tumor patients and provide new ideas and strategies for the field of tumor therapy.

Human RAD51 protein (HsRad51)-promoted DNA strand exchange, a crucial step in homologous recombination, is regulated by proteins and calcium ions. The activator protein Swi5-Sfr1 and Ca2+ ions stimulate different reaction steps and induce a perpendicular orientation of DNA bases in the presynaptic complex. To investigate the importance of base orientation in the strand exchange reaction, we examined the Ca2+ concentration dependence of strand exchange activities and structural changes in the presynaptic complex. Our results show that optimal D-loop formation (strand exchange with closed circular DNA) requires Ca2+ concentrations greater than 5 mM, while 1 mM is sufficient for strand exchange between two oligonucleotides. The structural change, which is evidenced by an increase in fluorescence intensity of poly(dεA) (a poly(dA) analog), reaches a plateau at 1 mM Ca2+. Meanwhile, the linear dichroism signal intensity at 260 nm, which is indicative of rigid perpendicular DNA base orientation, requires >2 mM Ca2+ for saturation and thus correlates with the stimulation of D-loop formation. Therefore, Ca2+ exerts two different effects. Thermal stability measurements suggest that HsRad51 binds two Ca2+ ions with KD values of 0.3 mM and 2.5 mM, implying that one step is stimulated by one Ca2+ bond and the other by two Ca2+ bonds. We further discuss the parallels between Mg2+ activation of RecA and Ca2+ activation of HsRad51.

Management of calcium and phosphate in biofluids is key to maintaining physiological mineral homeostasis (i.e., appropriate mineralization of hard tissues and an absence of mineral deposition in soft tissues). This review describes and contrasts the ways vertebrates manage calcium phosphate in two biological fluids (breast milk and serum) and illustrates the benefits of mineral sequestration by proteins. In milk, phosphoprotein-sequestered calcium magnesium phosphates provide nutritional support, whereas in serum, protein-sequestered calcium phosphates control transport and delivery of calcium and phosphate to tissues for biological function or excretion. In addition, subsets of sequestered phosphates in serum have been identified as culprits underlying ectopic deposition of calcium phosphates and toxicity.

Applying of blood biopolymers to regulate the phase composition is promising in designing the hydroxyapatite-based hybrid biomaterials with controllable resorbability. Hybrid materials based on hydroxyapatite and platelet-poor plasma (PPP) were formed in conditions of chemical precipi-tation at pH 11, [Ca2+] / [PO43–] ratio 1.67, PPP volume fraction of 6–24%, maturing time of 4–9 days. Mineral component of the materials was represented as 53% hydroxyapatite / 47% amor-phous calcium phosphate after 4 days of maturation, and 100% hydroxyapatite after 9 days of maturation. Varying PPP content from 6% to 24% provided forming of materials with rather de-fined content of amorphous calcium phosphate and biopolymer component, having desired mor-phology ranging from typical apatitic conglomerates to hybrid apatite-biopolymer fibers. Co-precipitated hybrid materials based on hydroxyapatite and PPP are promising for bone regen-eration in osteoplastic and maxillofacial applications.

The review presents the most developed by date hypotheses on the mechanisms of the influence of low-frequency magnetic fields (LFMF) on organisms. Biophysical models that explain the resonance-like responses of biological systems to LFMF with a specific frequency and amplitude are described. Two groups can be distinguished among these models: one considers ions-cofactors of proteins as the primary targets for the LFMF influence, and the other regards the magnetic moments of particles in biomolecules. Attention is paid to the dependence of resonance-like LFMF effects on the cell type. A radical-pair mechanism of the magnetic field's influence on biochemical processes is described with the example of cryptochrome. Conditions for this mechanism's applicability to explain the biological effects of LFMF are given. A model of the influence of LFMF on radical pairs in biochemical oscillators, which can explain the frequency-amplitude efficiency windows of LFMF, is proposed.

This review article deals with the design of bioactive calcium phosphate coatings deposited on metallic substrates to produce bone implants. The bioceramic coating properties are used to create a strong bonding between the bone implants and the surrounding bone tissue. They provide a fast response after implantation and increase the lifespan of the implant in the body environment. The first part of the article describes the different compounds belonging to the calcium phosphate family and their main properties for applications in biomaterials science. The calcium to phosphorus atomic ratio (Ca/P)at. and the solubility (Ks) of these compounds define their behavior in a physiological environment. Hydroxyapatite is the gold standard among calcium phosphate materials, but other chemical compositions/stoichiometries have also been studied for their interesting properties. The second part reviews the most usual deposition processes to produce bioactive calcium phosphate coatings for bone implant applications. Plasma spraying is the main industrial process, but magnetron sputtering, pulsed laser deposition, electrospray deposition, electrophoretic deposition, and electrodeposition are also widely studied in academic and industrial research. The last part describes the main physicochemical properties of calcium phosphate coatings and their impact on the bioactivity of bone implants in a physiological environment.

Ecological ternary cements (ECP) were perpared with powders of phosphogypsum (PG), fly ash (FA) and portland cement (PC). The evolution mechanism of the hydration product structure was characterized through macro and micro experiments.The thermodynamic characteristics of solid phase, solid solution phase and aqueous solution in process of hydration about phosphogypsum-fly ash-cement ternary cementitious system were studied based on the Gibbs-free-energy C-S-H thermodynamic model and GEM-Selektor software, and compared with experimental results. The results show that in the hydration reaction the thermodynamic interaction between mineral single-phase and hydration products plays an important role in the spatio-temporal distribution of ions in the cementitious system. The values of CaO、SiO2Hand H2Ohyd gradually increased with the increase of Ca/Si ratio, while the values of CaOext and H2OOH showed a positive proportional relationship, and the values of SiO2H and SiO2 showed an inverse proportional relationship. GEM-Selektor is accurate in the simulation calculation of the total amount of AFt and AFm mineral phases which quantitatively analysis the correlation between C-S-H gels formation and C3S with complex decomposition ion groups.

Context: Persea Americana is reported to have medicinal value. Calcium Carbide (CaC2), a fruit-ripening agent, has been shown to be toxic to body organs. Objective: To determine the effect of avocado seed extract (ASE) on CaC2-induced hepatotoxicity in rats. Methodology: Four experimental groups, each of 5 adult wistar rats were fed respectively with normal diets (group A); 250mg/kg ASE (group B); 100mg/kg CaC2 (group C); combination of 100mg/kg CaC2 and 250mg/kg ASE – group D. Changes in the rats’ behaviours, body weights, and liver function were assessed over 21 days. Data were analyzed using SPSS. The cumulated rat weights, rat liver weights and serum liver enzyme levels for groups B, C, and D rats were compared to group A. Results: Abnormal behavior was most observed in group C rats. Rats in group A showed a significant increase in weight before and three weeks following administration of feeds while rats in groups B, C, and D showed significant decrease in weight – more marked in group C rats. Only the mean liver weights of rats in group C showed significant decrease compared to that in group A, p = 0.001. Similarly, only the cumulated liver enzyme levels of rats in group C demonstrated significant increase when compared to group A rats - indicating hepatotoxicity. Conclusion In this study, hepatotoxicity occurred in CaC2-administered rats. However, the combination of CaC2 and ASE showed no liver toxicity indicating a mitigating effect of ASE to CaC2-induced hepatotoxicity.

Reducing the amount of precipitation in summer in the Chernozems area alters soil organic matter (SOM). To compensate for the lack of moisture, farmers are introducing new agricultural technologies such as no-till cultivation. In turn, no-till practices influence the composition of SOM. We examined the impacts of the rise of aridity and no-till technology on the chemical composition of bioavailable and recalcitrant pools of OM. The properties of SOM were assessed using double-shot pyrolysis with gas chromatography/mass spectrometry (GC/MS). The thermolabile substances that are volatilised in the first stage of pyrolysis (300°C) are considered the bioavailable pool. Accordingly, substances are obtained in the second pyrolysis stage (500°C) were attributed to the recalcitrant pool. Identified in both steps of pyrolysis, products were assigned to different chemical groups (lignin-derivative, polysaccharide-fragments, indoles, etc.) and relative abundances were calculated. In work for the separation of substances, a polar column was used for chromatography of the thermolabile fraction. With an increase in aridity in Сhernozems, the content in the bioavailable pool of polysaccharide fragments decreased and the proportion of indoles increased. In the recalcitrant pool, the abundance of six-membered rings with nitrogen and aromatic compounds decreases at the same time the contents of unsubstituted and O-substituted acyclic compounds as well as pyridine increases. The influence of the NT was more noticeable in the recalcitrant OM. The NT practice promotes biological activity and to rich in nitrogen compounds the bioavailable OM; this process contributes to the accumulation of carbon in the recalcitrant OM.

Aquatic animals have unique physiological mechanisms to absorb and retain minerals from their diets and water. Research and development in the area of mineral nutrition of farmed fish and crustaceans have been relatively slow and major gaps exist in the knowledge of trace element requirements, physiological functions and bioavailability from feed ingredients. Quantitative dietary requirements have been reported for three macroelements (calcium, phosphorus and magnesium) and six trace minerals (zinc, iron, copper, manganese, iodine and selenium) for selected fish species. Mineral deficiency signs in fish include reduced bone mineralization, anorexia, lens cataracts (zinc), skeletal deformities (phosphorus, magnesium, zinc), fin erosion (copper, zinc), nephrocalcinosis (magnesium deficiency, selenium toxicity), thyroid hyperplasia (iodine), muscular dystrophy (selenium) and hypochromic microcytic anaemia (iron). An excessive intake of minerals from either diet or gill uptake causes toxicity and therefore a fine balance between mineral deficiency and toxicity is vital for aquatic organisms to maintain their homeostasis either through increased absorption or excretion. Release of minerals from uneaten or undigested feed and from urinary excretion can cause eutrophication of natural waters, which requires additional consideration in feed formulation. The current knowledge in mineral nutrition of fish is briefly reviewed.

Beta cells couple stimulation by glucose with insulin secretion and impairments in this coupling play a central role in diabetes mellitus. To clarify the effect of cAMP and the role of Epac2A in intracellular calcium signals and intercellular coupling, we performed functional multicellular calcium imaging in beta cells in mouse pancreas tissue slices after stimulation with glucose and forskolin in wild-type and Epac2A knock-out mice. Increased cAMP evoked calcium signals in otherwise sub-stimulatory glucose and beta cells from Epac2A knock-out mice displayed a faster activation. During the plateau phase, beta cells from Epac2A knock-out mice displayed a slightly higher active time in response to glucose compared with wild-type littermates, and increased cAMP increased the active time via a large increase in oscillation frequency and small decrease in oscillation duration in both Epac2A knock-out and wild-type mice. Functional network properties during stimulation with glucose did not differ in Epac2A knock-out mice, but the presence of Epac2A was crucial for the protective effect of increased cAMP in preventing a decline in beta cell functional connectivity with time. Finally, increased cAMP prolonged beta cell activity during deactivation in an Epac2A-independent manner.

Calcium carbonate cements have been synthesized by mixing amorphous calcium carbonate and vaterite powders with water to form a cement paste and study how mechanical strength is created during the setting reaction. In-situ XRD was used to monitor the transformation of ACC and vaterite phases into calcite and a rotational rheometer was used to monitor the strength evolution. There are two characteristic time scales of the strengthening of the cement paste. The short timescale of the order 1 hour is controlled by smoothening of the vaterite grains, allowing closer and therefore adhesive contacts between the grains. The long timescale of the order 10-50 hours is controlled by the phase transformation of vaterite into calcite. This transformation is, unlike in previous studies using stirred reactors, found to be mainly controlled by diffusion in the liquid phase. The evolution of shear strength with solid volume fraction is best explained by a fractal model of the paste structure.

Matrix Metaloproteinase-2 (MMP-2) is an extracellular Zn²⁺ protease specific to type I and IV collagens. Its expression is associated with several inflammatory, degenerative, and malignant diseases. Conformational properties, domain movements, and interactions between MMP-2 and its associated metal ions were characterized using a 1.0 µs molecular dynamics simulation. Dihedral principle component analysis revealed 10 families of conformations with the greatest degree of variability occurring in the link region connecting the catalytic and hemopexin domains. Dynamics cross correlation analysis indicated domain movements corresponding to opening and closing of the hemopexin domain in relation to the fibronectin and catalytic domains facilitated by the link region. Interaction energies were calculated using the MMPBSA-interaction entropy analysis method and revealed strong binding energies for the catalytic Zn²⁺ ion 1, Ca²⁺ ion 1, and Ca²⁺ ion 3 with significant conformational stability at the binding sites of Zn²⁺ ion 1 and Ca²⁺ ion 1. Ca²⁺ ion 2 diffuses freely away from its crystallographically defined binding site. Zn²⁺ ion 2 plays a minor role in conformational stability of the catalytic domain while Ca²⁺ ion 3 is strongly attracted to the highly electronegative sidechains of the Asp residues around the central β-sheet core of the hemopexin domain.

Hypertension is a common and growing medical problem that leads to enormous cardiovascular and kidney disease worldwide. While many drugs exist to treat hypertension, there is large individual variation in how a given individual responds to different agents, which contributes to dismal rates of hypertension control. While demographic factors predict which drugs may work better in certain individuals, a great degree of this variation has a genetic basis. In recent years, genome wide association studies have begun to identify specific gene variants that predict drug response to particular agents. This review identifies the major genetic variants influencing antihypertensive response that have emerged from this growing body of work. For novel genetic variants without a previously known biologic basis in blood pressure, it is crucial to validate initial findings in subsequent studies. This information may eventually lead to a more personalized approach to hypertension management that will improve blood pressure control and patient outcomes. The integration of this large amount of data and its real world application will be highly challenging, but strategies to accomplish this are discussed.

There have been a great number of investigations about the influence of weak magnetic fields on biological systems, such as isolated cells and whole organisms. This is also a subject of considerable medical concern since old epidemiologic observations have indicated a possible tumorigenic effect of these fields. Their mechanism of action, however, is not firmly established. A large number of biological effects of electromagnetic fields have been attributed either to the production of reactive oxygen species (ROS) or to the entrance Ca²⁺ in the cell. A new biochemical pathway is proposed that covers these two possibilities: the primary effect of the magnetic field would be by the mechanism of radical pairs resulting in the production of ROS; these could activate the ion channels TRPM2 producing cellular inflow of Ca²⁺, which would induce the calcium dependent effects. Thus, a large number of biological effects observed up to the present could be explained.

Myocardial heterogeneity is an attribute of the normal heart. We have developed integrative models of cardiomyocytes from the subendocardial (ENDO) and subepicardial (EPI) ventricular regions that take into account experimental data on specific features of intracellular electromechanical coupling in the guinea pig heart. The models adequately simulate experimental data on the action potential and contraction of the ENDO and EPI cells. The modeling results predict that heterogeneity in the parameters of calcium handling and myofilament mechanics in isolated ENDO and EPI cardiomyocytes via cooperative mechanisms of mechano-calcium-electric feedback are essential to produce the differences in Ca²⁺ transients and contraction profiles and may further enhance transmural differences in the electrical properties between the cells. Simulation results predict that ENDO cells have greater sensitivity to changes in afterload than EPI cells. These data are important for understanding the behavior of cardiomyocytes in the intact heart.

Alzheimer´s disease (AD) is characterized by the brain deposition of senile plaques composed by amyloid-β peptides (Aβ) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE) has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 during 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1 and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme were also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.

Lysophosphatidic acid (LPA) type 3 (LPA3) receptor mutants were generated in which the sites detected phosphorylated were substituted by non-phosphorylatable amino acids. Substitutions were made in the intracellular loop 3 (IL3 mutant), the carboxyl terminus (Ctail), and both domains (IL3/Ctail). The wild-type (WT) receptor and the mutants were expressed in T-REx HEK293 cells, and the consequences of the substitutions were analyzed employing different functional parameters. Agonist- and LPA-mediated receptor phosphorylation was diminished in the IL3 and Ctail mutants and essentially abolished in the IL3/Ctail mutant, indicating that the main sites were substituted and distributed in both domains. The WT and mutant receptors increased intracellular calcium and ERK 1/2 phosphorylation in response to LPA and PMA. An increase in baseline ERK phosphorylation was detected in the IL3/Ctail mutant. LPA and PMA-induced receptor interaction with β-arrestin 2 and LPA3 internalization were severely diminished in the mutants. Mutant-expressing cells also exhibit increased baseline proliferation and response to different stimuli, which were inhibited by the antagonist Ki16425, suggesting a role of LPA receptors in this process. Migration in response to different attractants was markedly increased in the Ctail mutant, which the Ki16425 antagonist also attenuated.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification in low and high-risk cases for early progression in metastatic disease is necessary. At now PSA-DT represents the best parameter to define low and high risk BCR PC, but a real precision medicine is strongly suggested to define a tailored management of patients with BCR. Before defining management, it is necessary to exclude the presence of low volume metastasis associated with PSA progression using new generation imaging preferably with PSMA PET/CT. Low risk BCR cases should be actively observed without early systemic therapies. Early treatment of low risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such the development of castration resistance before the appearance of metastases (non-metastatic castration resistant PC). Patients with high risk BCR benefit from early systemic therapy. The primary end point must be metastasis-free survival (MFS), even with the same overall survival (OS). The EMBARK study is able to impact on the management of high risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSI) and ADT combination therapy. In high risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining the quality of life unchanged in an asymptomatic phase of the disease. The possibility of using ARSI alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than the intensification of the combination therapy. Continued use versus discontinuation upon reaching undetectable PSA levels of enzalutamide plus leuprolide intensified therapy needs to be better defined with further analysis. Real world analysis must verify the significant results obtained in the context of a phase 3 study.

Colony-stimulating factor 1 receptor (CFS-1R) is a myeloid receptor with a crucial role in monocyte survival and differentiation. Its overexpression is associated with aggressive tumor characterized by an immunosuppressive microenvironment and poor prognosis. CSF-1R ligands, IL-34 and M-CSF, are produced by many cells in the tumor microenvironment (TME), suggesting a key role for the receptor in the crosstalk between tumor, immune and stromal cells in the TME. Recently, CSF-1R expression was reported at the cell membrane of cancer cell from different solid tumors, capturing the interest of various research group interested in investigating the role of this receptor in non-myeloid cells. This review summarizes current data available on the expression and activity of CSF-1R in different tumor types. Notably, CSF-1R+ cancer cells have been shown to produce CSF-1R ligands, indicating that CSF-1R signaling is positively regulated in autocrine manner in cancer cells. Recent research demonstrated that CSF-1R signaling enhances cell transformation by supporting tumor cell proliferation, invasion, stemness and drug resistance. In addition, this review covers recent therapeutic strategies, including monoclonal antibodies and small molecule inhibitors, targeting the CSF-1R and designed to block the pro-oncogenic role of CSF-1R in cancer cell.

This comprehensive review delves into the multifaceted aspects of ERK signaling and the intricate mechanisms underlying distinct cellular fates. ERK1 and ERK2 (ERK) govern proliferation, transformation, epithelial-mesenchymal transition, differentiation, senescence, or cell death, con-tingent upon activation strength, duration, and context. The biochemical mechanisms underlying these outcomes are inadequately understood, shaped by signaling feedback and the spatial localization of ERK activation. Generally, ERK activation aligns with the Goldilocks principle in cell fate determination. Excessive or insufficient ERK activity inhibits growth, whereas moderated activation supports proliferation and survival. Unraveling the intricacies of how the degree of ERK activation dictates cell fate requires deciphering mechanisms encompassing protein stability, transcription factors downstream of ERK, and the chromatin landscape.

Phosphate (Pi) starvation is a critical factor limiting crop growth, development, and productivity. Rice (Oryza sativa) R2R3-MYB transcription factors function in the transcriptional regulation of plant responses to various abiotic stresses and micronutrient deprivation, but little is known about their roles in Pi starvation signaling and Pi homeostasis. Here we identified the R2R3-MYB transcription factor gene OsMYB58, which shares high sequence similarity with AtMYB58. OsMYB58 expression was induced more strongly by Pi starvation than by other micronutrient deficiencies. Overexpressing OsMYB58 in Arabidopsis thaliana and rice inhibited plant growth and development under Pi-deficiency conditions. In addition, overexpression of OsMYB58 in plants exposed to Pi deficiency strongly affected root development, including seminal root, lateral root, and root hair formation. Overexpressing OsMYB58 strongly decreased the expression of the rice microRNAs, OsmiR399a and OsmiR399j. By contrast, overexpressing OsMYB58 strongly increased the expression of rice PHOSPHATE 2 (OsPHO2), whose expression is repressed by miR399 during Pi starvation signaling. OsMYB58 functions as a transcriptional repressor of the expression of its target genes, as determined by a transcriptional activity assay. These results demonstrate that OsMYB58 negatively regulates OsmiR399-dependent Pi starvation signaling by enhancing OsmiR399s expression.

The development of the ovarian antral follicle is a complex, highly regulated process. Oocytes orchestrate and coordinate the development of mammalian ovarian follicles, and the rate of follicular development is governed by a developmental program intrinsic to the oocyte. Characterizing oocyte signatures during this dynamic process is critical for understanding oocyte maturation and follicular development. Although the transcriptional signature of sheep oocytes matured in vitro and preovulatory oocytes have been previously described, the transcriptional changes of oocytes in antral follicles have not. Here, we used single-cell transcriptomics (SmartSeq2) to characterize sheep oocytes from small, medium, and large antral follicles. We characterized the transcriptomic landscape of sheep oocytes during antral follicle development, identifying unique features in the transcriptional atlas, stage-specific molecular signatures, oocyte-secreted factors, and transcription factor networks. Notably, we identified specific gene and signaling pathways in each antral follicle stage that may reflect oocyte quality and in vitro maturation competency. Additionally, we discovered key biological processes that drive the transition from small to large antral follicles, revealing hub genes involved in follicle recruitment and selection. Thus, our work provides a comprehensive characterization of the single-oocyte transcriptome, filling a gap in the mapping of the molecular landscape of sheep oogenesis. We also provide key insights into the transcriptional regulation of the critical stages of antral follicular development, which is essential for understanding how the oocyte orchestrates follicular development.

Breast cancer (BCa) is the most frequently diagnosed malignant tumor in women and is also one of the leading causes of cancer-related death. Most breast tumors are hormone-dependent and estrogen signaling plays a critical role in promoting the survival and malignant behaviors of these cells. Estrogen signaling involves ligand-activated cytoplasmic estrogen receptors that translocate to the nucleus with various co-regulators such as steroid receptor co-activator (SRC) family members, and bind to the promoters of target genes and regulate their expression. SRC-3 is a member of this family that interacts with, and enhances the transcriptional activity of the ligand activated estrogen receptor. Although SRC-3 has important roles in normal homeostasis and developmental processes, it has been shown to be amplified and overexpressed in breast cancer and to promote malignancy. The malignancy-promoting potential of SRC-3 is diverse and involves both promoting malignant behavior of tumor cells and creating a tumor microenvironment that has an immunosuppressive phenotype. SRC-3 also inhibits the recruitment of tumor-infiltrating lymphocytes with effector function and promotes stemness. Furthermore, SRC-3 is also involved in the development of resistance to hormone therapy and immunotherapy during breast cancer treatment. The versatility of SRC-3 in promoting breast cancer malignancy in this way makes it a good target, and methodical targeting of SRC-3 probably will be important for the success of breast cancer treatment.

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/Akt/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we will explore recent advancements in understanding the role of the EGFR/PI3K/Akt/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies

Plant roots host various microorganisms around and inside their roots, known as the root microbiome. To become healthy and productive, plants should keep under surveillance niches around the roots to recognize disease-causing microbes and similarly exploit the services of beneficial microorganisms in nutrient acquisition, stress mitigation and growth promotion. Here we presented the communication strategies between plant roots and root-associated microbes in improving plant growth and yield. Understanding how plant root and root-associated microbes communicate is vital in designing ecofriendly strategies for targeted disease suppression and improved plant growth that will help in sustainable agriculture.

Plant growth-promoting rhizobacteria (PGPR) are members of the plant rhizomicrobiome that enhance plant growth and stress resistance by increasing nutrient availability to the plant, producing phytohormones or other secondary metabolites, stimulating plant defense responses against abiotic stresses and pathogens, or fixing nitrogen. The use of PGPR to increase crop yield with minimal environmental impact is a sustainable and readily applicable replacement for a portion of chemical fertilizer and pesticides required for the growth of high-yielding varieties. Increased plant health and productivity have long been gained by applying PGPR as commercial inoculants to crops, although with uneven results. The establishment of plant-PGPR relationships requires the exchange of chemical signals and nutrients between the partners, and polyamines (PAs) are an important class of compounds that act as physiological effectors and signal molecules in plant-microbe interactions. In this review we focus on the role of PAs in interactions between PGPR and plants. We describe the basic ecology of PGPR and production and function of PAs in them and in the plants with which they interact. We examine the metabolism and the roles of PAs in PGPR and plants individually and during their interaction with one another. Lastly, we describe some directions for future research.

Panax ginseng C. A. Meyer (P. ginseng), has been widely used in traditional Chinese medicine (TCM). It contains a number of chemical components and possesses a variety of pharmacological activities. Alzheimer's disease (AD) is neurodegenerative disease that creates a huge burden on the lives and health of individuals. In recent years, studies have indicated that the chemical components of P. ginseng, especially ginsenosides, play a pronounced positive role in the prevention and treatment of neurological diseases. This review aimed to summarize currently studies on chemical components and the mechanisms action in AD intervention treatment of P. ginseng, especially ginsenosides. In this review, the components of P. ginseng and their respective active effects were first introduced. Then the key molecular mechanisms and signaling pathways of P. ginseng were introduced, and its different active ingredients in the prevention and treatment of Alzheimer's disease-related pathogenesis were also summarized from the pathogenesis of AD Aβ generation and aggregation, hyperphosphorylation of tau protein，oxidant stress，neuroinflammation，mitochondrial damage，disorder of neurotransmitter and gut microbiota. Signaling pathway networks related to the action of ginseng active ingredients was constructed, which could serve as a therapeutic target for Alzheimer's disease. In addition to a detailed report on P. ginseng in improving Alzheimer's disease-related pathogenesis, the application of the current technology, spatial metabonomics in AD therapeutics and diagnostics were later discussed. Spatial metabonomics could be applied to investigate the multi-target intervention of P. ginseng on Alzheimer's disease. Research perspectives for the study of P. ginseng in the treatment of Alzheimer's disease were provided for further studies.

CAR-T therapy has achieved considerable treatment success in hematologic tumors by using patient derived autologous αβ T cells. There is an impetus to broaden the applicability of this approach by using a third-party donor derived CAR-T cell product which has a potent anti-tumor function but a constrained GVHD property. In this study, CAR-T cells were prepared from Vγ9Vδ2 T cells expanded by using a novel prodrug PTA and their anti-tumor functions were assessed in conjunction with persistency, localization, and phenotype. γδ T cells were successfully transduced with a CAR specific to CEA with signaling domains of CD3ζ and CD28 (CEA.CAR-γδ T cells), and exhibited potent tumor killing function in vitro. In a xenograft mouse model, CEA.CAR-γδ T cells suppressed CEA+ tumor growth though a limited time window. CEA.CAR-γδ T cells persisted and accumulated in the tumor even after tumor progression, however, ex vivo analysis revealed that those recovered at different time points from PBMC, spleen and tumors gradually lost tumor reactivity as assessed by IFN-γ production. Provision of GITR co-stimulation enhanced anti-tumor function of CEA.CAR-γδ T cells, the result of which imposes additional measurers to be adopted in CAR-γδ T cells for an allogeneic adoptive immunotherapy.

TGF-ꞵ signaling is a vital regulator for maintaining articular cartilage homeostasis. Runx transcription factors, downstream targets of TGF-ꞵ signaling, have been studied in the context of osteoarthritis (OA). Although Runx partner core binding factor β (Cbfβ) is known to play a pivotal role in chondrocyte and osteoblast differentiation, the role of Cbfβ in maintaining articular cartilage remains obscure. This study investigated Cbfβ as a novel anabolic modulator of TGF-ꞵsignaling and determined its role in articular cartilage homeostasis. Cbfβ significantly decreased in aged mouse articular cartilage and human OA cartilage. Articular chondrocyte-specific Cbfb-deficient mice (Cbfb△ac/△ac) exhibited early cartilage degeneration at 20 weeks old and developed OA at 12 months old. Cbfb△ac/△ac mice showed enhanced OA progression under the surgical-induced mice OA model. Mechanistically, forced expression of Cbfβ rescued Col2α1 and Runx1 expression in Cbfβ-deficient chondrocytes. TGF-ꞵ1-mediated Col2α1 expression failed despite the pSmad3 activation under TGF-ꞵ1 treatment in Cbfβ-deficient chondrocytes. Cbfβ protected Runx1 from proteasomal degradation through Cbfβ/Runx1 complex formation. These results indicate that Cbfβ is a novel anabolic regulator for cartilage homeostasis, suggesting that Cbfβ could protect OA development by maintaining the integrity of the TGF-ꞵ1 signaling pathway in articular cartilage.

Polybrominated diphenyl ethers (PBDE) are a group of flame retardants used in a variety of artificial materials. Despite phasing out in most industrial countries, they persist in the environment and human tissues due to their persistence, lipophilicity, and bioaccumulation. Populational and experimental studies demonstrate male reproductive toxicity of PBDEs including increased incidence of genital malformations (hypospadias and cryptorchidism), altered weight of testes and other reproductive tissues, altered testes histology and transcriptome, decreased sperm production and sperm quality, altered epigenetic regulation of developmental genes in spermatozoa and altered secretion of reproductive hormones. A broad range of mechanistic hypotheses of PBDE reproductive toxicity has been suggested. Among these hypotheses, oxidative stress, disruption of estrogenic signaling, and mitochondria disruption are affected by PBDE concentrations much higher, than concentrations found in human tissues, making them unlikely links between exposures and adverse reproductive outcomes in the general population. Robust evidence suggests that at environmentally relevant doses, PBDEs and their metabolites may affect male reproductive health via mechanisms including AR antagonism and the disruption of a complex network of metabolic signaling.

The modification of proteins by small ubiquitin-related modifier (SUMO) molecules, SUMOylation, is a key post-translational modification involved in a variety of biological processes such as chromosomes organization, DNA replication and repair, transcription, nuclear transport, and cell signaling transduction. In recent years, emerging evidence has shown that SUMOylation regulates the development and homeostasis of the skeletal system, with its dysregulation causing skeletal diseases, suggesting that SUMOylation pathways may serve as a promising therapeutic target. In this review, we summarize the current understanding of the molecular mechanisms by which SUMOylation pathways regulate skeletal cells in the physiological and disease contexts.

Ciliopathies are genetic syndromes that link skeletal dysplasias to dysfunction of primary cilia. Primary cilia are sensory organelles synthesized by intraflagellar transport (IFT) - A and B complexes, which traffic protein cargo along a microtubular core. We have reported that deletion of IFT-A gene, Thm2, together with a null allele of its paralog, Thm1, causes a small skeleton with small mandible or micrognathia in juvenile mice. Using micro-computed tomography, here we quantify the craniofacial defects of Thm2^-/-;Thm1^aln/- triple allele mutant mice. At postnatal day 14, triple allele mutant mice exhibit micrognathia, maxillary hypoplasia, and a decreased facial angle due to shortened maxilla, premaxilla, and nasal bones, reflecting altered development of facial anterior-posterior elements. In contrast, other ciliopathy-related craniofacial defects, such as cleft lip and/or palate, hypo-/hypertelorism, broad nasal bridge, craniosynostosis, and facial asymmetry, were not observed, suggesting development of the facial transverse dimension is intact. Calvarial-derived osteoblasts of triple allele mutant mice showed reduced bone formation in vitro that was ameliorated by Hedgehog agonist, SAG. Together, these data indicate that Thm2 and Thm1 genetically interact to regulate bone formation and sculpting of the postnatal face. The triple allele mutant mice present as a novel model to study craniofacial bone development.

Our health requires continual protein synthesis for maintaining and repairing tissues. For protein synthesis to function, all the essential (indispensable) amino acids (IAA) that must be available in the diet, along with those AAs that the cells can synthesize, the dispensable amino acids. Here we review studies that have shown the location of the detector for IAA deficiency in the brain, specifically for recognition of IAA deficient diets (IAAD diets) in the anterior piriform cortex (APC), with subsequent responses in downstream brain areas. The APC is highly excitable, uniquely suited to serve as an alarm for reductions in IAAs. With a balanced diet, these neurons are kept from over-excitation by GABAergic inhibitory neurons. Because several transporters and receptors on the GABAergic neurons have rapid turnover times, they rely on intact protein synthesis to function. When an IAA is missing, its unique tRNA cannot be charged. This activates the enzyme General Control Nonderepressible 2 (GCN2) that is important in the initiation phase of protein synthesis. Without the inhibitory control supplied by GABAergic neurons, excitation in the circuitry is free to signal an urgent alarm. Studies in rodents have shown rapid recognition of IAA deficiency by quick rejection of the IAAD diet.

With a highly efficient optical absorption capability, bismuth selenide (Bi2Se3) nanomaterial can be used as an outstanding photothermal agent for anti-tumor treatment and shows promise in the field of nanotechnology-based biomedicine. However, little research has been done on the relevant mechanism underlying the photothermal killing effect of Bi2Se3 nanomaterial. Herein, the photothermal effects of Bi2Se3 nanoparticles on A549 cells were explored with emphasis put on autophagy. Firstly, we characterized the structure and physicochemical property of the synthesized Bi2Se3 and confirmed their excellent photothermal conversion efficiency (35.72%), photostability, biocompatibility and ability of photothermal killing on A549 cells. Enhanced autophagy was detected in Bi2Se3-exposed cells under an 808 nm laser. Consistently, an elevated expression ratio of LC3-II to LC3-I, a marker of autophagy occurrence, was induced in Bi2Se3-exposed cells upon NIR irradiation. Meanwhile, the expression of cleaved-PARP was increased in the irradiated cells dependently on the exposure concentrations of Bi2Se3 nanoparticles. Pharmacological inhibition of autophagy by 3-methyladenine (3-MA) further strengthened the photothermal killing effect of Bi2Se3. Meanwhile, stress-related signaling pathways including p38 and SAPK/JNK were activated coupled with the attenuated PI3K/Akt signaling. Our study figures out that autophagy and the activation of stress-related signaling pathways were involved in the photothermal killing of cancerous cells by Bi2Se3, which provides a more understanding of photothermal nanomaterials.

With the global climate anomalies and the destruction of ecological balance, water shortage has become a serious ecological problem facing all mankind, and drought has become a key factor restricting the development of agricultural production. Therefore, it is essential to study the drought tolerance of crops. On the basis of previous studies, we reviewed the effects of drought stress on plant morphology and physiology, including the changes of external morphology and internal structure of root, stem and leaf, the effects of drought stress on osmotic regulation sub-stances, drought-induced proteins and active oxygen metabolism of plants. In this paper, the main drought stress signals and signal transduction pathways in plants are described, and the functional genes and regulatory genes related to drought stress are listed respectively. We summarize the above aspects in order to provide valuable background knowledge and theoret-ical basis for future agriculture and forestry breeding and cultivation.

The glioma-associated oncogene (GLI) family consists of GLI1, GLI2, and GLI3 in mammals, and is the effector in the Hedgehog signaling pathway. This family has important roles in the development and homeostasis of various tissues. To achieve these roles, the GLI family has widespread outputs. GLI activity is therefore strictly regulated at multiple levels, including via post-translational modifications for context-dependent GLI target gene expression. Conversely, dysregulated GLI activation has strong links with a variety of cancers. The protein arginine methyl transferase (PRMT) family is also associated with embryogenesis, homeostasis, and cancer via epigenetic modifications and signal transduction. In the PRMT family, PRMT1, PRMT5, and PRMT7 reportedly regulate GLI1 and GLI2 activity. PRMT1 methylates GLI1 to upregulate its activity and target gene expression. Cytoplasmic PRMT5 methylates GLI1 and is involved in GLI1 protein stabilization. In contrast, nucleic PRMT5 interacts with MENIN to suppress growth arrest-specific protein 1 expression, which assists Hedgehog ligand binding to Patched, indirectly resulting in downregulated GLI1 activity. PRMT7-mediated GLI2 methylation upregulates its activity through the dissociation of GLI2 and Suppressor of Fused. Therefore, PRMT1, PRMT5, and PRMT7 regulate GLI activity at multiple levels, and PRMT-mediated GLI dysregulation may be involved in cancer formation.

Many studies were done in the development of drought stress-tolerant transgenic plants, including crop plants. Rice is considered to be a vital crop target for improving drought stress tolerance. Much transgenic rice showed improved drought stress tolerance was reported to date. They are genetically engineered plants that are developed by using genes that encode proteins involved in drought stress regulatory networks. These proteins include protein kinases, transcription factors, enzymes related to osmoprotectant or plant hormone synthesis, receptor-like kinase. Of the drought stress-tolerant transgenic rice plants described in this review, most of them display retarded plant growth. In crop crops, plant health is a fundamental agronomic trait that can directly affect yield. By understanding the regulatory mechanisms of retarded plant growth under drought stress, conditions are necessary precursors to developing genetically modified plants that result in high yields.

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine if additional alkaloids in the extracts contribute to Hh signaling inhibition, we replicated the concentrations of these alkaloids observed in extracts using commercially available standards and compared the inhibitory potential of the extracts to alkaloid standard mixtures using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts contribute to Hh signaling inhibition.

Crosstalk between the BMP and TGF-β signaling pathways regulates many complex developmental processes from the earliest stages of embryogenesis throughout adult life. In many situations, the two signaling pathways act reciprocally. For example, TGF-β signaling is generally pro-fibrotic whereas BMP signaling is anti-fibrotic and pro-calcific. Sex-specific differences occur in many diseases including cardiovascular pathologies. Differing ratios of fibrosis and calcification in stenotic valves suggests that BMP/TGF-β signaling may vary in men and women. In this review, we focus on the current understanding of the interplay between sex and BMP/TGF-β signaling and pose several unanswered questions.

Sinulariolide, a natural product extracted from cultured-type soft coral Sinularia flexibilis, possesses bioactivity against the movement of several types of cancer cell. However, the molecular pathway of its effects on human bladder cancer remain poorly understood. Using a human bladder cancer cell line as an in vitro model, this study investigated the underlying mechanism of sinulariolide against cell migration/invasion in TSGH-8301 cells. We found that sinulariolide inhibited TSGH-8301 cell migration/invasion, and the effect was concentration-dependent. Furthermore, the protein expressions of matrix metalloproteinases (MMPs) MMP-2 and MMP-9, as well as urokinase, were significantly decreased after 24-h sinulariolide treatment. Meanwhile, the increased expressions of tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 were in parallel with an increased concentration of sinulariolide. Finally, the expressions of several key phosphorylated proteins in the mTOR signaling pathway were also downregulated by sinulariolide treatment. Our results demonstrated that sinulariolide has significant effects against TSGH-8301 cell migration/invasion, and its effects were associated with decreased levels of MMP-2/-9 and urokinase expression, as well as increased TIMP-1/TIMP-2 expression. The inhibitory effects were mediated by reducing phosphorylation proteins of the PI3K, AKT and mTOR signaling pathway. The findings suggested that sinulariolide is a good candidate for advanced investigation with the aim of developing a new drug for the treatment of human bladder cancer.

High temperature (HT) geothermal wells can provide green power 24h a day 7 days a week. Harsh environmental and operational conditions, long-term durability requirements of such wells require special cementitious composites for well construction. This paper reports a comprehensive assessment of geothermal cement composites in cyclic pressure function laboratory tests, field exposures in an HT geothermal well (300-350oC) as well as a numerical model to complement the experimental results. Performances of calcium-aluminate-cement (CAC)-based composites and calcium free cement were compared against reference Ordinary Portland Cement (OPC)/silica blend. The stability and degradation of the tested materials was characterized by crystalline composition, thermo-gravimetric, and elemental analyses, morphological studies, water-fillable porosity, and mechanical properties measurements. All CAC-based formulations outperformed the reference blend both in the function and exposure tests. The reference OPC/silica lost its mechanical properties during the 9-month well exposure through extensive HT carbonation, while properties of the CAC-based blends improved over that period. The Modified Cam-Clay (MCC) plasticity parameters of several HT cement formulations were extracted from triaxial and Brazilian tests and verified against the experimental results of function cyclic tests. These parameters can be used in well integrity models to predict field-scale behavior of the cement sheath under geothermal well conditions.

Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (Ca_Vs). Calcium entering through Ca_Vs is key for multiple neuronal processes. In this review, we will summarize recent findings that link Ca_Vs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of Ca_Vs structure, classification, function, expression and pharmacology. Next, we will summarize tools and databases to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in Ca_V genes when available. We will review pharmacological evidence of the use of Ca_V modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of Ca_Vs.

The present study showcases a series of crystallization experiments using a specially designed double diffusion system to grow crystals belonging to the calcium carbonate-phosphate system. The experimental U-shaped device comprised two vertical solution containers, separated by a horizontal column of silica hydrogel. Each container was filled with 0.5 M CaCl2 and 0.5 M Na2CO3 solutions, which diffused through the gel column over time. Na3PO4 solutions, with 50 and 500 ppm concentrations, were incorporated into the gel in different experiments, resulting in a homogeneous distribution of phosphate concentrations within the diffusion column. After 15 and 30 days incubation period post-nucleation, the crystals formed in different sections of the gel were carefully extracted and studied with scanning electron microscopy and electron microprobe. Additionally, Raman spectra were collected from the samples using a confocal Raman microscope, providing further insights into their molecular composition and structural properties. The obtained results show that under the induced experimental conditions (i) phosphate incorporates into calcite´s structure, and (ii) the growth of calcium phosphates in the presence of carbonate ions involves the sequential, heterogeneous nucleation of CO3-bearing OCP/HAP-like phases with Raman spectral characteristics very similar to those of bioapatites.

Hypertension is a frequent risk factor for cardiovascular diseases and the prevalence rate is continuously rising. Multiple pathophysiological mechanisms are responsible for hypertension, necessitating a combination of drugs from different classes for best management. Combination therapy is five times more effective in decreasing blood pressure compared to escalating the dose of a single agent. As per the ACCOMPLISH trial analysis, coupling a renin-angiotensin system inhibitor with a calcium channel blocker is more effective than the combination of a renin-angiotensin system inhibitor with diuretics in reducing major cardiovascular events, cardiovascular-related mortality, and the progression of chronic kidney disease. The renin-angiotensin system can be suppressed by inhibiting the angiotensin-converting enzyme or angiotensin type 1 receptor (AT1R), resulting, in decreased vascular smooth muscle contraction, heart performance, and reduced aldosterone synthesis. Calcium channel blockers work by inhibiting L-type calcium channels, reducing heart performance via negative inotropic, chronotropic, and bathmotropic effects, along with reducing vascular smooth muscle contraction. Diuretics exert their antihypertensive impact by changing body fluid volume and electrolytes. Initially, hypertension treatment commences with a single medication but often, different classes of two or more antihypertensive medications are necessary for achieving the target blood pressure goal. Sometimes, for Resistant hypertension four different classes of antihypertensive medications are necessary to reach the target blood pressure goal.

The regenerated magnesia-calcium brick samples that had added 0, 1.5, 3.0 wt.% aluminium oxide (Al2O3) were prepared by using spent magnesia-calcium bricks, fused magnesia and Al2O3 powder additive as the main raw materials. The phases, microstructures, room temperature and hot flexural strength, resistance to cement clinker corrosion and strength of coating adherence were investigated respectively. It indicated that the addition of Al2O3 increased mainly resulting in the content of tetracalcium aluminoferrite (C4AF) and tricalcium aluminate (C3A) increased in the regenerate samples. The bulk density, the room temperature flexural strength and the strength of coating adherence all increased, while the hot flexural strength and corrosion resistance both deteriorated along with the increase of Al2O3 addition. It was because that on the one hand the low melting point phases of C4AF and C3A improved the sinterability of the regenerated samples during the burning stage, on the other hand they melted or existed in liquid phase during the experimental temperature (1573 K and 1823 K) which degraded hot flexural strength and corrosion resistance, and enhanced the strength of coating adherence as the wettability of the liquid phase. The content of Al2O3 in the regenerated magnesia-calcium brick should not be higher than 1.1 wt.%, considering its room and high-temperature performances for cement rotary kiln.

The role of calcium ions (Ca2+) is extensively documented and comprehensively understood in eukaryotic organisms. Nevertheless, emerging insights, primarily derived from studies on human pathogenic bacteria, suggest that this ion also holds a pivotal role in prokaryotes. In this review, our primary focus will be on unraveling the intricate Ca2+ toolkit within prokaryotic organisms, with particular emphasis on its implications in plant growth promoting rhizobacteria (PGPR). To pinpoint and identify homologues of Ca2+ channels, pumps, exchangers, and Calcium-Binding Proteins (CaBPs) we undertook an in silico exploration in the genomes of four distinct PGPR strains using as query prokaryotic sequences that were experimentally confirmed to play a role in regulating intracellular calcium concentration ([Ca2+]i) or sensing and transducing this essential cation. These investigations were conducted in Pseudomonas chlororaphis subsp. aurantiaca SMMP3, P. donghuensis SVBP6, Pseudomonas sp. BP01, and Methylobacterium sp. 2A. which have been isolated and characterized within our research laboratories. We also present experimental data to evaluate the influence of exogenous Ca2+ concentrations ([Ca2+]ex) on the growth dynamics of these isolated strains

Due to the severe environmental impact of the CO2 emissions associated with the production of Ordinary Portland Cement (OPC) and the increasing demand for this commodity material, the development of alternative products has become a global concern. One alternative to OPC, or alitic-based clinkers, are amorphous-wollastonitic low calcium hydraulic binders (AWLCs). This new class of hydraulic binders, described in the literature for the first time in 2015, may significantly reduce the CO2 emissions associated with its production, resulting from its lower calcium content, but also from the fact that its production technology can be fully electrified. In this paper it is provided a state-of-the-art review, providing a comprehensive description on the latest research, summarizing both the physico-chemical and mechanical characteristics for this type of hydraulic binders, as well as possible routes for its production at an industrial scale.

Aerobic exercise training (AET) has been used in the management of heart disease. AET may, totally or partially, restore the activity and/or expression of proteins that regulate calcium (Ca2+) handling, optimize intracellular Ca2+ flow, and attenuate cardiac functional impairment in failing hearts. However, the literature presents conflicting data regarding the effects of AET on Ca2+ transit and cardiac function in rats with heart failure resulting from aortic stenosis. The objective of this study was to evaluate the effects of AET on calcium handling and cardiac function in rats with heart failure due to aortic stenosis. Wistar rats were distributed into two groups: control (Sham; n= 61) and aortic stenosis (AoS; n= 44). After 18 weeks, the groups were redistributed into: non-exposed to exercise training (Sham, n = 28 and AoS, n = 22) and trained (Sham-ET, n = 33 and AoS-ET, n = 22) for 10 weeks. Treadmill exercise training was performed with a velocity equivalent to the lactate threshold. Echocardiogram, isolated papillary muscle, and isolated cardiomyocyte analyzed cardiac function. During isolated papillary muscle assay and isolated cardimyocyte was evaluated Ca2+. The expression of regulatory proteins of diastolic Ca2+ was analyzed via Western Blot. AET attenuated the diastolic dysfunction and benefited the systolic function. AoS-ET animals presented better response to post-rest contraction, and SERCA2a and L-type Ca2+ channels blocked than the AoS. Furthermore, AET was able to improve aspects of the mechanical function and the responsiveness of the myofilaments to the Ca2+ of the AoS-ET animals. AoS animals presented alteration in the protein expression of the SERCA2a and NCX, and AET restored SERCA2a and NCX levels near normal values. Therefore, AET increased SERCA2a activity, improved the cellular Ca2+ influx mechanism, and increased myofilament responsiveness to Ca2+, attenuating cardiac dysfunction at cellular, tissue, and chamber levels in animals with aortic stenosis and heart failure.

Transient Receptor Potential Vanilloid 4 (TRPV4) channel is a non-selective cation channel, mostly permeable to calcium (Ca2+), which participates to intracellular Ca2+ handling in cardiac cells. It is widely expressed through the body and is activated by a large spectrum of physico-chemical stimuli, conferring it a role in a variety of sensorial and physiological functions. With-in the cardiovascular system, TRPV4 expression was reported in cardiomyocytes, endothelial cells (ECs) and smooth muscle cells (SMCs) where it modulates mitochondrial activity, Ca2+ ho-meostasis, cardiomyocytes electrical activity and contractility, cardiac embryonic development, fibroblast proliferation but also vascular permeability, dilatation and constriction. On the other hand, TRPV4 channels participate in several cardiac pathological processes such as development of cardiac fibrosis, hypertrophy, ischemia-reperfusion injuries, heart failure, myocardial infarc-tion, and arrhythmia. In this manuscript, we provide an overview of TRPV4 channel implica-tions in cardiac physiology and discuss the potential of TRPV4 channel as therapeutic target against cardiovascular diseases.

Several observational studies have indicated the potential associations between calcium, vitamin D(Vit-D) and irritable bowel syndrome (IBS). However, the causal relationship deduced from these studies is subjected to residual confounding factors and reverse causation. Therefore, we aim to explore the bidirectional causal effects between serum calcium, Vit-D, PTH and IBS at the genetic level by a two-sample Mendelian randomization (MR) analysis. Sensitivity analyses were performed to evaluate the robustness. The estimates were presented as odds ratio (OR) with their 95% confidence intervals (CIs). The results of the inverse-variance-weighted method did not re-veal any causal relationship shared between genetically predisposed calcium (OR = 0.92, 95% CI: 0.80-1.06, P = 0.25) and Vit-D (OR = 0.99, 95% CI: 0.83-1.19, P = 0.94) level and the risk of IBS. The bidirectional analysis demonstrated that genetic predisposition to IBS was associated with a de-creased level of PTH (beta: -0.19, 95%CI: -0.34 to -0.04, P = 0.01). In conclusion, the present study indicates no causal relationship between the serum calcium and Vit-D concentrations and the risk of IBS. The potential mechanisms by which IBS affects serum PTH need to be further investigated.

Materials based on Mg2+-containing phosphates are gaining great relevance in the field of bone tissue repair via regenerative medicine methods. Magnesium ions, together with condensed phosphate ions, play a significant role in the process of bone remodeling, affecting the early stage of bone regeneration through active participation in the process of osteosynthesis. Here we pro-vide a comprehensive overview of the usage of biomaterials based on magnesium phosphate and magnesium calcium phosphate in bone reconstruction. The role of magnesium ions in angiogene-sis, an important process associated with osteogenesis, is considered. Finally, the biological properties of magnesium phosphates for bone regeneration are summarized. They show promis-ing results in terms of use as bone replacement material.

The combination of calcium phosphates (CaP) with bioactive glasses (BG) has received an increased interest in the field of bone tissue engineering. In the present work, biphasic calcium phosphates (BCP) obtained by hydrothermal transformation (HT) of cuttlefish bone (CB) were coated with a Sr-, Mg- and Zn-doped sol-gel derived BG. The scaffolds were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The initial CB structure was maintained after HT and the scaffold functionalization did not jeopardize the internal structure. The results of in vitro bio-mineralization after immersing the BG coated scaffolds in simulated body fluid (SBF) showed extensive formation of bone-like apatite onto the surface of the scaffolds. Overall, the functionalized CB derived BCP scaffolds revealed promising properties for their use in bone tissue engineering field.

The present study is the second step (concerning the normal-diet restoration) of the our previous one (concerning the calcium-free diet) to determine whether the normal-diet restoration, with/without concomitant PTH(1-34) administration, can influence amounts and deposition sites of the total bone mass. Histomorphometric evaluations and immunohistochemical analysis for Sclerostin expression were conducted on the vertebral bodies and femurs in rat model. The final goals are: i) to define timing and manners of bone mass changes when calcium is restored in the diet; ii) to analyze the different involvement of the two bony architectures having different metabolism (i.e. trabecular versus cortical bone); iii) to verify the eventual role of PTH(1-34) administration. Results evidenced the greater involvement of the trabecular bone with respect to the cortical one, in answering to different calcium diet content, and the effect of PTH mostly in the recovery of trabecular bony architecture. The main findings emerged from the present study are: i) the importance of the interplay between mineral homeostasis and skeletal homeostasis in modulating and guiding bone answers to dietary/metabolic alterations and ii) the evidence that the more involved bony architecture is the trabecular one, the most susceptible to the dynamical balance of the two homeostases.

The increasing use of energy resources recovered from the subsurface environments and the resulting carbon imbalance in the environment has motivated the need to develop thermodynamically downhill pathways to convert and store CO₂ as water insoluble calcium or magnesium carbonates. While previous studies extensively explored aqueous routes to produce calcium and magnesium carbonates from CO₂, there has been a limited scientific understanding of the phase evolution and textural changes during the direct gas-solid conversion routes to produce calcium carbonate from calcium hydroxide, which is one of the abundant constituents of alkaline industrial residues. With increasing interest in developing integrated pathways for capturing, converting and storing CO₂ from dilute flue gases, understanding the compositions of the product phases as they evolve is essential for evaluating the efficacy of a given processing route. Therefore, in this study, we investigate the phase evolution and the corresponding textural changes as calcium hydroxide is converted to calcium carbonate under the continuous flow of CO₂ at an ambient pressure of 1 atm and on heating continuously from 30 °C to 500 °C using in-operando wide angle X-ray scattering (WAXS), small angle X-ray scattering (SAXS), and ultra-small angle X-ray scattering (USAXS) measurements.

LPA3 receptors were expressed in TREx HEK 293 cells, and their signaling and phosphorylation were studied. The agonist, lysophosphatidic acid (LPA), increased intracellular calcium and ERK phosphorylation through pertussis toxin-insensitive processes. Phorbol myristate acetate, but not LPA, desensitizes LPA3-mediated calcium signaling. The agonists and the phorbol ester-induced LPA3 internalization. Pitstop 2 (clathrin heavy chain inhibitor) markedly reduced LPA-induced receptor internalization; in contrast, phorbol ester-induced internalization was only delayed. LPA induced rapid β-arrestin-LPA3 receptor association. The agonist and the phorbol ester induced marked LPA3 receptor phosphorylation, and phosphorylation sites were detected using mass spectrometry. Phosphorylated residues were detected in the intracellular loop 3 (S221, T224, S225, and S229) and in the carboxyl terminus (S321, S325, S331, T333, S335, Y337, and S343). Interestingly, phosphorylation sites are within sequences predicted to constitute β-arrestin binding sites. These data provide insight into LPA3 receptor signaling and regulation.

(1) Background: TNF inhibitors (TNFi) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40 % of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFi have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces a “Reverse Signaling” (RS) in cells. We previously showed that certolizumab, a Fab’ TNFi, activates RS in human primary monocytes, at least in part through the transcription factor NRF2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of 6 genes induced by NRF2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3 % accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term, test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.

Ruxolitinib has been approved by FDA for the treatment of myeloproliferative neoplasms such as polycythemia vera and idiopathic myelofibrosis. Although ruxolitinib has been in the clinic for more than ten years, surprisingly, no JAK2 drug resistant mutations have been identified in patients. At the moment, it is not clear whether the absence of JAK2 mutations in MPN patients is due to a lack of JAK2 addiction or residues that mediate the drug resistance compromising the JAK2 function. To find out this, we established a Ba/F3 cell-based screening strategy to predict mutations in JAK2-V617F that cause resistance towards ruxolitinib. In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. All the ruxolitinib resistant JAK2 variants displayed sensitivity towards Type II JAK2 inhibitor CHZ-868. Finally, our study also shows that HSP90 inhibitors are potent against ruxolitinib resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.

The differentiation of ESCs into cardiomyocytes in vitro is an excellent and reliable model system for studying normal cardiomyocyte development in mammals, modeling cardiac diseases, and for use in drug screening. Mouse ESC differentiation still provides relevant biological information about cardiac development. However, the current methods for efficiently differentiating ESCs into cardiomyocytes are limiting. Here, we describe a “WNT Switch” method to efficiently commit mouse ESCs into cardiomyocytes using the small molecule WNT signaling modulators CHIR99021 and XAV939 in vitro. This method significantly improves the yield of beating cardiomyocytes, reduces number of treatments, and is less laborious.

Once discovered, cancer stem cells have become a hot topic in the research of cancer therapy. These cells possess stem cell-like self-renewal and differentiation capacities and are important factors that dominate cancer metastasis, therapy- resistance and recurrence. What's worse, their own characteristics make them difficult to be eliminated. Colorectal cancer is the third most common cancer and the second leading cause of cancer death worldwide. Targeting colorectal cancer stem cells (CRCSCs) can inhibit colorectal cancer metastasis, enhance therapeutic efficacy, and reduce recurrence. Here, we introduced the origin, marker proteins, identification, cultivation and research techniques of CRCSCs, summarized the signaling pathways that regulate the stemness of CRCSCs, such as Wnt, JAK/STAT3, Notch, and Hh signaling pathway. In addition to these, we also reviewed anti-CRCSC drugs targeting signaling pathways，markers，and other regulators in recent years. These will help researchers gain insight into the current agents targeting to CRCSCs, explore new cancer drugs, and propose potential therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a ravaging disease whose poor prognosis requires a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggested to rather focus on the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer secreted proteins in the complex TME tumor-stroma crosstalk, to sched lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.

Sodium butyrate (NaB) is one of the short-chain fatty acids and is notably produced in large amounts from dietary fiber in the gut. Recent evidence suggests that NaB induces cell proliferation and apoptosis. The skeletal muscle is rich in plenty of mitochondrial. However, it is unclear how NaB acts on host muscle cells and whether it is involved in mitochondria-related functions in myocytes. The present study aimed to investigate the role of NaB treatment on the proliferation, apoptosis, and mitophagy of bovine skeletal muscle satellite cells (BSCs). The results showed that NaB inhibited the proliferation and promoted apoptosis of BSCs, and promoted mitophagy in a time and dose-dependent manner in BSCs. In addition, 1mM NaB increased the mitochondrial ROS level, decreased the mitochondrial membrane potential (MMP), increased the number of autophagic vesicles in mitochondria, and increased the mitochondrial DNA(mtDNA) and ATP level. The effects of the mTOR pathway on BSCs were investigated, and the results showed that 1mM NaB inhibited the mRNA and protein expression of mTOR and genes AKT1, FOXO1, and EIF4EBP1 in the mTOR signaling pathway, while the addition of PP242, an inhibitor of the mTOR signaling pathway, also inhibited mRNA and protein expression levels of mTOR, AKT1, FOXO1, and EIF4EBP1, and promoted mitophagy and apoptosis, which were consistent with the effect of NaB treatment. In conclusion, NaB might promote mitophagy and apoptosis in BSCs by inhibiting the mTOR signaling pathway. Our results would expand the knowledge of sodium butyrate on bovine skeletal muscle cell state and mitochondrial function.

Porcine epidemic diarrhea virus (PEDV) has caused great damage to the global pig industry. The innate immunity plays a significant role in resisting viral infection, however, the exact role of innate immunity in the anti-PEDV response has not been fully elucidated. In this study, we observed that various porcine innate immune signaling adaptors are involved in the anti-PEDV activity. Among these, TRIF and MAVS showed the strongest anti-PEDV activity. The endogenous TRIF, MAVS and STING were selected for further examination of anti-PEDV activity. Agonist stimulation experiments showed that TRIF, MAVS and STING signaling all have obvious anti-PEDV activity. The siRNA knockdown assay showed that TRIF, MAVS and STING are also all involved in anti-PEDV response, and their remarkable effects on PEDV replication were confirmed in TRIF-/-, MAVS-/- and STING-/- Vero cells. For further verification, the anti-PEDV activity of TRIF, MAVS and STING could be reproduced in porcine IPEC-DQ cells. In summary, this study reveals that multiple pattern recognition receptor (PRR) signaling pathways of porcine innate immunity play an important role in the anti-PEDV infection, providing new and useful antiviral knowledge for prevention and control of PEDV spreading.

Type 2 diabetes mellitus (T2DM) accounts for one-sixth of deaths, globally, whereas cancer is the second leading cause of death in the U.S. T2DM is a known risk factor for many cancers. This review examines the link of Reactive oxygen Species (ROS)-altered metabolic and signaling pathways in T2DM to cancer. These reprogrammed metabolic and signaling pathways are activated that contribute to diabetic complications, impact redox balance (Oxidative Stress), and have differential roles in early and late stages of cancer. If the respiratory chain is highly reduced (as under hyperglycemic conditions) or if reduced cofactors accumulate, ROS are greatly elevated. ROS may cause mutations in mitochondrial DNA (mtDNA) that result in further ROS elevation. Amplification of ROS results in activation of PKC, an overarching signaling pathway that activates MAPK with subsequent regulation of several factors that result in pathophysiological manifestations of T2DM and cancer. Upregulation of PKC leads to deregulation of NF-kß that regulates the PKB/P13/Akt pathway that orchestrates cell survival, growth, proliferation, and glucose metabolism manifested in cancer. It also affects Insulin Receptor Substrate (IRS-1), decreasing insulin stimulated glucose transport and glucose uptake, disrupting subsequent cell signaling pathways contributing to the development of T2DM. Dyslipidemia is a hallmark of T2DM and cancer. ROS-induced lipid peroxidation leads to systemic inflammation, producing inflammatory prostaglandins, cytokines and chemokines that result in tumor proliferation, rapid tumor growth, and modulation of immunity. The dual role of ROS in early and late stages of cancer make antioxidant therapy precarious and may be responsible for controversial results. A system that delivers an antioxidant directly to mitochondria may be useful in inhibiting formation of ROS early during the pre-diabetic stage whereas antioxidant therapy must be halted in later stages to retard metastasis.

It was found that patients with comorbidities of obesity and diabetes have a high risk of breast cancer occurrence and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanism is still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. It was observed that the onset of breast tumor and latency period per tumor development were early in GR-Ob rats compared to respective lean rats. It was found that 62% of obese rats were bearing tumors, and in comparison, only 21% of the lean animals developed breast tumors. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in quick cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that the onset of the tumor and its development was faster in a spontaneous obese rat model with impaired glucose tolerance than their lean counterparts, with a higher percentage of tumor incidence.

The fall armyworm (FAW), Spodoptera frugiperda, has become one of the most important pests on corn in China since it invaded in 2019. Although FAW has not been reported to cause widespread damage to rice plants in China, it has been sporadically found feeding in the field. If FAW infests rice in China, the fitness of other insect pests on rice may be influenced. However, how FAW and other insect pests on rice interact remains unknown. In this study, we found that the infestation of FAW larvae on rice plants prolonged the developmental duration of the brown planthopper (BPH, Nilaparvata lugens (Stål)) eggs, and plants damaged by gravid BPH females did not induce defenses that influenced the growth of FAW larvae. Moreover, co-infestation by FAW larvae on rice plants did not influence the attractiveness of volatiles emitted from BPH-infested plants to Anagrus nilaparvatae, an egg parasitoid of rice planthoppers. FAW larvae were able to prey on BPH eggs laid on rice plants and grew faster compared to those larvae that lacked available eggs. Studies revealed that the delay in development of BPH eggs on FAW-infested plants was probably related to the increase in levels of jasmonoyl-isoleucine, abscisic acid and the defensive compounds in the rice leaf sheaths on which BPH eggs were laid. These findings indicate that if FAW invades rice plants in China, the population density of BPH may be decreased by intraguild predation and induced plant defenses, whereas the population density of FAW may be increased.

Enterovirus A71 (EV-A71) infection is a major cause of hand, foot and mouth disease (HFMD) which may be occasionally associated with severe neurological complications. There are currently a lack of treatment options for EV-A71 infection. The Raf-MEK-ERK signaling pathway, in addition to its critical importance in the regulation of cell growth, differentiation and survival, has been shown to be essential for virus replication. In this study, we investigated the anti-EV-A71 activity of vemurafenib, a clinically approved B-Raf inhibitor used in the treatment of late stage melanoma. Vemurafenib exhibits potent anti-EV-A71 effect in cytopathic effect inhibition and viral load reduction assays, with half maximal effective concentration (EC50) at nanomolar concentration. Mechanistically, vemurafenib interrupts both EV-A71 genome replication and assembly. These findings expand the list of potential antiviral candidates of anti-EV-A71 therapeutics.

Insect herbivores have a wide range of life cycles and feeding habits, making them extremely diverse. With their host plants, they form close relationships and suppress their defense mecha-nisms. Molecular elicitors are the key bio-elements in detection and recognition of attacking enemies in tissue consumption. Insect oral secretion, frass, and fluid of egg deposition contain bio-logical active molecules called herbivore-associated elicitors (HAEs) are recognized by pattern recognition receptors (PRRs). However, in insect herbivores, little is known about the molecular basis of signal transduction and regulation of plant resistance. Many plants distinguish insect feeding from wounding by HAEs presenting in their oral secretions (OS) and induce local and systemic responses against arthropod feeding. PRRs perceive HAEs in the oral secretion of cater-pillars in a species-specific manner to elicit exclusive defense responses. HAEs-PRRs interactions induce plant resistance by reprogramming plant metabolism and transcriptional machinery. Quantitative, timely, and coordinated plant response initiate early signalling events including Ca+2, reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs). We have discussed how early signalling cascades converge into the accumulation of phytohormones that regulate down-stream special metabolites against herbivores. In this review, we have drawn a hypothetical model of PPRs-HAEs mediated induced responses in plants and discussed how PRRs-HAEs interactions based on molecular mechanism that elicit short- and long-term induced defenses in plants. The identification of plant target insect herbivore PRRs-HAEs interactions will help to explore the fundamental molecular mechanisms of host manipulation and may generate prospects to develop novel pest resistance strategies.

Plants characterized by a soft or weak steam, such as climbing plants, need to find a potential support (e.g., wooden trunk) to reach greater light exposure. Since Darwin’s research on climbing plants, several studies on their searching and attachment behaviors have demonstrated their unique ability to process different support features to modulate their movements accordingly. Nevertheless, the strategies underlying this ability are yet to be uncovered. The present research tries to fill this gap by investigating how the interaction between above- (i.e., stem, tendril, …) and belowground (i.e., the root system) plant organs influence the kinematics of the approach-to-grasp movement. With three-dimensional (3D) kinematical analysis, we characterized the movement of pea plants (Pisum sativum L.) towards a support with different thicknesses above and belowground (i.e., thin below, thick aboveground, or the opposite). As a control condition, the plants were presented to supports with the same thickness below- and aboveground (i.e., either entirely thin or thick). The results suggest an integration between the information from below- and aboveground for driving the reach-to-grasp behavior of the aerial plant organs. Information about the support conveyed by the root system seems particularly important to fulfil the end-goal of the movement.

The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and -catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.

The Ras family of proteins is tethered to the inner leaflet of the cell membranes which play an essential role in signal transduction pathways that promote cellular proliferation, survival, growth, and differentiation. KRas-4B, the most mutated Ras isoform in different cancers, has been under extensive study for more than two decades. Here we have focused our interest on the influence of cholesterol on the orientations that KRas-4B adopts with respect to the plane of the anionic model membranes. How cholesterol in the bilayer might modulate preferences for specific orientation states is far from clear. Herein, after analyzing data from in total 4000 ns-long MD simulations for four KRas-4B systems, properties such as the area per lipid and thickness of the membrane as well as selected radial distribution functions, penetration of different moieties of KRas-4B, and internal conformational fluctuations of flexible moieties in KRas-4B have been calculated. It has been shown that high cholesterol content in the PM favors OS1, exposing the effector-binding loop for signal transduction in the cell from the atomic level. We confirm that high cholesterol in the PM helps KRas-4B mutant stay in its constitutively active state, which suggests that high cholesterol intake can increase mortality and may promote cancer progression for cancer patients. We propose that during the treatment of KRas-4B-related cancers, reducing the cholesterol level in the PM and sustaining cancer progression by controlling the plasma cholesterol intake might be taken into account in anti-cancer therapies.

Curcumin is one of the bioactive metabolites of turmeric (Curcuma longa), known for its pleiotropic pharmacological actions, including antioxidant and anti-inflammation, anticholinesterase, immunomodulation, and neuroprotection. Substantial evidence suggests the therapeutic benefits of curcumin against neurodegenerative disorders, including Alzheimer’s disease (AD), acting on a diverse array of brain targets that make the molecular mechanisms complicated. System biology level-investigation could potentially present a comprehensive molecular mechanism to delineate the neuropharmacological action of curcumin. In this study, we used integrated system pharmacology and molecular simulation analysis to gain insights into the underlying mechanism of curcumin action against AD. Network pharmacology study identified curcumin-targeted potential cellular pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling, neurotrophin signaling, toll-like receptor (TLR) signaling, and autophagy, and proteins such as tropomyosin receptor kinase B (TrkB), liver X-receptor-beta (LXR-β), estrogen receptor-β (ER-β), mammalian target of rapamycin (mTOR), TLR-2, N-methyl-D-acetate receptor subunit 2B (GluN2B), β-secretase and glycogen synthase kinase-3β (GSK-3β), which are intimately associated with neuronal growth and survival, immune response, and inflammation. Moreover, the molecular modeling further verified that curcumin showed a significant binding affinity to mTOR, TrkB, LXR-β, TLR-2, ER-β, GluN2B, β-secretase, and GSK-3β, which are the crucial regulators of molecular and cellular processes associated with AD. Together, the present system pharmacology and in silico findings demonstrate that curcumin might play a significant role in modulating AD-pathobiology, supporting its therapeutic application for the prevention and treatment of AD.

Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was detected also for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86 and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light-chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429 and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in D. melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effect. Nevertheless, PC gradually develops resistance, relapses and spreads. Most patients develop, indeed, castrate-resistant PC (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, TrkA. NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its cross talk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchyme transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.