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Azadirachta indica or neem is recognized for its unique properties, both against insects and in improving human health. However, proteomics studies of this plant's response to abiotic stresses have yet to be reported. Application of this technique highly depends on efficient and optimized sample preparation, in deriving highly reproducible proteomics data. The present study highlights the comparison of protein extraction method which effectively recovers proteins from recalcitrant phenolic-rich tissues of neem callus. Four protocols based on TCA-acetone or/and phenol extraction methods were compared. The TCA-acetone complemented with PVPP method was the most effective approach and generated the greatest total protein yields, spot number, good resolution, and spot intensities. Subsequently, the differential proteomics performed revealed that proteins associated with oxidoreduction, energy, transcriptional, stress response, respiration, and cell division were differentially regulated in salinity stress treatment. Meanwhile, the expression of proteins classified in the group of energy, photosynthesis, protein synthesis, oxidoreduction, and post-transcriptional regulation was altered in the JA-stressed callus. The accumulation of AZA was also noticeably reduced in salinity- and JA-treated callus, suggesting these tested stress parameters were not effective in improving AZA production in the neem callus. Overall, this analysis provides valuable information on the application of plant tissue culture as an alternative for sustainable production of major bioactive constituents in A. indica. Together, the proteomics results brought forward a possible fundamental representation of the mechanism associated with salinity and JA tolerance in the neem callus. [ABSTRACT FROM AUTHOR]

The human endometrium is only receptive to an implanting blastocyst in the mid-secretory phase of each menstrual cycle. Such time-dependent alterations in function require intricate interplay of various factors, largely coordinated by estrogen and progesterone. Abnormal endometrial receptivity is thought to contribute to two-thirds of the implantation failure in humans and therefore significantly hindering IVF success. Despite the incontrovertible importance of endometrial receptivity in implantation, the precise mechanisms involved in the regulation of endometrial receptivity remain poorly defined. This is mainly due to a lack of proper in vitro models that recapitulate the in vivo environment of the receptive human endometrium. Organoids were recently established from human endometrium with promising features to better mimic the receptive phase. Endometrial organoids show long-term expandability and the capability to preserve the structural and functional characteristics of the endometrial tissue of origin. This three-dimensional model maintains a good responsiveness to steroid hormones in vitro and replicates key morphological features of the receptive endometrium in vivo, including pinopodes and pseudostratified epithelium. Here, we review the current findings of endometrial organoid studies that have been focused on investigating endometrial receptivity and place an emphasis on methods to further refine and improve this model. [ABSTRACT FROM AUTHOR]

Synchronized crosstalk between the embryo and endometrium during the periconception period is integral to pregnancy establishment. Increasing evidence suggests that the exchange of extracellular vesicles (EVs) of both embryonic and endometrial origin is a critical component of embryo–maternal communication during peri-implantation. Here, we investigated whether embryonic signals in the form of EVs can modulate the endometrial epithelial cell secretome. Receptive endometrial analog RL95-2 cells were supplemented with trophoblast analog JAr cell-derived EVs, and the secretory protein changes occurring in the RL95-2 cells were analyzed using mass spectrometry. EVs of non-trophoblastic origin (HEK 293 cells) were used as the control EV source to supplement endometrial cells. Trophoblast cell-derived EVs enriched endometrial epithelial cell secretions with proteins that support embryo development, attachment, or implantation, whereas control EVs were unable to induce the same effect. The present study suggests that embryonic signals in the form of EVs may prime receptive endometrial epithelial cells to enrich their secretory proteome with critical proteomic molecules with functional importance for periconception milieu formation. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation. [ABSTRACT FROM AUTHOR]

G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors. Class B1 GPCRs constitute a subfamily of 15 receptors that characteristically contain large extracellular domains (ECDs) and respond to long polypeptide hormones. Class B1 GPCRs are critical regulators of homeostasis, and, as such, many are important drug targets. While most transmembrane proteins, including GPCRs, are recalcitrant to crystallization, recent advances in cryo-electron microscopy (cryo-EM) have facilitated a rapid expansion of the structural understanding of membrane proteins. As a testament to this success, structures for all the class B1 receptors bound to G proteins have been determined by cryo-EM in the past 5 years. Further advances in cryo-EM have uncovered dynamics of these receptors, ligands, and signaling partners. Here, we examine the recent structural underpinnings of the class B1 GPCRs with an emphasis on structure–function relationships. [ABSTRACT FROM AUTHOR]

The power of the Gond rulers in Central India, like all the kingdoms, was evident in architectural activities. The Gond rulers shifted their capital multiple times, and each time, they constructed magnificent forts and temples that mark their presence. The Vishnu temple at Ramnagar, located in the Mandla district of Madhya Pradesh, is one such royal temple constructed by the Gonds and is an essential landmark for understanding their architectural style. GondThe Gond king Hridayeshvara was the one to establish Ramnagar (22.6115° N, 80.5084° E) as the capital of the Gonds in 1667 CE and constructed a fort here. The fort houses an inscription commemorating the construction of the Viṣṇu temple by Sundari Devi, the queen of King Hridayeshvara. It was Sundari Devi only who got the aforementioned inscription inscribed, which is written in Devanagari script, with the language being Sanskrit. The Ramnagar stone inscription is the only archaeological source having the confirmed dates for the architectural activities of the Gond rulers. The proposed research paper argues that the architecture of the temple and the style of the inscription, when studied in the more extensive spectrum of the history of Gonds, points toward the possibility that the Viṣṇu temple at Ramnagar augmented the socio-political status of the queen Sundari devi. Moreover, the Ramnagar inscription played a twin role in uplifting Sundari Devi, along with the temple she constructed to the highest alcove in the political hierarchy. [ABSTRACT FROM AUTHOR]

The hydrolysis of substituted 3-(3-cyanothiophen-2-yl)imino-3H-furan-2-ones was studied. It was found that the reaction proceeds with the opening of the furan ring and the formation of the corresponding 4-oxo-2-(3-cyanothiophen-2-yl)aminobut-2-enoic acids. The antibacterial activity of the obtained compounds against Staphylococcus aureus, Escherichia coli and Candida albicans was studied. [ABSTRACT FROM AUTHOR]

Targeting the allosteric sites on G-protein coupled receptors (GPCRs) for drug discovery is attracting increased interest. Given a GPCR target, identifying the allosteric binding sites in it remains a challenge. Previous works from our and other labs suggest the intracellular region below the middle of the transmembrane (TM) domain that spatially overlaps with the G-protein binding site could contain a common allosteric site for all GPCRs. We performed several bioinformatics analyses on this site for more than 100 representative human GPCR structures. Results of the studies confirmed that the proposed region contains an allosteric site that is druggable for 89% of the GPCRs and is not 100% identical between a GPCR and its most similar homolog for 94% of the GPCRs. The physico-chemical properties and amino acid composition of this site vary among and within GPCR classes. Since this proposed region occupies the space existing in all GPCRs of known structure, it could represent a common host of an allosteric site for all GPCRs that can be targeted for structure-based allosteric drug design. [ABSTRACT FROM AUTHOR]

We report the discovery of two new 2‐aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon‐like peptide 1 receptor (GLP‐1R) for the treatment of type 2 diabetes. One of the chemotypes, (S‐1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP‐1R PAMs. When combined with GLP‐1 peptide, S‐1 increased the GLP‐1R activity in a dose‐dependent manner in a cell‐based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S‐1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293‐CREB cell line. Insulin secretion studies found S‐1 combined with GLP‐1 increased insulin secretion by 1.5‐fold at 5 μM. In a mechanistic study, evidence is provided that the synergistic effect of S‐1 with GLP‐1 may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2‐aminothiophene derivatives are a new and promising class of GLP‐1R PAMs. [ABSTRACT FROM AUTHOR]

Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) receptors belong to the pharmaceutically important Class B family of GPCRs and are involved in many biologically significant signalling pathways. Its incretin peptide ligand GLP-1 analogues are effective treatments for Type 2 diabetes. Although developing non-peptide low MW drugs targeting GLP-1 receptors remains elusive, considerable progress has been made in discovering non-peptide agonists and positive allosteric modulators (PAMs) of GLP-1 receptors with demonstrated efficacy. Many of these compounds induce biased signalling in GLP-1 receptor-mediated functional pathways. High-quality structures of GLP-1 receptors in both inactive and active states have been reported, revealing detailed molecular interactions between GLP-1 receptors and non-peptide agonists or PAMs. These progresses raise the exciting possibility of developing non-peptide drugs of GLP-1 receptors as alternative treatments for Type 2 diabetes. The insight into the interactions between the receptor and the non-peptide ligand is also useful for developing non-peptide ligands targeting other Class B GPCRs. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 receptor (GLP-1R) is a well-known drug target for the treatment of type 2 diabetes mellitus (T2DM). However, the currently marketed peptidyl GLP-1R agonist drugs are restricted by the requirement of injection. Hence, there is a continued need to develop orally bioavailable small molecule GLP-1R agonist drugs that could be beneficial for the treatment of T2DM. In this study, we report a new strategy to predict small molecule GLP-1R agonists with machine learning approach. Several regression and classification models were built based on support vector machine algorithm and diverse compounds with molecular properties and structural fingerprints as descriptors. For regression models, the ten-fold cross-validation squared correlation coefficient (q2, for training sets) and determination coefficient (r2, for test sets) of the optimized models were greater than 0.6, respectively. For classification models, the overall predictive accuracies were around or over 90% (for test sets). The results demonstrated that these reliable models could be used to identify highly active agonists for the purpose of virtual screening. The important properties and structural fragments for GLP-1R agonists derived from these models can be used for the novel GLP-1R agonist scaffold design. [ABSTRACT FROM AUTHOR]

Background: The embryo implantation process is crucial for the correct establishment and progress of pregnancy. During implantation, the blastocyst trophectoderm cells attach to the epithelium of the endometrium, triggering intense cell-to-cell crosstalk that leads to trophoblast outgrowth, invasion of the endometrial tissue, and formation of the placenta. However, this process, which is vital for embryo and foetal development in utero, is still elusive to experimentation because of its inaccessibility. Experimental implantation is cumbersome and impractical in adult animal models and is inconceivable in humans.Objective and Rationale: A number of custom experimental solutions have been proposed to recreate different stages of the implantation process in vitro, by combining a human embryo (or a human embryo surrogate) and endometrial cells (or a surrogate for the endometrial tissue). In vitro models allow rapid high-throughput interrogation of embryos and cells, and efficient screening of molecules, such as cytokines, drugs, or transcription factors, that control embryo implantation and the receptivity of the endometrium. However, the broad selection of available in vitro systems makes it complicated to decide which system best fits the needs of a specific experiment or scientific question. To orient the reader, this review will explore the experimental options proposed in the literature, and classify them into amenable categories based on the embryo/cell pairs employed.The goal is to give an overview of the tools available to study the complex process of human embryo implantation, and explain the differences between them, including the advantages and disadvantages of each system.Search Methods: We performed a comprehensive review of the literature to come up with different categories that mimic the different stages of embryo implantation in vitro, ranging from initial blastocyst apposition to later stages of trophoblast invasion or gastrulation. We will also review recent breakthrough advances on stem cells and organoids, assembling embryo-like structures and endometrial tissues.Outcomes: We highlight the most relevant systems and describe the most significant experiments. We focus on in vitro systems that have contributed to the study of human reproduction by discovering molecules that control implantation, including hormones, signalling molecules, transcription factors and cytokines.Wider Implications: The momentum of this field is growing thanks to the use of stem cells to build embryo-like structures and endometrial tissues, and the use of bioengineering to extend the life of embryos in culture. We propose to merge bioengineering methods derived from the fields of stem cells and reproduction to develop new systems covering a wider window of the implantation process. [ABSTRACT FROM AUTHOR]

The Glucagon-like peptide 1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes and GLP-1R agonist-based therapies represent an effective approach which results in several GLP-1 analog drugs. However, the development of nonpeptidic agonist drugs targeting GLP-1R remains unsuccessful. A promising strategy aims to develop orally bioavailable, small-molecule positive allosteric modulators of GLP1-1R. Taking advantage of the recently reported cryo-EM structure of GLP-1R at its active state, we have performed structure-based screening studies which include potential allosteric binding site prediction and in silico screening of drug-like compounds, and conducted in vitro testing and site-specific mutagenesis studies. One compound with low molecular weight was confirmed as a positive allosteric modulator of GLP-1R as it enhances GLP-1′s affinity and efficacy to human GLP-1R in a dose dependent manner. This compound also stimulates insulin secretion synergistically with GLP-1. With the molecular weight of 399, this compound represents one of the smallest known GLP-1R PAMs, and demonstrates other favorable drug-like properties. Site-specific mutagenesis studies confirmed that the binding site of this compound partially overlaps with that of a known antagonist in the transmembrane domain. These results demonstrate that structure-based approach is useful for discovering nonpeptidic allosteric modulators of GLP-1R and the compound reported here is valuable for further drug development. [ABSTRACT FROM AUTHOR]

Antioxidant systems modulate oxidant-based signaling networks and excessive removal of oxidants can prevent beneficial acclimation responses. Evidence from mutant, transgenic, and locally adapted natural plant systems is used to interpret differences in the capacity for antioxidation and formulate hypotheses for future inquiry. We focus on the first line of chloroplast antioxidant defense, pre-emptive thermal dissipation of excess absorbed light (monitored as nonphotochemical fluorescence quenching, NPQ) as well as on tocopherol-based antioxidation. Findings from NPQ-deficient and tocopherol-deficient mutants that exhibited enhanced biomass production and/or enhanced foliar watertransport capacity are reviewed and discussed in the context of the impact of lower levels of antioxidation on plant performance in hot/dry conditions, under cool temperature, and in the presence of biotic stress. The complexity of cellular redox-signaling networks is related to the complexity of environmental and endogenous inputs as well as to the need for intensified training and collaboration in the study of plant-environment interactions across biological sub-disciplines. [ABSTRACT FROM AUTHOR]

Study Question: Is Rab11a GTPase, a regulator of intracellular trafficking, of significance in endometrial functions?Summary Answer: Rab11a is an important component of the cascades involved in equipping the endometrial epithelium (EE) with 'adhesiveness' and 'cohesiveness'.What Is Known Already: Cell adhesion molecules (CAMs) have been investigated extensively for modulation in their endometrial expression during the peri-implantation phase. However, the mechanisms by which CAMs are transported to the EE surface have not received the same attention. Rab11a facilitates transport of specific proteins to the plasma membrane in endothelial cells, fibroblasts, embryonic ectodermal cells, etc. However, its role in the transport of CAMs in EE remains unexplored.Study Design, Size, Duration: In-vitro investigations were directed towards deciphering the role of Rab11a in trafficking of CAMs (integrins and E-cadherin) to the cell surface of Ishikawa, an EE cell line. Towards this, Rab11a stable knockdown (Rab-kd) and control clones of Ishikawa were generated. JAr (human trophoblastic cell line) cells were used to form multicellular spheroids. Pre-receptive (n = 6) and receptive (n = 6) phase endometrial tissues from women with proven fertility and receptive phase (n = 6) endometrial tissues from women with unexplained infertility were used.Participants/materials, Setting, Methods: Rab-kd and control clones were used for in-vitro assays. Live cells were used for biotinylation, JAr spheroid assays, flow cytometry, trans-epithelial electrical resistance assays and wound-healing assays. Lysosome and Golgi membranes were isolated by ultracentrifugation. Confocal microscopy, immunoblotting, qRT-PCR and immunohistochemistry were employed for assessing the expression of Rab11a, integrins and E-cadherin.Main Results and the Role Of Chance: shRNA-mediated attenuation of Rab11a expression led to a significant (P < 0.01) decline in the surface localization of αVβ3 integrin. Cell surface protein extracts of Rab-kd clones showed a significant (P < 0.05) reduction in the levels of αV integrin. Further, a significant (P < 0.01) decrease was observed in the percent JAr spheroids attached to Rab-kd clones, compared to control clones. Rab-kd clones also showed a significant (P < 0.001) decline in the total levels of E-cadherin. This was caused neither by reduced transcription nor by increased lysosomal degradation. The role of Rab11a in maintaining the epithelial nature of the cells was evident by a significant increase in the migratory potential, presence of stress-fibres and a decrease in the trans-epithelial resistance in Rab-kd monolayers. Further, the levels of endometrial Rab11a and E-cadherin in the receptive phase were found to be significantly (P < 0.05) lower in women with unexplained infertility compared to that in fertile women. Taken together, these observations hint at a key role of Rab11a in the trafficking of αVβ3 integrin and maintenance of E-cadherin levels at the surface of EE cells.Large-scale Data: N/A.Limitations, Reasons For Caution: The in-vitro setting of the study is a limitation. Further immunohistochemical localizations of Rab11a and CAMs were conducted on a limited number of human endometrial samples.Wider Implications Of the Findings: Rab11a-mediated trafficking of endometrial CAMs in EE cells can be explored further for its potential as a target for fertility regulation or infertility management.Study Funding/competing Interest(s): This study was funded by the Indian Council of Medical Research (ICMR), the Department of Science and Technology (DST), the Council of Scientific and Industrial Research (CSIR), Government of India. No competing interests are declared. [ABSTRACT FROM AUTHOR]

Being the native flora of saline soil, halophytes are well studied for their salt tolerance and adaptation mechanism at the physiological, biochemical, molecular and metabolomic levels. However, these saline habitats are getting contaminated due to various anthropogenic activities like urban waste, agricultural runoff, mining, industrial waste that are rich in toxic metals and metalloids. These toxic metals impose detrimental effects on growth and development of most plant species. Halophytes by virtue of their tolerance to salinity also show high tolerance to heavy metals which is attributed to the enhanced root to shoot metal translocation and bioavailability. Halophytes rapidly uptake toxic ions from the root and transport them toward aerial parts by using different transporters which are involved in metal tolerance and homeostasis. A number of defense related physiological and biochemical strategies are known to be crucial for metal detoxification in halophytes however; there is paucity of information on the molecular regulators. Understanding of the phenomenon of cross-tolerance of salinity with other abiotic stresses in halophytes could very well boost their potential use in phytoremediation. In this article, we present an overview of heavy metal tolerance in case of halophytes, associated mechanisms and cross-tolerance of salinity with other abiotic stresses. [ABSTRACT FROM AUTHOR]

We review the role of a family of transcription factors and their regulons in maintaining high photosynthetic performance across a range of challenging environments with a focus on extreme temperatures and water availability. Specifically, these transcription factors include CBFs (C-repeat binding factors) and DREBs (dehydration-responsive element-binding), with CBF/DREB1 primarily orchestrating cold adaptation and other DREBs serving in heat, drought, and salinity adaptation. The central role of these modulators in plant performance under challenging environments is based on (i) interweaving of these regulators with other key signaling networks (plant hormones and redox signals) aswell as (ii) their function in integrating responses across thewhole plant, fromlight-harvesting and sugar-production in the leaf to foliar sugar export and water import and on to the plant's sugar-consuming sinks (growth, storage, and reproduction). The example of Arabidopsis thaliana ecotypes from geographic origins with contrasting climates is used to describe the links between natural genetic variation in CBF transcription factors and the differential acclimation of plant anatomical and functional features needed to support superior photosynthetic performance in contrasting environments. Emphasis is placed on considering different temperature environments (hot versus cold) and light environments (limiting versus high light), on trade-offs between adaptations to contrasting environments, and on plant lines minimizing such trade-offs. [ABSTRACT FROM AUTHOR]

Proteomics has emerged as a highly promising bioanalytical technique in various aspects of applied biological research. In Indian academia, proteomics research has grown remarkably over the last decade. It is being extensively used for both basic as well as translation research in the areas of infectious and immune disorders, reproductive disorders, cardiovascular diseases, diabetes, eye disorders, human cancers and hematological disorders. Recently, some seminal works on clinical proteomics have been reported from several laboratories across India. This review aims to shed light on the increasing use of proteomics in India in a variety of biological conditions. It also highlights that India has the expertise and infrastructure needed for pursuing proteomics research in the country and to participate in global initiatives. Research in clinical proteomics is gradually picking up pace in India and its future seems very bright. [ABSTRACT FROM AUTHOR]

Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) have been recognized as important signaling compounds of major importance in a number of developmental and physiological processes in plants. The existence of cellular compartments enables efficient redox compartmentalization and ensures proper functioning of ROS-dependent signaling pathways. Similar to other organisms, the production of individual ROS in plant cells is highly localized and regulated by compartment-specific enzyme pathways on transcriptional and post-translational level. ROS metabolism and signaling in specific compartments are greatly affected by their chemical interactions with other reactive radical species, ROS scavengers and antioxidant enzymes. A dysregulation of the redox status, as a consequence of induced ROS generation or decreased capacity of their removal, occurs in plants exposed to diverse stress conditions. During stress condition, strong induction of ROS-generating systems or attenuated ROS scavenging can lead to oxidative or nitrosative stress conditions, associated with potential damaging modifications of cell biomolecules. Here, we present an overview of compartment-specific pathways of ROS production and degradation and mechanisms of ROS homeostasis control within plant cell compartments. [ABSTRACT FROM AUTHOR]