Receptor System Research Articles

Expression of Concern: Minocycline Suppresses Interleukine-6, Its Receptor System and Signaling Pathways and Impairs Migration, Invasion and Adhesion Capacity of Ovarian Cancer Cells: In Vitro and In Vivo Studies.

Expression of Concern: Minocycline Suppresses Interleukine-6, Its Receptor System and Signaling Pathways and Impairs Migration, Invasion and Adhesion Capacity of Ovarian Cancer Cells: In Vitro and In Vivo Studies.

Adrenergic receptor system as a pharmacological target in the treatment of epilepsy (Review).

Epilepsy is a complex and common neurological disorder characterized by spontaneous and recurrent seizures, affecting ~75 million individuals worldwide. Numerous studies have been conducted to develop new pharmacological drugs for the effective treatment of epilepsy. In recent years, numerous experimental and clinical studies have focused on the role of the adrenergic receptor (AR) system in the regulation of epileptogenesis, seizure susceptibility and convulsions. α1-ARs (α1A, α1B and α1D), α2-ARs (α2A, α2B and α2C) and β-ARs (β1, β2 and β3), known to have convulsant or anticonvulsant effects, have been isolated. Norepinephrine (NE), the key endogenous agonist of ARs, is considered to play a crucial role in the pathophysiology of epileptic seizures. However, the effects of NE on different ARs have not been fully elucidated. Although the activation of some AR subtypes produces conflicting results, the activation of α1, α2 and β receptor subtypes, in particular, produces anticonvulsant effects. The present review focuses on NE and ARs involved in epileptic seizure formation and discusses therapeutic approaches.

Oxytocin neurons in the paraventricular nucleus and fear empathy among male mice.

Recent studies have identified empathy deficit as a core impairment and diagnostic criterion for people with autism spectrum disorders; however, the improvement of empathy focuses primarily on behavioural interventions without the target regulation. We sought to compare brain regions associated with empathy-like behaviours of fear and pain, and to explore the role of the oxytocin-oxytocin receptor system in fear empathy. We used C57BL mice to establish 2 models of fear empathy and pain empathy. We employed immunofluorescence histochemical techniques to observe the expression of c-Fos throughout the entire brain and subsequently quantified the number of c-Fos-positive cells in different brain regions. Furthermore, we employed chemogenetic technology to selectively manipulate these neurons in Oxt-Cre-/+ mice to identify the role of oxytocin in this process. The regions activated by fear empathy were the anterior cingulate cortex, basolateral amygdala, nucleus accumbens, paraventricular nucleus (PVN), lateral habenula, and ventral and dorsal hippocampus. The regions activated by pain empathy were the anterior cingulate cortex, basolateral amygdala, nucleus accumbens, and lateral habenula. We found that increasing the activity of oxytocin neurons in the PVN region enhanced the response to fear empathy. This enhancement may be mediated through oxytocin receptors. This study included only male animals, which restricts the broader interpretation of the findings. Further investigations on circuit function need to be conducted. The brain regions implicated in the regulation of fear and pain empathy exhibit distinctions; the activity of PVN neurons was positively correlated with empathic behaviour in mice. These findings highlight the role of the PVN oxytocin pathway in regulating fear empathy and suggest the importance of oxytocin signalling in mediating empathetic responses.

Abstract A019: The role of tumor transcriptional variability in evading acute CD8+ T cell exposure in melanoma

Abstract Throughout melanoma progression and immunotherapy treatment, melanoma cells often develop an ability to evade the immune system. Thus, there is a pressing need to identify and target the melanoma cell-intrinsic mechanisms underlying immune evasion. Our laboratory has pioneered the identification of transcriptional pathways that underlie melanoma progression. We have found that within even clonal melanoma cell populations, subclones of cells demonstrate tremendous heterogeneity in their transcriptional state. We previously demonstrated that these varying transcriptional states correspond to varying sensitivities of melanoma cells to stressors such as targeted therapies, and that these states can be stable across multiple cell divisions. We hypothesize that varying transcriptional states also correspond to cells that have differing abilities to evade CD8+ T cells, which are major effector cells against melanoma. To study the interactions between melanoma cells and CD8+ T cells, we engineered an ovalbumin antigen and OT-I T cell receptor system using mouse melanoma cell lines. We combined this system with DNA barcoding, which enables us to track subclones of cells undergoing immune selection. When cocultured together in vitro, ovalbumin-expressing melanoma cells are effectively killed by OT-I cells. However, we find that subclones of melanoma cells consistently possess different sensitivity to OT-I cells, and these differences are not due to their genetic background nor their ability to express and present ovalbumin. We then leveraged our DNA barcoding system with single cell RNA sequencing (scRNA-seq) to link the lineage and transcriptional state of single melanoma cells that persist through OT-I coculture. By expanding on these preliminary results, we aim to identify novel melanoma cell targets to decrease immune evasion. Citation Format: Raymond W.S. Ng, Sydney M Shaffer. The role of tumor transcriptional variability in evading acute CD8+ T cell exposure in melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A019.

Iron uptake pathway of Escherichia coli as an entry route for peptide nucleic acids conjugated with a siderophore mimic.

Bacteria secrete various iron-chelators (siderophores), which scavenge Fe3+ from the environment, bind it with high affinity, and retrieve it inside the cell. After the Fe3+ uptake, bacteria extract the soluble iron(II) from the siderophore. Ferric siderophores are transported inside the cell via the TonB-dependent receptor system. Importantly, siderophore uptake paths have been also used by sideromycins, natural antibiotics. Our goal is to hijack the transport system for hydroxamate-type siderophores to deliver peptide nucleic acid oligomers into Escherichia coli cells. As siderophore mimics we designed and synthesized linear and cyclic Nδ-acetyl-Nδ-hydroxy-l-ornithine based peptides. Using circular dichroism spectroscopy, we found that iron(III) is coordinated by the linear trimer with hydroxamate groups but not by the cyclic peptide. The internal flexibility of the linear siderophore oxygen atoms and their interactions with Fe3+ were confirmed by all-atom molecular dynamics simulations. Using flow cytometry we found that the designed hydroxamate trimer transports PNA oligomers inside the E. coli cells. Growth recovery assays on various E. coli mutants suggest the pathway of this transport through the FhuE outer-membrane receptor, which is responsible for the uptake of the natural iron chelator, ferric-coprogen. This pathway also involves the FhuD periplasmic binding protein. Docking of the siderophores to the FhuE and FhuD receptor structures showed that binding of the hydroxamate trimer is energetically favorable corroborating the experimentally suggested uptake path. Therefore, this siderophore mimic, as well as its conjugate with PNA, is most probably internalized through the hydroxamate pathway.

THE PATHOGENIC ROLE OF MICROBIAL TRIMETHYLAMINE IN IBD ASSOCIATED INTESTINAL FIBROSIS

Abstract INTRODUCTION Intestinal fibrosis significantly contributes to the burden of inflammatory bowel diseases (IBD). No specific anti-fibrotic therapy is available. Two modifiable risk factors that may be exploited to limit fibrosis in IBD are the diet and gut microbiome. In the metaorganismal metabolism model, microbes metabolize dietary components to primary metabolites that may themselves signal through host receptor systems or be further metabolized to secondary metabolites by other microbes or host enzymes to exert a physiological or pathophysiological effect. We hypothesize that gut microbes profoundly influence intestinal fibrosis through small molecule metabolites and may provide novel targets to address the fibrotic burden in IBD. METHODS To understand how the trimethylamine-N-oxide (TMAO) pathway is affected by inflammation in the intestine, LC-MS was used to quantitate a dietary precursor, choline, primary microbial metabolite, trimethylamine (TMA), and secondary metabolite, TMAO, in mice subjected to acute DSS colitis. The cellular effects of choline, TMA, and TMAO on the deposition of fibronectin and collagen I were quantitated in primary human intestinal myofibroblasts (HIMFs). Single cell RNA-sequencing (scRNA-seq) data were interrogated to determine whether expression of the TMA-to-TMAO converting enzyme, FMO3, was downregulated in human intestinal cells of Crohn’s disease patients. RESULTS Acute DSS colitis showed increased TMA and reduced levels of TMAO, in colon tissue, which is consistent with reduced TMA-to-TMAO conversion by FMO3. Additionally, TMA was increased in intestinal contents, which suggests that microbial production of TMA from choline may also be upregulated during intestinal inflammation. In HIMFs, TMA, but not its dietary precursor, choline, nor the secondary metabolite, TMAO, increased the deposition of the extracellular matrix proteins fibronectin and collagen I. scRNA-seq analysis of the mesenchymal compartment of human intestine revealed expression of FMO3 specifically in the fibroblast cluster and downregulation of this expression in Crohn’s disease (CD) strictures compared to controls, an observation that could contribute to TMA accumulation in vivo. CONCLUSION TMA is increased in experimental colitis and activates fibroblasts towards a pro-fibrogenic phenotype. This may be mediated by reduced levels of FMO3. We next aim to measure TMAO pathway metabolites in human tissues, functionally block the TMAO pathway in vivo, and explore TMA signaling through its putative receptor, trace amine-associated receptor 5 (TAAR5). Diet-microbe-host interaction pathways represent an untapped opportunity for therapeutic intervention in multiple human disease states, such as inflammatory bowel diseases (IBD).

Electrochemical nanosensor based on Ag-doped TiO2 nanotubes for detecting ascorbic acid

This work describes the development of an electrochemical nanosensor for the quantitative determination of ascorbic acid (AA). The transducer and receptor system of the nanosensor is based on a silver-doped titanium oxide nanotube (Ag-TiO2NTs) electrode synthesized by a one-step electrochemical anodization method followed by an annealing treatment. The synthesis was carried out at a constant potential of 30 V for 45 min in an organic electrolyte in the presence of F- ions and the dopant. The obtained structure was then subjected to morphological and compositional analysis. In addition, its analytical response to ascorbic acid was evaluated. The analytical techniques employed included scanning electron microscopy (SEM), X-ray diffraction (DRX), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV). The results demonstrate the growth of a highly ordered nanotube array with average dimensions of 80 nm, 19 nm and 1660 nm for diameter, wall thickness and length, respectively, and suggest a major composition of silver-doped titanium oxide. The synthesized Ag-TiO2NTs successfully recorded electroanalytical activity for ascorbic acid, with a non-reversible, diffusion-controlled, and mostly capacitive electrochemical profile. It showed low resistance to change transfer and registered a sensitivity of 216.24μA/(mM∙cm2) and a detection limit of 11.1 μM in a linear range of 840–4000 μΜ. The sensor demonstrated repeatability and reproducibility with RSD values of 5.5% and 2.8%, respectively. In addition, it showed selectivity for AA in the presence of glucose at AA/GLU values (1:1, 1:10 and 1:100).

Nicotine is associated with smoking dependence and vascular inflammation through cotinine: A mediation analysis.

The main alkaloid component in cigarettes is nicotine. Cotinine, a metabolite of nicotine, is capable of causing dependence effects through endless mechanisms modulated by the ion channel nicotinic acetylcholine receptors nAChRs. Nicotine and cotinine can also cause damage to blood vessels through a chronic inflammatory process mediated by the Ligand-Tie2 Angiopoietin Receptor system. Hypoxic conditions that occur due to vascular inflammation cause a decrease in the concentration of nitric oxide (NO). This study aimed to evaluate the relationship between NO levels and cotinine through the expression of nAChRs that mediate the nicotine dependence mechanism and Tie2 (Tyrosine Kinase 2) expression. A cross-sectional study was conducted with 200 participants grouped into two groups based on their smoking status: 100 smokers and 100 non-smokers. All participants were men aged 20-40 years with no history of cardiovascular disease, diabetes mellitus, or dyslipidemia, and were not currently on medication. According to the parameters used, all blood samples were taken from peripheral blood for analysis using the ELISA kit or Colorimetric Assay Kit. Cigarette consumption increases blood cotinine concentrations in smokers and causes dependence by modulating nAChRs. The study indicates an emerging cycle regarding nicotine-cotinine consumption and nAChRs expression. In addition, the data in this study showed a significant relationship (p<0.001) regarding the cycle formed with decreased NO levels as a result of damage caused by Tie2-mediated inflammation. There is a relationship between NO levels and cotinine through nAChRs, which mediate the nicotine dependence mechanism and Tie2 expression.

Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate

Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug activity analysis on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies revealed that palbociclib-MHI-148 conjugate resulted in an almost 100-fold increase in cytotoxicity compared to palbociclib alone. This shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI-148 was due to increased DNA damage, as indicated by an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including TP53, TNFR1, TRAIL, FADD and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of TNFR1, consistent with an observed increase in the secretion TNFα, followed by TNFR1 endocytosis at 48 h. The treatment of patient GBM cells with the palbociclib-MHI-148 conjugate prevented TNFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favoured the TNFR1-mediated apoptotic response rather than the pro-inflammatory response pathway. Notably, pharmacological inhibition of endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palbociclib-MHI-148-induced cell death. These results show a novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical NFκB signalling using our previously reported palbociclib-HMCD conjugate.9u5DmcuTyYJ7m7Hnyrq7sRVideo

Targeting Human Glucocorticoid Receptors in Fear Learning: A Multiscale Integrated Approach to Study Functional Connectivity.

Fear extinction is a phenomenon that involves a gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how brain regions communicate during these processes. Stress, a ubiquitous aspect of life, influences fear learning and extinction by changing the activity of the amygdala, prefrontal cortex, and hippocampus, leading to enhanced fear responses and/or impaired extinction. Glucocorticoid receptors (GRs) are key to the stress response and show a dual function in fear regulation: while they enhance the consolidation of fear memories, they also facilitate extinction. Accordingly, GR dysregulation is associated with anxiety and mood disorders. Recent advancements in cognitive neuroscience underscore the need for a comprehensive understanding that integrates perspectives from the molecular, cellular, and systems levels. In particular, neuropharmacology provides valuable insights into neurotransmitter and receptor systems, aiding the investigation of mechanisms underlying fear regulation and potential therapeutic targets. A notable player in this context is cortisol, a key stress hormone, which significantly influences both fear memory reconsolidation and extinction processes. Gaining a thorough understanding of these intricate interactions has implications in terms of addressing psychiatric disorders related to stress. This review sheds light on the complex interactions between cognitive processes, emotions, and their neural bases. In this endeavor, our aim is to reshape the comprehension of fear, stress, and their implications for emotional well-being, ultimately aiding in the development of therapeutic interventions.

Flexible Artificial Mechanoreceptor Based on Microwave Annealed Morphotropic Phase Boundary of HfxZr1‐xO2 Thin Film

AbstractThe development of artificial tactile receptor systems is important in the fields of prosthetic devices, interfaces for the metaverse, and sensors. A pressure sensor and memory device may be used in this system to replicate the tactile detecting capabilities of human skin. The implementation of systems that take into account mass production and miniaturization is still difficult. Here, a flexible artificial tactile receptor built using conventional semiconductor processes that combine a vertically stacked piezoelectric sensor with neuromorphic memory is presented. As a fundamental component for both sensors and memory, hafnium zirconium oxide (HZO) formed by using semiconductor deposition technique is introduced. Due to its exceptional piezoelectric performance, the morphotropic phase boundary of HZO is studied. The entire materials and processes are highly compatible with conventional semiconductor processes, including microwave annealing‐based low‐temperature crystallization. Even after 10,000 times of bending stress, the sensor and memory constructed on a flexible substrate exhibit consistent pressure detection characteristics over a wide range of 2–25 kPa. The feasibility of the approach is further demonstrated by a deep neural network simulation, which reached 90.8% braille recognition accuracy. Wearable electronics and medical devices are two examples of industrial domains that can use these flexible, exceptionally durable devices.

BRAIDing receptors for cell-specific targeting.

Systemic toxicity is a major challenge in the development of therapeutics. Consequently, cell-type-specific targeting is needed to improve on-target efficacy while reducing off-target toxicity. Here, we describe a cell-targeting system we have termed BRAID (BRidged Activation by Intra/intermolecular Division) whereby an active molecule is divided into two inactive or less active parts that are subsequently brought together via a so-called 'bridging receptor' on the target cell. This concept was validated using the WNT/β-catenin signaling system, demonstrating that a multivalent WNT agonist molecule divided into two inactive components assembled from different epitopes via the hepatocyte receptor βKlotho induces signaling specifically on hepatocytes. These data provide proof of concept for this cell-specific targeting strategy, and in principle, this may also allow activation of multiple signaling pathways where desirable. This approach has broad application potential for other receptor systems.

BRAIDing receptors for cell-specific targeting

Systemic toxicity is a major challenge in the development of therapeutics. Consequently, cell-type-specific targeting is needed to improve on-target efficacy while reducing off-target toxicity. Here, we describe a cell-targeting system we have termed BRAID (BRidged Activation by Intra/intermolecular Division) whereby an active molecule is divided into two inactive or less active parts that are subsequently brought together via a so-called ‘bridging receptor’ on the target cell. This concept was validated using the WNT/β-catenin signaling system, demonstrating that a multivalent WNT agonist molecule divided into two inactive components assembled from different epitopes via the hepatocyte receptor βKlotho induces signaling specifically on hepatocytes. These data provide proof of concept for this cell-specific targeting strategy, and in principle, this may also allow activation of multiple signaling pathways where desirable. This approach has broad application potential for other receptor systems.

The plasticity of neuropeptide Y-Y1 receptor system on Tac2 neurons contributes to mechanical hyperknesis during chronic itch.

Rationale: In the physiological states, the act of scratching protects the person from harmful substances, while in certain pathological conditions, the patient suffers from chronic itch, both physically and mentally. Chronic itch sufferers are more sensitive to mechanical stimuli, and mechanical hyperknesis relief is essential for chronic itch treatment. While neuropeptide Y-Y1 receptor (NPY-Y1R) system is known to play a crucial role in modulating mechanical itch in physiological conditions, it is elusive how they are altered during chronic itch. We hypothesize that the negative regulatory effect of Y1Rs on Tac2 neurons, the key neurons that transmit mechanical itch, declines during chronic itch. Methods: We combined transgenic mice, chemogenetic manipulation, immunofluorescence, rabies virus circuit tracing, and electrophysiology to investigate the plasticity of Y1Rs on Tac2 neurons during chronic itch. Results: We found that Tac2 neurons receive direct input from Npy neurons and that inhibition of Npy neurons induces activation of Tac2 neurons. Moreover, the expression of Y1Rs on Tac2 neurons is reduced, and the regulatory effect is also reduced during chronic itch. Conclusion: Our study clarifies the plasticity of Y1Rs on Tac2 neurons during chronic itch and further elucidates the mechanism by which NPY-Y1R system is responsible for modulating mechanical itch. We highlight Y1Rs as a promising therapeutic target for mechanical hyperknesis during chronic itch.

The analgesic effect of paeoniflorin: A focused review.

Pain has been a prominent medical concern since ancient times. Despite significant advances in the diagnosis and treatment of pain in contemporary medicine, there is no a therapeutic cure for chronic pain. Chinese herbaceous peony, a traditional Chinese analgesic herb has been in clinical use for millennia, with widespread application and substantial efficacy. Paeoniflorin (PF), the main active ingredient of Chinese herbaceous peony, has antioxidant, anti-inflammatory, anticancer, analgesic, and antispasmodic properties, among others. The analgesic effect of PF, involving multiple critical targets and pain regulatory pathways, has been a hot spot for current research. This article reviews the literature related to the analgesic effect of PF in the past decade and discusses the molecular mechanism of the analgesic effect of PF, including the protective effects of nerve cells, inhibition of inflammatory reactions, antioxidant effects, reduction of excitability in nociceptor, inhibition of the nociceptive excitatory neuroreceptor system, activation of the nociceptive inhibitory neuroreceptor system and regulation of other receptors involved in nociceptive sensitization. Thus, providing a theoretical basis for pain prevention and treatment research. Furthermore, the prospect of PF-based drug development is presented to propose new ideas for clinical analgesic therapy.

Recent updates on potential of VEGFR-2 small-molecule inhibitors as anticancer agents.

The vascular endothelial growth factor receptor (VEGFR) system is the key component for controlling angiogenesis in cancer cells. Blocking vascular endothelial growth factor receptor 2 (VEGFR2) signalling is one of the most promising approaches to hindering angiogenesis and the subsequent growth of cancer cells. The USFDA-approved small-molecule drugs targeting VEGFR-2 are developing drug resistance over the course of chemotherapy, and cardiac-related side effects are consistently being reported; hence, there is an urgent need for more safe and effective anticancer molecules. The present review focuses on the structure and physiology of VEGFR-2 and its involvement in the progression of cancer cells. The recent updates from the last five years through papers and patents on structure-activity relationships, pharmacophoric attributes, molecular docking interactions, antiangiogenic assays, cancer cell line studies, and the potencies (IC50) of VEGFR-2 inhibitors are discussed herein. The common structural framework requirements, such as the Asp-Phe-Gly (DFG) motif of VEGFR-2 interacting with the HBD-HBA region in the ligand molecules, the central aryl ring occupying the linker region, and a variety of bio-isosteres, can enhance activity against VEGFR-2. At one end, the heteroaryl moiety is essential for interaction within the ATP-binding site of VEGFR-2, while the terminal hydrophobic tail occupies the allosteric binding site. Three to five bond spacers between the heteroaryl and HBD-HBA regions provided a better result towards VEGFR-2 inhibition, mirroring the behaviors of standard drugs. The in-depth analysis of recent updates on VEGFR-2 inhibitors presented in this paper will help prospective synthetic and medicinal chemists to discover new lead molecules for the treatment of various cancers.

Glucose-dependent insulinotropic polypeptide receptor systems in the hypothalamus and the brainstem regulate feeding and weight through distinct pathways.

The report by Adriaenssens et al. in JCI Insight 22 May 2023 explored the role and property of the neurons that express glucose-dependent insulinotropic polypeptide receptor (GIPR) in the brainstem and hypothalamus. The chemogenetic activation of the brainstem GIPR neurons and that of the hypothalamic GIPR neurons showed different feeding and behavior responses. The brainstem GIPR neurons projected to the paraventricular hypothalamus and lateral parabrachial nucleus. Fluorescent-labeled, stabilized peptide GIPR agonist (GIPRA), peripherally injected, localized to the area postrema, nucleus tractus solitarius, median eminence and arcuate hypothalamus. This report showed the role of brainstem GIPR neurons in receiving GIPRA to drive the neural circuit to reduce feeding and bodyweight. In this commentary, distinct and possible cooperative roles of the hypothalamic and the brainstem GIPR pathways will also be discussed.

Validating Fractalkine receptor as a target and identifying candidates for drug discovery against type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases employing abnormal levels of insulin. Enhancing the insulin production is greatly aided by the regulatory mechanisms of the Fractalkine receptor (CX3CR1) system in islet β-cell function. However, elements including a high-fat diet, obesity, and ageing negatively impact the expression of CX3CR1 in islets. CX3CL1/CX3CR1 receptor-ligand complex is now recognized as a novel therapeutic target. It suggests that T2DM-related β-cell dysfunction may result from lower amount of these proteins. We analyzed the differential expression of CX3CR1 gene samples taken from persons with T2DM using data obtained from the Gene Expression Omnibusdatabase. Homology modeling enabled us to generate the three-dimensional structure of CX3CR1 and a possible binding pocket. The optimized CX3CR1 structure was subjected to rigorous screening against a massive library of 693 million drug-like molecules from the ZINC15 database. This screening process led to the identification of three compounds with strong binding affinity at the identified binding pocket of CX3CR1. To further evaluate the potential of these compounds, molecular dynamicssimulations were conducted over a 50 nstime scale to assess the stability of the protein-ligand complexes. These simulations revealed that ZINC000032506419 emerged as the most promising drug-like compound among the three potent molecules. The discovery of ZINC000032506419 holds exciting promise as a potential therapeutic agent for T2Dand other related metabolic disorders. These findings pave the way for the development of effective medications to address the complexities of T2DM and its associated metabolic diseases.

Oxytocin Receptor-Expressing Neurons in the Medial Preoptic Area Are Essential for Lactation, whereas Those in the Lateral Septum Are Not Critical for Maternal Behavior

Introduction: In nurturing systems, the oxytocin (Oxt)-oxytocin receptor (Oxtr) system is important for parturition, and essential for lactation and parental behavior. Among the nerve nuclei that express Oxtr, the lateral septal nucleus (LS) and medial preoptic area (MPOA) are representative regions that control maternal behavior. Methods: We investigated the role of Oxtr- and Oxtr-expressing neurons, located in the LS and MPOA, in regulating maternal behavior by regulating Oxtr expression in a region-specific manner using recombinant mice and adeno-associated viruses. We quantified the prolactin (Prl) concentrations in the pituitary gland and plasma when Oxtr expression in the MPOA was reduced. Results: The endogenous Oxtr gene in the neurons of the LS did not seem to play an essential role in maternal behavior. Conversely, decreased Oxtr expression in the MPOA increased the frequency of pups being left outside the nest and reduced their survival rate. Deletion of Oxtr in MPOA neurons prevented elevation of Prl levels in plasma and pituitary at postpartum day 2. Discussion/Conclusion: Oxtr-expressing neurons in the MPOA are involved in the postpartum production of Prl. We confirmed the essential functions of Oxtr-expressing neurons and the Oxtr gene itself in the MPOA for the sustainability of maternal behavior, which involved Oxtr-dependent induction of Prl.

Innate immune modulation in transplantation: mechanisms, challenges, and opportunities.

Organ transplantation is characterized by a sequence of steps that involve operative trauma, organ preservation, and ischemia-reperfusion injury in the transplant recipient. During this process, the release of damage-associated molecular patterns (DAMPs) promotes the activation of innate immune cells via engagement of the toll-like receptor (TLR) system, the complement system, and coagulation cascade. Different classes of effector responses are then carried out by specialized populations of macrophages, dendritic cells, and T and B lymphocytes; these play a central role in the orchestration and regulation of the inflammatory response and modulation of the ensuing adaptive immune response to transplant allografts. Organ function and rejection of human allografts have traditionally been studied through the lens of adaptive immunity; however, an increasing body of work has provided a more comprehensive picture of the pivotal role of innate regulation of adaptive immune responses in transplant and the potential therapeutic implications. Herein we review literature that examines the repercussions of inflammatory injury to transplantable organs. We highlight novel concepts in the pathophysiology and mechanisms involved in innate control of adaptive immunity and rejection. Furthermore, we discuss existing evidence on novel therapies aimed at innate immunomodulation and how this could be harnessed in the transplant setting.