Receptor Signaling Research Articles

Synthesizing network pharmacology, bioinformatics, and in vitro experimental verification to screen candidate targets of Salidroside for mitigating Alzheimer's disease.

Alzheimer's disease (AD) is a neurological disorder leading to cognitive deficits. Salidroside (Sal), a primary bioactive ingredient extracted from the roots of Rhodiola rosea L., has potent neuroprotective effects in AD. However, studies on potential targets for Sal-anchored AD are limited. In this study, we combined network pharmacology, bioinformatics, and experimental validation to identify potential targets of Sal treating AD. First, we screened 10 pyroptosis-related genes (PRGs) in Sal and AD using public databases. Then, we used Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis to explore the biological functions of the shared PRGs (Sal and AD). This finding exhibited that pathways linked to inflammation, like the nucleotide oligomerization domain (NOD)-like receptors signaling pathway, are important for Sal to help fight AD. The GeneMANIA functional results subsequently revealed an association between AD and the processes of inflammasome complex and inflammatory response. Additionally, nine hub genes were identified in the protein-protein interaction network of these shared PRGs. Subsequent analysis of the genes and phenotypes confirmed that these nine hub genes were directly correlated with AD. Subsequently, an in vitro AD model was created using rat adrenal pheochromocytoma cell line (PC12) cells induced by amyloid β-peptide (Aβ) 25-35 (20µM). Sal significantly reduced the pyroptosis caused by Aβ 25-35 in PC12 cells and decreased the expression levels of IL-1β, CASP1, IL-18, PYCARD, and NLRP3. Furthermore, molecular docking and molecular dynamics simulations confirmed that Sal could stably bind to NLRP3. Druggability analysis revealed that Sal had excellent druggability. These results demonstrated that Sal could alleviate AD by targeting IL-1β, CASP1, IL-18, PYCARD, and NLRP3 to regulate the NLRP3-mediated pyroptosis signaling pathway.

Nonylphenol and Cetyl Alcohol Polyethoxylates Disrupt Thyroid Hormone Receptor Signaling to Disrupt Metabolic Health.

Surfactants are molecules with both hydrophobic and hydrophilic structural groups that adsorb at the air-water or oil-water interface and serve to decrease the surface tension. Surfactants combine to form micelles that surround and break down or remove oils, making them ideal for detergents and cleaners. Two of the most important classes of nonionic surfactants are alkylphenol ethoxylates (APEOs) and alcohol ethoxylates (AEOs). APEOs and AEOs are high production-volume chemicals that are used for many industrial and residential purposes, including laundry detergents, hard-surface cleaners, paints, and pesticide adjuvants. Commensurate with better appreciation of the toxicity of APEOs and the base alkylphenols, use of AEOs has increased, and both sets of compounds are now ubiquitous environmental contaminants. We recently demonstrated that diverse APEOs and AEOs induce triglyceride accumulation and/or pre-adipocyte proliferation in vitro. Both sets of contaminants have also been demonstrated as obesogenic and metabolism disrupting in a developmental exposure zebrafish model. While these metabolic health effects are consistent across models and species, the mechanisms underlying these effects are less clear. This study sought to evaluate causal mechanisms through reporter gene assay assessments, relative binding affinity assays, co-exposure experiments, and use of both human cell and zebrafish models. We report that antagonism of thyroid hormone receptor signaling appears to mediate at least a portion of the polyethoxylate-induced metabolic health effects. These results suggest further evaluation is needed, given the ubiquitous environmental presence of these thyroid disrupting contaminants and reproducible effects in human cell models and vertebrate animals.

Molecular mechanisms of obesity predisposes to atopic dermatitis

Obesity is a prevalent metabolic disease that reduces bacterial diversity, colonizes the epidermis with lipophilic bacteria, and increases intestinal pro-inflammatory species, all of which lead to impaired epithelial barriers. Adipose tissue secretes immunomodulatory molecules, such as adipokines, leptin, and adiponectin, which alters the morphology of adipocytes and macrophages as well as modulates T cell differentiation and peripheral Th2-dominated immune responses. Atopic dermatitis (AD) and obesity have similar pathological manifestations, including inflammation as well as insulin and leptin resistance. This review examines the major mechanisms between obesity and AD, which focus on the effect on skin and gut microbiota, immune responses mediated by the toll like receptor (TLR) signaling pathway, and changes in cytokine levels (TNF-a, IL-6, IL-4, and IL13). Moreover, we describe the potential effects of adipokines on AD and finally mechanisms by which PPAR-γ suppresses and regulates type 2 immunity.

A conserved juxtamembrane motif in plant NFR5 receptors is essential for root nodule symbiosis

Establishment of root nodule symbiosis is initiated by the perception of bacterial Nod factor ligands by the plant LysM receptor kinases NFR1 and NFR5. Receptor signaling initiating the symbiotic pathway depends on the kinase activity of NFR1, while the signaling mechanism of the catalytically inactive NFR5 pseudokinase is unknown. Here, we present the crystal structure of the signaling-competent Lotus japonicus NFR5 intracellular domain, comprising the juxtamembrane region and pseudokinase domain. The juxtamembrane region is structurally well defined and forms two α-helices, αA and αA', which contain an exposed hydrophobic motif. We demonstrate that this "juxtamembrane motif" promotes NFR5-NFR5 and NFR1-NFR5 interactions and is essential for symbiotic signaling. Conservation analysis reveals that the juxtamembrane motif is present throughout NFR5-type receptors and is required for symbiosis signaling from barley RLK10, suggesting a conserved and broader function for this motif in plant-microbe symbioses.

Molecular and Cellular Mechanisms Involved in the Pathophysiology of Retinal Vascular Disease—Interplay Between Inflammation and Oxidative Stress

Retinal vascular diseases encompass several retinal disorders, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and retinal vascular occlusion; these disorders are classified as similar groups of disorders due to impaired retinal vascularization. The aim of this review is to address the main signaling pathways involved in the pathogenesis of retinal vascular diseases and to identify crucial molecules and the importance of their interactions. Vascular endothelial growth factor (VEGF) is recognized as a crucial and central molecule in abnormal neovascularization and a key phenomenon in retinal vascular occlusion; thus, anti-VEGF therapy is now the most successful form of treatment for these disorders. Interaction between angiopoietin 2 and the Tie2 receptor results in aberrant Tie2 signaling, resulting in loss of pericytes, neovascularization, and inflammation. Notch signaling and hypoxia-inducible factors in ischemic conditions induce pathological neovascularization and disruption of the blood–retina barrier. An increase in the pro-inflammatory cytokines—TNF-α, IL-1β, and IL-6—and activation of microglia create a persistent inflammatory milieu that promotes breakage of the blood–retinal barrier and neovascularization. Toll-like receptor signaling and nuclear factor-kappa B are important factors in the dysregulation of the immune response in retinal vascular diseases. Increased production of reactive oxygen species and oxidative damage follow inflammation and together create a vicious cycle because each factor amplifies the other. Understanding the complex interplay among various signaling pathways, signaling cascades, and molecules enables the development of new and more successful therapeutic options.

Hypoxia-adenosinergic regulation of B cell responses

Hypoxic microenvironments induce widespread metabolic changes that have been shown to be critical in regulating innate and adaptive immune responses. Hypoxia-induced changes include the generation of extracellular adenosine followed by subsequent signaling through adenosine receptors on immune cells. This evolutionarily conserved “hypoxia-adenosinergic” pathway of hypoxia → extracellular adenosine → adenosine receptor signaling has been shown to be critical in limiting and redirecting T cell responses including in tumor microenvironments and the gut mucosa. However, the question of whether hypoxic microenvironments are involved in the development of B cell responses has remained unexplored until recently. The discovery that germinal centers (GC), the anatomic site in which B cells undergo secondary diversification and affinity maturation, develop a hypoxic microenvironment has sparked new interest in how this evolutionarily conserved pathway affects antibody responses. In this review we will summarize what is known about hypoxia-adenosinergic microenvironments in lymphocyte development and ongoing immune responses. Specific focus will be placed on new developments regarding the role of the hypoxia-adenosinergic pathway in regulating GC development and humoral immunity.

Molecular mechanisms of acquired idiopathic generalized anhidrosis: differential gene expression and potential therapeutic targets

Eccrine sweat glands are essential for thermoregulation. Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder characterized by the absence of sweating, leading to severe complications like heatstroke and skin dryness. The underlying etiology remains unknown, complicating diagnosis and treatment. This study aimed to elucidate the genetic mechanisms of AIGA by analysing the gene expression in eccrine sweat glands using the GSE193125 dataset from the NCBI Gene Expression Omnibus (GEO). This study identified differentially expressed genes (DEGs) (genes that show statistically significant differences in expression levels in AIGA), with JUN and CCN1 significantly downregulated in anhidrotic lesions of AIGA patients. Receiver operating characteristic (ROC) curve demonstrated the accuracy of these genes in classification (JUN = 0.88 and CCN1 = 0.77). Gene and protein interaction networks which are defined as networks of physical interactions between genes and proteins, constructed using GeneMANIA and STRING, revealed substantial physical interactions among them. Gene set enrichment analysis highlighted the neuroinflammatory and estrogen receptor signaling pathways are associated with this condition, suggesting hormonal regulation’s role in the anhidrosis mechanism. Key miRNAs, including hsa-let-7b-5p, hsa-miR-10b-5p, and hsa-miR-124-3p, are associated with the DEGs, underscoring the importance of post-transcriptional and transcriptional regulation. Through the Drug Gene Interaction Database (DGIdb), ciprofibrate is identified as a potential therapeutic agent targeting the JUN gene. Molecular docking confirmed a strong binding affinity between ciprofibrate and JUN, suggesting ciprofibrate could modulate JUN activity and regulate AIGA symptoms. ADMET analysis, which refers to the assessment of absorption, distribution, metabolism, excretion, and toxicity of a drug or compound, is crucial for evaluating its pharmacokinetic and safety profile. The analysis indicated that ciprofibrate has favourable pharmacokinetic properties and a relatively safe toxicity profile. This comprehensive bioinformatics approach, integrating gene expression analysis, miRNA identification, and drug interaction, provides valuable insights into anhidrosis molecular pathology and highlights ciprofibrate’s potential as a targeted therapeutic strategy. Despite limitations, including a small sample size and reliance on computational predictions, this study paves the way for further research and potential therapeutic interventions for AIGA.

Activation of 5-HT7 receptors in the mouse dentate gyrus does not affect theta-burst-induced plasticity at the perforant path synapse.

The study examined the effects of 5-HT7 receptor activation on GABAergic transmission within the dentate gyrus and plasticity at the glutamatergic perforant path input. Immunofluorescence imaging was performed using transverse hippocampal slices from transgenic mice expressing green fluorescent protein (GFP) under the Htr7 promoter. This was followed by whole-cell patch clamp electrophysiological recordings assessing the effects of pharmacologically activating 5-HT7 receptors on spontaneous inhibitory postsynaptic currents recorded from dentate granule cells and hilar mossy cells-two glutamatergic neuron types present in the dentate gyrus. Extracellular recordings of field excitatory postsynaptic potentials were then performed to assess whether 5-HT7 receptor activation influenced theta-burst stimulation-evoked plasticity of the perforant path synaptic input. It was found that parvalbumin and somatostatin interneurons in the dentate gyrus expressed GFP, which suggests they express 5-HT7 receptors. However, activation of 5-HT7 receptors had no effect on GABAergic transmission targeting mossy cells or granule cells. There was also no effect of 5-HT7 receptor activation on perforant path plasticity either with intact or blocked GABAA receptor signaling. The presence of 5-HT7 receptors in a subset of parvalbumin and somatostatin interneurons in the mouse dentate gyrus could mean that they are involved in the inhibitory control of dentate gyrus activity. However, this potential effect was not evident in slice recordings of inhibitory transmission targeting principal cells and did not affect perforant path plasticity. Further experiments are needed to fully elucidate the functional role of these receptors in the dentate gyrus.

PSA Kinetics Affect Prognosis in Patients With Castration-resistant Prostate Cancer Treated With Enzalutamide.

There is little evidence regarding the predictive value of prostate-specific antigen (PSA) kinetics in patients with castration-resistant prostate cancer treated with an androgen receptor signaling inhibitor. This study investigated the correlation between PSA kinetics and prognosis in patients with castration-resistant prostate cancer treated with enzalutamide. We analyzed data from 103 patients who received enzalutamide as primary treatment for castration-resistant prostate cancer at our hospital, focusing on the associations between overall survival and PSA kinetics variables, such as maximal PSA response, PSA nadir, and time to PSA nadir. The median PSA level at the initiation of enzalutamide was 18.1 ng/ml (interquartile range=7.9-61.2 ng/ml). The median maximal PSA response rate was 88% (interquartile range 55-98), and the median PSA nadir was 1.84 (interquartile range (IQR)=0.38-14.7) ng/ml. The median time to PSA nadir was 19 (IQR=6-28.5) weeks. Maximal PSA response rate <90% [hazard ratio (HR)=2.28, 95% confidence interval (CI)=1.03-5.03, p=0.0413], PSA nadir >2 ng/ml (HR=2.30, 95%CI=1.05-5.07, p=0.0379), time to nadir <19 weeks (HR=2.48, 95%CI=1.15-5.35, p=0.0204) were all independently predictive of shortened overall survival even after adjusting for pre-treatment factors. Maximal PSA response, PSA nadir, and time to PSA nadir correlated with survival in patients with castration-resistant prostate cancer receiving enzalutamide as a first-line therapy.

Androgen Receptor Signaling Inhibitor Withdrawal Syndrome After Castration-resistant Prostate Cancer.

Androgen-deprivation therapy is an extremely effective treatment for progressive prostate cancer. Previously, the first-line treatment for progressive prostate cancer was combined androgen blockade (CAB). If the disease progressed to castration-resistant prostate cancer, the administration of androgen receptor signaling inhibitors (ARSIs) was recommended. When elevated serum prostate-specific antigen (PSA) levels are seen during CAB treatment, it is important to suspect antiandrogen withdrawal syndrome (AWS), discontinue CAB, and monitor the changes in the serum PSA levels. If a reduction in the patient's PSA levels is subsequently observed, antiandrogens should be discontinued and the patient should be followed, but if their PSA level rises they should be transitioned to ARSI treatment. Recently, there have been reports of withdrawal syndrome (WS) after ARSI treatment. With the increased use of ARSIs, such as abiraterone acetate, enzalutamide, apalutamide, and dalorutamide, it is necessary to consider ARSI WS when a patient's serum PSA level increases during ARSI treatment. Unnecessary treatment can be avoided if the confirmation of ARSI WS is prioritized. Conversely, if it is not confirmed there is a risk that second-line treatment will be delayed. This is a review of recent studies of ARSI WS. It also discusses future prospects in this field.

TNFRSF10D expression as a potential biomarker for cisplatin-induced damage and ovarian tumor relapse prediction

Among gynecological malignancies, ovarian cancer (OC) presents the most challenging diagnostic scenario. Despite exhaustive efforts, up to 90% of patients treated with taxane/platinum-based chemotherapy experience relapse, leading to poor survival rates. Identifying new molecular markers that can characterize disease aggressiveness, chemoresistance, recurrence risk, and metastasis is crucial. This study aimed to assess the susceptibility of three ovarian tumor cell lines (TOV-21G, SKOV-3, and OV-90) to cisplatin and paclitaxel, and to investigate the influence of these treatments on the mRNA expression of TANK, RIPK1, NFKB1, TNFRSF10D, and TRAF2. Among the cell lines, SKOV-3 ovarian adenocarcinoma cells demonstrated the highest resistance to cisplatin treatment (0.125mg/mL), followed by TOV-21G (0.076mg/mL) and OV-90 cells (0.028mg/mL). Regarding paclitaxel treatment, the SKOV-3 cell line exhibited the highest resistance (1.4µg/mL), followed by OV-90 (1.3µg/mL) and TOV-21G cells (0.9µg/mL). Gene expression analysis after paclitaxel treatment remained unchanged; however, after cisplatin treatment, TNFRSF10D was observed to be upregulated nearly 100-fold in SKOV-3 compared to all other cell lines studied. SKOV-3 is described as cisplatin and tumor necrosis factor-resistant. Despite the defective signaling of the TNFRSF10D receptor for apoptosis, it can activate the NFKB transcription factor through non-canonical TRAIL signaling, contributing to a pro-inflammatory immune response. In light of this, damage associated with cisplatin increases TNFRSF10D expression and may promote cell survival through non-canonical NFKB pathway activation. This suggests that resistance to TRAIL-induced apoptosis in these cells could serve as a promising chemoresistance biomarker in OC.

Network Pharmacological Analysis of Hydroxychloroquine Intervention in the Treatment of Iga Nephropathy.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the mechanism. PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was performed. 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine closely. This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.

Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia.

The B cell receptor (BCR) signalling pathway has an integral role in the pathogenesis of many B cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma, diffuse large B cell lymphoma and Waldenström macroglobulinaemia. Bruton tyrosine kinase (BTK) is a key node mediating signal transduction downstream of the BCR.The advent of BTK inhibitors has revolutionized the treatment landscape of B cell malignancies, with these agents often replacing highly intensive and toxic chemoimmunotherapy regimens as the standard of care. In this Review, we discuss the pivotal trials that have led to the approval of various covalent BTK inhibitors, the current treatment indications for these agents and mechanisms of resistance. In addition, we discuss novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders and combination doublet and triplet regimens, to provide insights on the best current treatment paradigms in the frontline setting and at disease relapse.

Glycyrrhizic acid and patchouli alcohol in Huoxiang Zhengqi attenuate intestinal inflammation and barrier injury via regulating endogenous corticosterone metabolism mediated by 11β-HSD1.

Ulcerative colitis (UC), a chronic inflammatory bowel disease, has become a significant public health challenge due to the limited effectiveness of available therapies. Huoxiang Zhengqi (HXZQ), a well-established traditional Chinese formula, shows potential in managing UC, as suggested by clinical and pharmacological studies. However, the active components and mechanisms responsible for its effects remain unclear. This study aimed to identify the bioactive components of HXZQ responsible for its therapeutic effects on UC and to elucidate their underlying mechanisms. The effect of HXZQ against dextran sodium sulfate (DSS) -induced colitis was investigated. Ingredients in HXZQ were characterized and analyzed in colitic mice using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). In vitro, biological activity of compounds was assessed using lipopolysaccharide (LPS)-induced Ana-1 cells and bone marrow-derived macrophages (BMDMs), tumor necrosis factor-alpha-induced Caco-2 cells, and isolated intestinal crypts from colitic mice. These results were confirmed in vivo. The targets of the components were identified through bioinformatics analysis and validated via molecular docking, enzyme inhibition assays, and in vivo experiments. Hematoxylin and eosin (HE) staining, periodic acid-Schiff (PAS) staining, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative real-time polymerase chain reaction (qPCR) were employed to confirm the pharmaceutical effects. A clinical equivalent dose of HXZQ (2.5 mL/kg) effectively treated DSS-induced colitis. 113 compounds were identified in HXZQ, with 35 compounds detected in colitic mice. Glycyrrhizic acid (GA) and patchouli alcohol (PA) emerged as key contributors to the anti-colitic effects of HXZQ. Further investigation revealed that HXZQ and its active components decreased the levels of pro-inflammatory cytokines TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) in colon, likely by inhibiting nuclear factor kappa-B (NF-κB) signaling pathway. This inhibition indirectly activated the intestinal farnesoid X receptor (FXR) signaling pathway, correcting bile acid imbalances caused by colitis. Additionally, these components significantly enhanced the expression of tight junction proteins ZO-1 and Occludin, as well as the adhesion protein E-cadherin, and reduced goblet cell loss, thereby repairing intestinal barrier injury. Mechanistically, GA and PA were found to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, leading to increased local active corticosterone levels in the intestine to exert anti-inflammatory effects. Notably, the inhibition of 11β-HSD1 with the selective inhibitor BVT ameliorated colitis in mice. HXZQ exhibits therapeutic effects on UC, primarily through GA and PA inhibiting 11β-HSD1. This suggests new natural therapy approaches for UC and positions 11β-HSD1 as a potential target for colitis treatment.

Fingolimod, a sphingosine-1-phosphate receptor modulator, prevents neonatal bronchopulmonary dysplasia and subsequent airway remodeling in a murine model.

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation.NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

Glucagon receptor activation contributes to the development of kidney injury.

The underlying causes of diabetic kidney disease are still largely unknown. New insights into the contributing causes of diabetic nephropathy are important to prevent this complication. Hyperglycemia and hypertension are some of the risk factors for diabetic nephropathy. However, the incidence of diabetic nephropathy is increasing despite efforts to normalize blood glucose levels and blood pressure. Therefore, other factors should be investigated as causes of diabetic nephropathy. We investigated whether long-term increased plasma levels of glucagon contribute to the development of pathophysiological changes in kidney function as seen in patients with diabetic nephropathy. Using mouse models of chronic activation and inactivation of glucagon receptor signaling, we investigated whether glucagon is involved in changes in renal function, renal structure, and transcriptional changes. We found several histopathological changes in the kidney, such as thickening of the parietal layer of Bowman's capsule, glomerular mesangial cell expansion, and significant albuminuria in the mice with activated glucagon receptor signaling. Opposite effects on mesangial area expansion and the development of albuminuria were demonstrated in mice with glucagon receptor inactivation. RNA sequencing data revealed that transcription of genes related to fatty acid metabolism, podocytes, Na+-K+-ATPase, and sodium/glucose transport was significantly changed in mice with activated glucagon receptor signaling. These data implicate that glucagon receptor signaling is involved in the development of kidney injury, as seen in type 2 diabetes, and that glucagon receptor is a potential therapeutic target in the treatment of diabetes. NEW & NOTEWORTHY This study suggests that the glucagon receptor is a potential therapeutic target in the treatment of diabetic kidney disease. We show, in mice, that long-term treatment with a glucagon analog showed not only pathophysiological changes and changes in renal function but also transcriptional changes in the kidneys, whereas opposite effects were demonstrated in mice with glucagon receptor inactivation. Therefore, the use of glucagon in a treatment regimen requires investigation of possible metabolic and renal abnormalities.

A long chain fatty acid receptor signaling as a new therapeutic target for stress-induced chronic pain

Psychological and social stresses are known to be risk factors for psychiatric disorders, including depression and anxiety. On the other hand, exposure to these stresses can also cause prolonged and severe pain. However, the pathological mechanism for stress-induced chronic pain is complex, and there are many unresolved aspects, and no effective therapeutic drugs have been established. Since the discovery of the long-chain fatty acid receptor GPR40/FFAR1 about 20 years ago, research on the mechanism that promotes insulin secretion in the pancreas has progressed. Previously, we have worked to elucidate the physiological effects of GPR40/FFAR1 in the central nervous system and has found that it is involved in the regulation of pain and emotion. Based on these findings, they are now investigating the involvement of fatty acid receptors signaling in the development of stress-related chronic pain. In this review, we discuss the status of psychological stress-related chronic pain and the GPR40/FFAR1-mediated and -striking regulatory mechanisms of stress-induced chronic pain, based on our findings using a mouse model of chronic pain created by loading postoperative pain to a social defeat stress model mouse that mimics psychosocial stress. We summarized about the involvement of fatty acid receptor signaling as a new therapeutic candidate for chronic pain in this review.

Mechanistic Study of Nidus Vespae Inhibiting Gastric Cancer in vitro through the JAK2/STAT3 Signaling Pathway.

Nidus Vespae, an animal-derived traditional Chinese medicine, has a long-standing history in treating inflammatory conditions and tumor-related diseases. Notably, Nidus Vespae decoction (NVD) has been shown to inhibit the proliferation of gastric cancer cells, although the underlying mechanisms remain unclear. of research: This study aimed to elucidate the efficacy and mechanisms by which NVD exerts its therapeutic effects on gastric cancer. We employed the Cell Counting Kit-8 (CCK-8) assay to assess the impact of NVD on gastric cancer cell proliferation, while flow cytometry was utilized to evaluate cell cycle arrest and apoptosis. Differentially expressed proteins (DEPs) were identified by proteomics analysis, which were further analyzed through Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Protein-protein interaction (PPI) analysis was conducted to identify the hub genes. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were conducted to assess mRNA and protein levels related to apoptosis, cell cycle regulation, and the JAK2/STAT3 pathway. Rescue experiments with Colivelin TFA confirmed the role of NVD in inhibiting gastric cancer cell proliferation. UPLC-HRMS and HS-SPME-GC-MS technologies were performed to analyze the composition of NVD, and the bioinformatics tool called BATMAN-TCM database was used for functional analyses. Our results demonstrated that NVD significantly hindered the proliferation of gastric cancer cells, initiated programmed cell death, and induced cell cycle arrest in G2/M or G0/G1 phases in various gastric carcinoma cells in vitro. The identified DEPs were involved in several cancer-related pathways and signal transduction processes, notably the JAK-STAT receptor signaling pathway. NVD was found to down-regulate the JAK2/STAT3 signaling cascade, and reactivation of STAT3 diminished its anti-gastric cancer effects. Finally, the ingredient-target-disease network analysis also verified the anti-tumor effect of NVD. This study highlights the potential of Nidus Vespae as a therapeutic agent for gastric cancer, providing insights into its molecular mechanisms of action.

Exploration and identification of diabetes targets in nursing: CDH1 and DVL1.

Diabetes is a chronic disease caused by absolute or relative insufficiency of insulin secretion and impaired insulin utilization. CDH1 and DVL1 role in diabetes and its nursing care is unclear. The diabetes dataset GSE21321 and GSE19790 profiles were downloaded from the gene expression omnibus (GEO) database. Perform differentially expressed genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network construction and analysis, functional enrichment analysis, gene set enrichment analysis (GSEA), immune infiltration analysis, and Comparative Toxicogenomics Database (CTD) analysis. Gene expression heat map was drawn. TargetScan was used to screen the miRNA that regulates central DEGs. 1983 DEGs were obtained. According to Gene Ontology (GO) analysis, they were mainly enriched in signal regulation, catenin complexes, and signal receptor binding. In Kyoto Encyclopedia of Gene and Genome (KEGG) analysis, they were mainly concentrated in the Rap1 signaling pathway, cAMP signaling pathway, and Hippo signaling pathway. The DEGs are mainly enriched in cell signaling, Wnt signaling vesicles, growth factor activity, and the interaction between neural active ligands and receptors. In the enrichment project of Metascape, BMP signaling pathways and cell population proliferation can be seen in the GO enrichment project. The soft threshold power in WGCNA is set to 5. A total of 15 modules were generated. Core gene expression heatmap showed that core genes (CTNNB1, CDH1, DVL1) were highly expressed in diabetes samples. CTD analysis showed thatCTNNB1, CDH1, DVL1were associated with weight gain, inflammation, and necrosis. CDH1 and DVL1 are highly expressed in diabetes and may become molecular targets for diabetes and its care.

Expression of Toll-like Receptor Genes and Antiviral Cytokines in Macrophage-like Cells in Response to Indole-3-carboxylic Acid Derivative

Ongoing outbreaks and often rapid spread of infections caused by coronaviruses, influenza, Nipah, Dengue, Marburg, monkeypox, and other viruses are a concern for health authorities in most countries. Therefore, the search for and study of new antiviral compounds are in great demand today. Since almost all viruses with pandemic potential have immunotoxic properties of various origins, particular attention is paid to the search and development of immunomodulatory drugs. We have synthesised a new compound related to indole-3-carboxylic acid derivatives (hereinafter referred to as the XXV) that has antiviral and interferon-inducing activity. The purpose of this work is to study the effect of the XXV on the stimulation of the expression of toll-like receptor genes, interferons, and immunoregulatory cytokines in a macrophage-like cell model. In this study, real-time PCR methods were used to obtain data on the transcriptional activity of genes in macrophage-like cells. Stimulation of the genes of toll-like receptors TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 was detected. A high-fold increase in stimulation (from 6.5 to 16,000) of the expression of the TLR3 and TLR4 genes was detected after 4 h of exposure to the XXV. Increased activity of interferon (IFNA1, IFNA2, IFNB1, IFNK, and IFNλ1) genes with simultaneous stimulation of the expression of interferon receptor (IFNAR1 and IFNAR2) genes and signalling molecule (JAK1 and ISG15) genes was detected. Increased fold stimulation of the expression of the cytokine genes IL6, TNFA, IL12A, and IL12B was also observed. Thus, it is shown that the XXV is an activator of TLR genes of innate immunity, which trigger signalling mechanisms of pathogen “recognition” and lead to stimulation of the expression of genes of proinflammatory cytokines and interferons.