A1 Receptor Research Articles

The association between serum complement 4 and relapse of primary membranous nephropathy: a multicenter retrospective cohort study

BackgroundRelapse after initial remission reduces renal survival in patients with primary membranous nephropathy (PMN). In this study, we aim to identify risk factors of relapse in PMN and construct a model to identify patients at high risk of relapse early.MethodsWe conducted a multi-center retrospective study using the China Renal Data System database, which includes data from 24 urban academic centers across China. A prediction model based on the Cox proportional hazards model was derived in the derivation group and validated in the validation group.Result515 patients with biopsy-proven PMN achieving initial remission were enrolled. 32.62% of patients subsequently relapsed during a median of 6.08 months. Lower serum albumin (Alb) (per 1 g/L decrease, hazard ratio [HR] =1.48, 95% confidence interval [CI] 1.29–1.78, p < 0.001), lower estimated glomerular filtration rate (eGFR) (per 10 mL/min/1.73m2 decrease, HR =1.14, 95% CI 0.97–1.49, p < 0.001), higher serum complement 4 (C4) (per 0.1 g/L increase, HR =1.89, 95% CI 1.32–3.22, p = 0.012), partial remission (PR) (HR =2.28, 95%CI 1.74–4.04, p < 0.001), and treatment with calcineurin inhibitors (CINs) (HR =1.33, 95%CI 1.04–1.64, p < 0.001) at the time of remission were risk factors for relapse. C-statistic, time-dependent areas under the receiver operating characteristic curve, and calibration plots confirmed that the model had excellent discrimination and calibration in predicting PMN relapse. The anti-phospholipase A2 receptor antibody (aPLA2Rab) titers and pathologic features did not substantially improve the model.ConclusionOur study confirms the well-known low Alb and eGFR, PR, and treatment of CNIs at the time of remission as risk factors for PMN relapse, but aPLA2Rab and pathologic features may not predict relapse. In addition, it is the first study to show serum C4 is associated with PMN relapse. We suggest that complement-targeted therapies may be a potential therapy to prevent PMN relapse.

A case of PLA2R-positive membranous nephropathy with subsequent development of IgG4-related disease

AbstractMembranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome. It is also known as a minor but established renal manifestation of Immunoglobulin G4-related disease (IgG4-RD). Previous reports suggest that MN can also be an initial manifestation of IgG4-RD, all of which are phospholipase A2 receptor (PLA2R)-negative MN. We describe a case of PLA2R-positive MN that subsequently developed other manifestations of IgG4-RD. A 60-year-old male with nephrotic syndrome was diagnosed as primary MN with positive staining for PLA2R on the initial renal biopsy, which remained in partial remission with supportive therapy using angiotensin II receptor blocker (ARB) without steroid. About 1 year later, a renal mass was detected during an annual checkup, and contrast-enhanced computed tomography revealed low-density masses in bilateral kidneys and the head of the pancreas. The findings of endoscopic biopsy of the pancreatic mass were consistent with autoimmune pancreatitis (AIP) and the second renal biopsy showed the findings of MN with tubulointerstitial nephritis, both of which led to a diagnosis of IgG4-RD. The second renal biopsy also showed positive PLA2R. The patient received oral glucocorticoid therapy for IgG4-RD, which improved IgG4-related AIP and renal masses and also resulted in complete remission of MN. To our knowledge, this is the first reported case of PLA2R-positive MN with subsequent development of IgG4-RD. It is sometimes difficult to determine whether PLA2R-positive MN occurring with IgG4-RD is primary MN or secondary MN associated with IgG4-RD. The possibility of developing IgG4-RD should be considered even when preceding MN is PLA2R-positive, suggesting of primary MN.

Exploring the potential pharmacological mechanism of aripiprazole against hyperprolactinemia based on network pharmacology and molecular docking

The current primary therapeutic approach for schizophrenia is antipsychotic medication, and antipsychotic-induced hyperprolactinemia occurs in 40–80% of patients with schizophrenia. Aripiprazole, an atypical antipsychotic belonging to the quinolinone derivative class, can reduce the likelihood of developing hyperprolactinemia, but the pharmacological mechanisms of this reduction are unknown. This study aimed to explore the molecular mechanism of action of aripiprazole in treating hyperprolactinemia based on network pharmacology and molecular docking techniques. This study identified a total of 151 potential targets for aripiprazole from the DrugBank, TCMSP, BATMAN-TCM, TargetNet, and SwissTargetPrediction databases. Additionally, 71 hyperprolactinemia targets were obtained from the PharmGKB, DrugBank, TTD, GeneCards, OMIM, and DisGENET databases. Utilizing Venny 2.1.0 software, an intersection of 27 genes was identified between aripiprazole and hyperprolactinemia. To construct a common target protein–protein interaction (PPI) network, the common targets obtained from both sources were input into the STRING database. The resulting PPI network was then imported into Cytoscape 3.7.2 software, which identified eight core targets associated with aripiprazole’s treatment of hyperprolactinemia. Subsequently, a PPI network was established for these targets. Enrichment analysis of the key targets was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes in the DAVID database. Additionally, molecular docking verification of the interaction between aripiprazole and the core targets was performed using AutoDock Vina software. Aripiprazole’s intervention in hyperprolactinemia primarily targets the following core proteins: Solute Carrier Family 6 Member 3 (SLC6A3), monoamine oxidase (MAO-B), Dopamine D2 receptor (DRD2), 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A), 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C), cytochrome P450 2D6 (CYP2D6), Dopamine D1 receptor (DRD1), Dopamine D4 receptor (DRD4). These targets are predominantly involved in biological processes such as the adenylate cyclase-activating adrenergic receptor signaling pathway, G-protein coupled receptor signaling pathway coupled to cyclic nucleotide second messenger, phospholipase C-activating G-protein coupled receptor signaling pathway, chemical synaptic transmission, and response to xenobiotic stimulus. Primary enrichment occurs in signaling pathways such as the neuroactive ligand-receptor interaction and serotonergic synapse pathways. Molecular docking results demonstrate a favorable affinity between aripiprazole and the core target proteins MAO-B, DRD2, SLC6A3, HTR2C, HTR2A, CYP2D6, DRD4, and DRD1. Network pharmacology predicted potential targets and signaling pathways for aripiprazole’s intervention in hyperprolactinemia, offering theoretical support and a reference basis for optimizing clinical strategies and drug development involving aripiprazole.

Structural insights into the agonist selectivity of the adenosine A3 receptor

Adenosine receptors play pivotal roles in physiological processes. Adenosine A3 receptor (A3R), the most recently identified adenosine receptor, is expressed in various tissues, exhibiting important roles in neuron, heart, and immune cells, and is often overexpressed in tumors, highlighting the therapeutic potential of A3R-selective agents. Recently, we identified RNA-derived N6-methyladenosine (m6A) as an endogenous agonist for A3R, suggesting the relationship between RNA-derived modified adenosine and A3R. Despite extensive studies on the other adenosine receptors, the selectivity mechanism of A3R, especially for A3R-selective agonists such as m6A and namodenoson, remained elusive. Here, we identify tRNA-derived N6-isopentenyl adenosine (i6A) as an A3R-selective ligand via screening of modified nucleosides against the adenosine receptors. Like m6A, i6A is found in the human body and may be an endogenous A3R ligand. Our cryo-EM analyses elucidate the A3R-Gi complexes bound to adenosine, 5’-N-ethylcarboxamidoadenosine (NECA), m6A, i6A, and namodenoson at overall resolutions of 3.27 Å (adenosine), 2.86 Å (NECA), 3.19 Å (m6A), 3.28 Å (i6A), and 3.20 Å (namodenoson), suggesting the selectivity and activation mechanism of A3R. We further conduct structure-guided engineering of m6A-insensitive A3R, which may aid future research targeting m6A and A3R, providing a molecular basis for future drug discovery.

Distinct Chrna5 mutations link excessive alcohol use to types I/II vulnerability profiles and IPN GABAergic neurons

Genome wide association and animal studies have implicated genetic variations in CHRNΑ5, encoding the α5 subunit-containing nicotinic acetylcholine receptors (α5*nAChRs), as a risk factor for developing alcohol use disorders (AUDs). To understand how α5*nAChR mutations may influence alcohol (EtOH) drinking behavior, we used a two-bottle choice procedure with intermittent access to alcohol in male and female transgenic mice expressing either the highly frequent human single nucleotide polymorphism (α5SNP/rs16969968) or a deletion of the Chrna5 gene (α5KO). AUDs-related preconsommatory traits (anxiety, sensation-seeking and impulsivity) were assessed with a battery of relevant tasks (elevated-plus maze, novel place preference and step-down inhibitory avoidance). The implication of the α5-expressing IPN GABAergic neurons in AUDs and related behavioral traits was verified using neurospecific lentiviral (LV)-induced reexpression of the α5 subunit in α5KOxGAD-Cre mice. Both α5SNP and α5KO mice showed over-consumption of EtOH, but displayed opposite vulnerability profiles consistent with Cloninger’s subtypes of human AUDs. α5SNP mice showed Type I-like characteristics, i.e., high anxiety, novelty avoidance, whereas α5KOs exhibited Type II-like features such as low anxiety and high impulsivity. LV re-expression of the α5 subunit in IPN GABAergic neurons restored the control of EtOH intake and improved the impulsive phenotype. We demonstrate that the SNP (rs16969968) or null mutation of Chrna5 result in increased volitional EtOH consumption but opposite effects on anxiety, novelty-seeking and impulsive-like behaviors that match Cloninger type I and II of AUDs, including sex-related variations. IPN GABAergic neurons expressing α5*nAChRs play a key role in limiting both EtOH drinking and motor impulsivity.

Adenosine-Dependent Arousal Induced by Astrocytes in a Brainstem Circuit.

Astrocytes play a crucial role in regulating sleep-wake behavior. However, how astrocytes govern a specific sleep-arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep-wake cycles with state-differential Ca2+ activity, peaking during transitions from sleep to wakefulness. Using chemogenetic and optogenetic approaches, they find that activating PZ astrocytes elicited and sustained wakefulness by prolonging arousal episodes while impeding transitions from wakefulness to non-rapid eye movement (NREM) sleep. Activation of PZ astrocytes specially induced the elevation of extracellular adenosine through the ATP hydrolysis pathway but not equilibrative nucleoside transporter (ENT) mediated transportation. Strikingly, the rise in adenosine levels induced arousal by activating A1 receptors, suggesting a distinct role for adenosine in the PZ beyond its conventional sleep homeostasis modulation observed in the basal forebrain (BF) and cortex. Moreover, at the circuit level, PZ astrocyte activation induced arousal by suppressing the GABA release from the PZGABA neurons, which promote NREM sleep and project to the parabrachial nucleus (PB). Thus, their study unveils a distinctive arousal-promoting effect of astrocytes within the PZ through extracellular adenosine and elucidates the underlying mechanism at the neural circuit level.

Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats.

In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT1D/1A and 5-HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved. Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1-5 Hz) or i.v. noradrenaline (0.01-0.5 μg·kg-1). 5-HT-related drug effects on adrenergic system were determined. Age-matched male rats were used as control. Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT1/5/7) and L-694,247 (5-HT1D), whereas the selective 5-HT2A/2B/2C (α-methyl-5-HT) and 5-HT3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT1A/1B/1F, 5-HT2B/2C, 5-HT4, 5-HT5A or 5-HT7) modified these vasoconstrictions. Only 1-PBG (5-HT3) modified the vasoconstrictions induced by exogenous noradrenaline. In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT1D receptor activation, whereas pre and/or postjunctional 5-HT3 and prejunctional 5-HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions.

Investigation into the biomolecular bases of blunted cocaine-induced glutamate release within the nucleus accumbens elicited by adolescent exposure to phenylpropanolamine

Globally, phenylpropanolamine (PPA) is a prevalent primary active ingredient in over-the-counter cough and cold, as well as weight-loss medications. Previously, we showed that a sensitization of cocaine-induced glutamate release within the nucleus accumbens (NAC) and the expression of cocaine-conditioned reward is not apparent in adult mice with a prior history of repeated PPA exposure during adolescence. As NAC glutamate is a purported driver of cocaine reward and reinforcement, the present study employed in vivo microdialysis and immunoblotting approaches to inform as to the receptor and transporter anomalies that might underpin the disrupted glutamate response to cocaine in adolescent PPA-exposed mice. For this, male and female C57BL/6J mice were pretreated, once daily, with either 0 or 40mg/kg PPA during post-natal days 35-44. Adolescent PPA pretreatment significantly altered the expression of mGlu2/3 and α2 receptors in the NAC, with less robust changes detected for EAAT2, D2 receptors, DAT and NET. However, we detected no overt change in the capacity of these receptors or transporters to affect extracellular glutamate levels in adolescent PPA-pretreated mice. The present findings contrast with the pronounced changes in the capacity of mGlu2/3 receptors, EAAT, DAT and NET to regulate NAC extracellular glutamate reported previously for juvenile PPA-pretreated mice, indicating further that the long-term biochemical consequences of PPA depend on the critical period of neurodevelopment during which an individual is PPA-exposed, although the specific biomolecular changes underpinning the cocaine phenotype produced by adolescent PPA remain to be elucidated.

MicroRNA-155-5p Differentially Regulates IL-13Rα1 and IL-13Rα2 Expression and Signaling Driving Abnormal Lung Epithelial Cell Phenotype in Severe Asthma.

MicroRNA (miR)-155-5p increases in innate and adaptive immune cells in response to IL-13 and is associated with the severity of asthma. However, little is known about its role in airway structural cells. Bronchial epithelial cells (BECs) isolated from healthy donors and patients with severe asthma were stimulated with IL-13. miR-155-5p expression and release were measured by real-time (RT)-PCR in BECs and in their derived exosomes. Modulation of miR-155-5p in BECs was performed using transfection of miR-155-5p inhibitor and mimic. IL-13 receptor α1 (IL-13Rα1), IL-13Rα2, MUC5AC, IL-8, and eotaxin-1 expression was measured by RT-PCR and Western blot analysis. The BEC repair process was assessed by a wound-healing assay. IL-13Rα1 and IL-13Rα2 expression and downstream pathways were evaluated by Western blot analysis. A dual luciferase assay was used to identify miR-155-5p target genes associated with IL-13R signaling. BECs from patients with severe asthma showed increased expression and exosomal release of miR-155-5p at baseline with amplification by IL-13 stimulation. BECs from patients with asthma expressed more IL-13Rα1 and less IL-13Rα2 than those from healthy donors, and IL-13Rα1 but not IL-13Rα2 induced miR-155-5p expression under IL-13 stimulation. miR-155-5p overexpression favored MUC5AC, IL-8, and Eotaxin-1 through the IL-13Rα1/SOCS1/STAT6 pathway while delaying the repair process by downregulating IL-13Rα2/MAPK14/c-Jun/c-fos signaling. The dual luciferase assay confirmed that miR-155-5p modulates both IL-13R pathways by directly targeting SOCS1, c-fos, and MAPK14. miR-155-5p is overexpressed in BECs from patients with severe asthma and regulates IL-13Rα1 and IL-13Rα2 expression and signaling, favoring expression of mucin- and eosinophil-related genes to the detriment of airway repair. These results show that miR-155-5p may contribute to airway epithelial cell dysfunction in patients with severe asthma.

Uncovering the therapeutic potential of green pea waste in breast cancer: a multi-target approach utilizing LC-MS/MS metabolomics, molecular networking, and network pharmacology

Background Pisum sativum(PS) is a universal legume plant utilized for both human and animal consumption, particularly its seeds, known as green peas. The processing of PS in food industries and households produces a significant amount of waste that needs to be valorized.MethodsIn this study, the metabolite profiles of the 70% ethanolic extracts of PS wastes, namely peels (PSP) and a combination of leaves and stems (PSLS), were investigated by liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry (LC-ESI-QTOF-MS/MS) followed by molecular networking.ResultsDifferent classes of metabolites were identified, being flavonoids and their derivatives, along with phenolic acids, the most abundant categories. Additionally, a comprehensive network pharmacology strategy was applied to elucidate potentially active metabolites, key targets, and the pathways involved in cytotoxic activity against breast cancer. This cytotoxic activity was investigated in MCF-7 and MCF-10a cell lines. Results revealed that PSLS extract exhibited a potent cytotoxic activity with a good selectivity index (IC50 = 17.67 and selectivity index of 3.51), compared to the reference drug doxorubicin (IC50 = 2.69 µg/mL and selectivity index of 5.28). Whereas PSP extract appeared to be less potent and selective (IC50 = 32.92 µg/mL and selectivity index of 1.62). A similar performance was also observed for several polyphenolics isolated from the PSLS extract, including methyl cis p-coumarate, trans p-coumaric acid, and liquiritigenin/ 7-methyl liquiritigenin mixture. Methyl cis p-coumarate showed the most potent cytotoxic activity against MCF-7 cell line and the highest selectivity (IC50 = 1.18 µg/mL (6.91 µM) and selectivity index of 27.42). The network pharmacology study revealed that the isolated compounds could interact with several breast cancer-associated protein targets including carbonic anhydrases 1, 2, 4, 9, and 12, as well as aldo-keto reductase family 1 member B1, adenosine A3 receptor, protein tyrosine phosphatase non-receptor type 1, and estrogen receptor 2.ConclusionThe uncovered therapeutic potential of PSLS and its metabolite constituents pave the way for an efficient and mindful PS waste valorization, calling for further in-vitro and in-vivo research.Graphical

Alleviation of Immobilization Stress or Fecal Microbiota-Induced Insomnia and Depression-like Behaviors in Mice by Lactobacillus plantarum and Its Supplement

Insomnia (sleeplessness) is a potential symptom of stress-induced depression/anxiety (DA), which induces TNF-α expression. Therefore, this study aimed to examine the effect of Lactobacillus (Lactiplantibacillus) plantarum P72, isolated as a strain suppressing lipopolysaccharide-induced expression of TNF-α in Caco2 cells, on DA and insomnia in immobilization stress (IS)- or cultured fecal microbiota (cFM)-treated mice. Oral administration of live or heat-killed P72 (hP72) reduced IS- or cFM-induced DA-like behaviors. They also reduced sleep latency time (SLT) and enhanced sleep duration (SLD). Additionally, P72 upregulated γ-aminobutyric acid (GABA), GABAA receptor α1, serotonin, and 5-HT1A receptor expression, which were downregulated by IS or cFM. Hempseed oil (HO) alone was ineffective against IS-induced DA- and insomnia-like behaviors, but its combination with P72 (PH) or hP72 (hPH) showed enhanced efficacy, reducing DA- and insomnia-like behaviors more strongly than P72 or HO alone. These also reduced the number of NF-κB-positive cells and the expression of TNF-α in the prefrontal cortex and colon. These results imply that P72 and its combination with HO can alleviate DA and insomnia by upregulating serotonergic and GABAergic systems through the suppression of NF-κB signaling.

Isolation, Characterization, and Anti-Inflammatory Effects of β-Sitosterol-β-D-Glucoside from Hygrophila auriculata: Experimental Validation, Molecular Docking, and Molecular Dynamics Simulations.

Hygrophila auriculata (K. Schum) Heine is known to treat various common aliment e.g. rheumatoid arthritis, kidney infections, jaundice, edema, and gout. This study aims to isolate bioactive components from the methanolic extract, assess their anti-inflammatory effects, and investigate their interactions with drug targets through docking and molecular dynamics simulations. Methanolic extract of H. auriculata furnished stigmast-5-en-3-ol-β-D-glucopyranoside (HA-06) which was characterized by using IR, NMR and mass spectral data. HA-06 alleviated carrageenan-induced inflammation in rats, while the methanolic extract of H. auriculata produced comparable results. The findings were similar to those of the positive control, indomethacin. The chemical structure of HA-06 was optimized using DFT at the B3LYP level and subsequently used for molecular docking against anti-inflammatory drug targets. HA-06 exhibited strong affinity towards phospholipase A2 and glucocorticoid receptor exhibiting binding energies of -11.25 kcal/mol and -11.07 kcal/mol, respectively.Molecular dynamics simulation was used to assess the dynamical stability of these two complexes and their native co-crystallized ligands. Principal component analysis, radius of gyration, free energy landscapes, solvent-accessible-surface-area, and root-mean square deviation/fluctuation all indicated stable interactions. Therefore, HA-06 could be a promising candidate for development into an effective therapy against inflammatory diseases targeting phospholipase A2 and glucocorticoid receptor.

Clinicopathological Features of Membranous Nephropathy Complicated by IgA Nephropathy: A Retrospective Analysis of Seven Cases.

Aims/Background Both membranous nephropathy (MN) and immunoglobulin A nephropathy (IgAN) are immune complex-mediated glomerular diseases, but the concurrent occurrence of these two conditions in the same patient is not common, a phenomenon that is currently not supported by clinical data in terms of treatment and prognosis. This study explores the clinical and pathological characteristics, as well as the treatment outcomes, of patients affected by MN and IgAN simultaneously. Methods The clinical data, pathological features, and diagnostic and therapeutic information of seven cases of MN complicated by IgAN, treated between December 2015 and December 2022, were retrospectively analyzed. Results Among the seven cases, there were two male and five female patients, with an average age of 57.3 ± 9.2 years. All patients presented with clinical manifestations of proteinuria and edema upon admission, with an average 24-hour urine protein of 3716.6 ± 1519.4 mg/24 h. Phospholipase A2 receptor (PLA2R) expression was detected in all seven cases, and nephrotic syndrome was clinically diagnosed in five cases. Additionally, all seven cases showed microscopic hematuria, with intermittent gross hematuria in two cases. All seven patients included in this study underwent renal biopsy. After disease staging, the patients had MN stages I-III and IgAN stages II-III. Pathological findings revealed abnormal glomerular basement membrane (GBM) and diffuse immunoglobulin G (IgG) deposition in the subepithelial space, predominantly of the IgG4 subtype. Simultaneously, there was diffuse mesangial zone deposition of immunoglobulin A (IgA) to varying degrees, co-localization of complement component C3 and IgA, and mesangial cell proliferation. Treatment strategies included angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in combination with steroids or immunosuppressive therapies such as tacrolimus, cyclophosphamide, and rituximab. After 2-6 months of treatment, all patients achieved complete remission with a favourable prognosis. Conclusion MN accompanied by IgAN tends to occur more frequently in middle-aged and elderly individuals, with a relatively low incidence. The latent feature of the comorbidities manifests as a form of IgAN superimposed on the background of MN. Utilizing ACEI or ARB in combination with steroids or various immunosuppressive therapies represents a potentially effective treatment strategy.

Membranous glomerulopathy in women: clinical repercussions

Introduction: Membranous glomerulopathy is one of the most common causes of nephrotic syndrome in adults, with particular prevalence in women. This condition is characterized by thickening of the glomerular basement membrane, resulting in significant proteinuria and other clinical complications. The disease may have primary etiologies, such as the presence of antibodies against the phospholipase A2 receptor, or secondary to conditions such as infections, neoplasias and autoimmune diseases. In women, the clinical repercussions of membranous glomerulopathy may be more complex, since the interaction between hormones and immunological factors may influence the course of the disease and the response to treatment. Methodology: The research was conducted using the PRISMA checklist, with data collection from articles published in the last 10 years in the PubMed, SciELO and Web of Science databases. Five descriptors were used: "membranous glomerulopathy", "nephrotic syndrome", "women", "treatment" and "clinical implications". Inclusion criteria consisted of studies that addressed membranous glomerulopathy specifically in women, articles that presented clinical data, and peer-reviewed studies. Exclusion criteria included publications not related to the female population, articles with insufficient data, and non-original reviews. Results: The review revealed that membranous glomerulopathy in women is associated with a higher incidence of complications, including venous thrombosis and arterial hypertension. Treatments ranged from immunosuppressive to targeted therapies, with varied results in terms of remission and adverse effects. The quality of life of patients was significantly affected by the disease, highlighting the need for multidisciplinary management. Conclusion: Membranous glomerulopathy in women presents unique characteristics and clinical challenges, which demand special attention in diagnosis and treatment. Understanding the clinical repercussions and personalizing therapeutic approaches are essential to improve the quality of life of patients affected by this complex condition.

Female patients exhibit altered vasopressin-induced coronary microvascular contractile response and molecular signaling following cardiac surgery

BackgroundEmerging data suggest women have worse outcomes than men following cardioplegia and cardiopulmonary bypass (CP/CPB). Altered coronary microvascular function affecting myocardial perfusion may contribute, but human translational studies are lacking. MethodsViable coronary microvessels (<200 μ m) were dissected from human atrial samples collected before and after CP/CPB from a subset of 108 patients enrolled. Ex vivo contractile responses to vasopressin were assessed using video microscopy. RNA deep-sequencing and immunoblotting were used to quantify gene and protein expression, respectively. ResultsCoronary microvessels exhibited increased vasopressin-induced contractile responses post-CP/CPB in males and females (p ​< ​0.0001). Females exhibited a decrease in microvascular contractile response versus males pre- (p ​= ​0.1) and post-CP/CPB (p ​= ​0.09) which approached significance. Myocardial vasopressin 1a receptor levels were increased in females versus males (p ​= ​0.001). Vasopressin-induced vasoconstriction predicted postoperative cardiac index. ConclusionsImpaired coronary microvascular contractile responses in females jeopardizing myocardial perfusion may underlie worse outcomes following cardiac surgery.

Psilocin, the Psychoactive Metabolite of Psilocybin, Modulates Select Neuroimmune Functions of Microglial Cells in a 5-HT2 Receptor-Dependent Manner

Neuroinflammation that is caused by microglia, the main immune cells of the brain, contributes to neurodegenerative diseases. Psychedelics, including psilocybin and lysergic acid diethylamide (LSD), possess certain anti-inflammatory properties and, therefore, should be considered as drug candidates for treating neuroinflammatory pathologies. When ingested, psilocybin is rapidly dephosphorylated to yield psilocin, which crosses the blood–brain barrier and exerts psychotropic activity by interacting with the 5-hydroxytryptamine 2A receptors (5-HT2ARs) on neurons. Since microglia express all three 5-HT2R isoforms, we hypothesized that, by interacting with these receptors, psilocin beneficially modulates select neuroimmune functions of microglia. We used microglia-like cell lines to demonstrate that psilocin, at non-toxic concentrations, did not affect the secretion of tumor necrosis factor (TNF) by immune-stimulated microglial cells, but significantly inhibited their phagocytic activity, the release of reactive oxygen species (ROS), and nitric oxide (NO) production. The inhibitory activity of psilocin on the latter two functions was similar to that of two selective 5-HT2R agonists, namely, 25I-NBOH and Ro60-0175. The role of this subfamily of receptors was further demonstrated by the application of 5-HT2R antagonists cyproheptadine and risperidone. Psilocin should be considered a novel drug candidate that might be effective in treating neuroimmune disorders, such as neurodegenerative diseases, where reactive microglia are significant contributors.

Aromatic Ring-Fused Amidine Based Allosteric Receptors Activated by Guest-Induced π-Conjugation Switching.

Amidine-substituted allosteric receptors 2a and 2b for benzenediols were synthesized. Receptor 2a with five-membered amidines exhibited greater allostericity than the amide-substituted receptor 1, while 2b with six-membered amidines exhibited less allostericity. NMR titration experiments revealed that a significant enthalpic factor was involved in the allostericity of these receptors. X-ray and DFT optimized structures of 2a and 2b revealed that 2a adopted a coplanar conformation with π-conjugation between the amidines and the phenylene ring of the hydrindacene framework, resulting in high allostericity due to inactivation of the initial binding.

Anxiolytic Efficacy of Indirubin: In Vivo Approach Along with Receptor Binding Profiling and Molecular Interaction with GABAergic Pathways.

Anxiety is a natural response to stress, characterized by feelings of worry, fear, or unease. The current research was conducted to investigate the anxiolytic effect of indirubin (IND) in different behavioral paradigms in Swiss albino mice. To observe the animal's behavioural response to assess anxiolytic activity, different tests were performed, such as the open-field (square cross, grooming, and rearing), swing, dark-light, and hole cross tests. The experimental mice were administered IND (5 and 10 mg/kg, p.o.), where diazepam (DZP) and vehicle were used as positive and negative controls, respectively. In addition, a combination treatment (DZP+IND-10) was provided to the animals to determine the modulatory effect of IND on DZP. Molecular docking approach was also conducted to determine the binding energy of IND with the GABAA receptor (α2 and α3 subunits) and pharmacokinetics were also estimated. The findings revealed that IND dose-dependently significantly (p<0.05) reduced the animal's movement exerting calming behavior like DZP. IND also demonstrated the highest docking score (-7.7 kcal/mol) against the α3 subunit, while DZP showed a lower docking value (-6.4 kcal/mol) than IND. The ADMET analysis revealed that IND has proper drug-likeness and pharmacokinetic characteristics. In conclusion, IND exerted anxiolytic effects through GABAergic Pathways.

Overview of Immunological Response in Urological Membranous Nephropathy: Focus on Cytokine and Treatment Options.

Membranous nephropathy (MN) is an autoimmune disease that is caused by the production of autoantibody against glomerular podocyte antigens by immune cells due to the lack of self-tolerance mechanisms. Similar to many autoimmune diseases, the pathogenesis of MN is still vague and many experiments are being conducted to detect the antigens and genetic reasons for MN illness. Recently, new antigens, such as exotosin 1/exotosin 2, neural EGF-like-1, semaphorin 3B, and protocadherin 7 have been identified in MN patients who did not have presence of antiphospholipase A2 receptor antigen. What is more, cytokines, which are molecules that regulate immune responses, have been found to have harmful effects in various autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and MN. The role of cytokines and treatment strategies in MN patients is discussed in this article. As the understanding of the disease improves, targeted therapies that focus on specific antigens or cytokines may be developed to effectively manage MN.

Cortical norepinephrine-astrocyte signaling critically mediates learned behavior.

Updating behavior based on feedback from the environment is a crucial means by which organisms learn and develop optimal behavioral strategies 1-3 . Norepinephrine (NE) release from the locus coeruleus (LC) has been shown to mediate learned behaviors 4-6 such that in a task with graded stimulus uncertainty and performance, a high level of NE released after an unexpected outcome causes improvement in subsequent behavior 7 . Yet, how the transient activity of LC-NE neurons, lasting tens of milliseconds, influences behavior several seconds later, is unclear. Here, we show that NE acts directly on cortical astrocytes via Adra1a adrenergic receptors to elicit sustained increases in intracellular calcium. Chemogenetic blockade of astrocytic calcium elevation prevents the improvement in behavioral performance. NE-activated calcium invokes purinergic pathways in cortical astrocytes that signal to neurons; pathway-specific astrocyte gene expression is altered in mice trained on the task, and blocking neuronal adenosine-sensitive A1 receptors also prevents post-reinforcement behavioral gain. Finally, blocking either astrocyte calcium dynamics or A1 receptors alters encoding of the task in prefrontal cortex neurons, preventing the post-reinforcement change in discriminability of rewarded and unrewarded stimuli underlying behavioral improvement. Together, these data demonstrate that astrocytes, rather than indirectly reflecting neuronal drive, play a direct, instrumental role in representing task-relevant information and signaling to neurons to mediate a fundamental component of learning in the brain.