Receptor System Research Articles

Interleukin Profiling in Atopic Dermatitis and Chronic Nodular Prurigo.

The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.

Isolation, purification, and characterization of lectins from medicinal plant Combretum glutinosum seeds endowed with analgesic and antiulcer properties

In the pursuit of safer and more effective treatments, there is a growing interest in plant-derived compounds, particularly lectins, because of their diverse pharmacological properties. This study focused on isolating, purifying, and characterizing lectin from Combretum glutinosum seeds (CGSLs) to assess its potential as an analgesic and antiulcer agent. CGSL extraction involved defatting and buffer extraction, followed by purification using ammonium sulfate fractionation and fetuin-agarose affinity column chromatography. The isolectins (iso-CGSLs), each consisting of 60 kDa and 57 kDa heterodimeric subunits, displayed glycoprotein properties with a 40 % neutral sugar content. They exhibited peak activity at 55 °C and remained stable for up to the fifth day at room temperature. The activity exhibited a pH dependence, peaking between 7.5 and 10.5, and all seemingly operated independently of metal ions. CGSL, at optimal doses ranging from 6 to 12 mg/kg, had significant analgesic effects on acetic acid-induced writhing and hot plate tests in mice. Evaluation using 0.7 % acetic acid resulted in notable pain reduction across all doses (P < 0.05). The analgesic effect of lectin was partially reversed by naloxone (a morphine antagonist), indicating partial involvement of the opioid receptor system. Furthermore, CGSL exhibited antiulcer effects in ethanol-induced gastric ulcer models in rats, highlighting its therapeutic potential as a natural alternative for analgesic and antiulcer treatments.

Remifentanil-induced hyperalgesia: the current state of affairs.

Remifentanil-induced hyperalgesia (RIH) is a part of a general opioid-induced hyperalgesia (OIH) syndrome, seemingly resulting from abrupt cessation of continuous remifentanil infusion at rates equal or exceeding 0.3 mcg/kg/min. The intricate mechanisms of its development are still not completely understood. However, hyperactivation of the N -methyl d -aspartate receptor system, descending spinal facilitation and increased concentration of dynorphin (a κ-opioid ligand) are commonly proposed as possible mechanisms. Several ways of prevention and management have been suggested, such as slow withdrawal of remifentanil infusion, the addition of propofol, pretreatment with or concomitant administration of ketamine, buprenorphine, cyclooxygenase-2 inhibitors (NSAIDs), methadone, dexmedetomidine. In clinical and animal studies, these strategies exhibited varying success, and many are still being investigated.

Dysregulation of kappa opioid receptor neuromodulation of lateral habenula synaptic function following a repetitive mild traumatic brain injury

Mild traumatic brain injury (mTBI) increases the risk of affective disorders, anxiety and substance use disorder. The lateral habenula (LHb) plays an important role in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between mTBI-induced LHb hyperactivity due to excitation/inhibition (E/I) imbalance and motivational deficits in male mice using a repetitive closed head injury mTBI model. A major neuromodulatory system that is responsive to traumatic brain injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function are unknown. Here, we first used retrograde tracing in male and female Cre mouse lines and identified several major KOR-expressing and two prominent Dyn-expressing inputs projecting to the mouse LHb, highlighting the medial prefrontal cortex (mPFC) and the ventromedial nucleus of the hypothalamus (VMH) as the main LHb-projecting Dyn inputs that regulate KOR signaling to the LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4 week post-injury. We observed sex-specific differences in spontaneous release of glutamate and GABA from presynaptic terminals onto LHb neurons with higher levels of presynaptic glutamate and GABA release in females compared to male mice. However, KOR effects on the spontaneous E/I ratios and synaptic drive ratio within the LHb did not differ between male and female sham and mTBI mice. KOR activation generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant but sex-similar reduction in net spontaneous E/I and synaptic drive ratios in LHb neurons of sham mice. Following mTBI, while responses to KOR activation at LHb glutamatergic synapses remained intact, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition where we observed a reduction in GABA release probability in response to KOR stimulation in LHb neurons of mTBI mice. Further analysis of percent change in spontaneous synaptic ratios induced by KOR activation revealed that independent of sex mTBI switches KOR-driven synaptic inhibition of LHb neurons (normally observed in sham mice) in a subset of mTBI mice toward synaptic excitation resulting in mTBI-induced divergence of KOR actions within the LHb. Overall, we uncovered the sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. We demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global KOR-driven synaptic inhibition within the mouse LHb independent of sex. The additional engagement of KOR-mediated action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons of a subset of mTBI mice.

Pilot trial of an electronic decision support to improve care for emergency department patients with acute heart failure.

Emergency department (ED) providers play an important role in the management of patients with acute heart failure (AHF). We present findings from a pilot study of an electronic decision support that includes personalized risk estimates using the STRIDE-HF risk tool and tailored recommendations for initiating guideline directed medical therapy (GDMT) among appropriate patients. Among ED patients treated for AHF who were discharged from the ED or the ED-based observation unit in two EDs from 1 January 2023 to 31 July 2023, we assess prescriptions to the four classes of GDMT at two intervals: (1) ED arrival and (2) ED discharge. Specifically, we report active prescriptions for beta-blockers (BBs), renin-angiotensin receptor system inhibitors (RASis), sodium-glucose transport protein 2 inhibitors (SGLT2is) and mineralocorticoid receptor antagonists (MRA) among patients with reduced ejection fraction (HFrEF) and mildly reduced (HFmrEF). Second, we describe rates of 30-day serious adverse events (SAE) (death, cardiopulmonary resuscitation, balloon-pump insertion, intubation, new dialysis, myocardial infarction or coronary revascularization) among patients predicted to be very low risk by STRIDE-HF and discharged home. Among 234 discharged patients, 55% were female and 76% were non-White. We found 51 (21.8%), 21 (9.0%) and 126 (53.8%) had HFrEF, HFmEF and HFpEF, respectively, while 36 (15.4%) were missing EF, and 51 (22%) were very low risk, 82 (35%) were low risk, 60 (26%) were medium risk and 41 (18%) were high risk. Among HFrEF patients, 68.6%, 66.7%, 25.5% and 19.6% were on a RASi, BB, SGLT2i and MRA, respectively, at ED arrival, while 42.9%, 66.7%, 14.3% and 4.8% of HFmrEF patients were on a RASi, BB, SGLT2i and MRA, respectively. Among patients with HFpEF, only 6 (4.8%) were on an SGLT2i at ED arrival. The most prescribed new medication at ED discharge was an SGLT2i, with a nearly 10% increase in the proportion of patients with an active prescription for SGLT2i at ED discharge among HFrEF and HFmEF patients. We observed no 30-day SAE among the 51 patients predicted to be very low risk and discharged home. Ongoing treatment with GDMT at ED arrival was sub-optimal. Initiation among appropriate patients at discharge may be feasible and safe.

Mechanisms and Functions of Sweet Reception in Oral and Extraoral Organs.

The oral detection of sugars relies on two types of receptor systems. The first is the G-protein-coupled receptor TAS1R2/TAS1R3. When activated, this receptor triggers a downstream signaling cascade involving gustducin, phospholipase Cβ2 (PLCβ2), and transient receptor potential channel M5 (TRPM5). The second type of receptor is the glucose transporter. When glucose enters the cell via this transporter, it is metabolized to produce ATP. This ATP inhibits the opening of KATP channels, leading to cell depolarization. Beside these receptor systems, sweet-sensitive taste cells have mechanisms to regulate their sensitivity to sweet substances based on internal and external states of the body. Sweet taste receptors are not limited to the oral cavity; they are also present in extraoral organs such as the gastrointestinal tract, pancreas, and brain. These extraoral sweet receptors are involved in various functions, including glucose absorption, insulin release, sugar preference, and food intake, contributing to the maintenance of energy homeostasis. Additionally, sweet receptors may have unique roles in certain organs like the trachea and bone. This review summarizes past and recent studies on sweet receptor systems, exploring the molecular mechanisms and physiological functions of sweet (sugar) detection in both oral and extraoral organs.

A single exposure to the predator odor 2,4,5-trimethylthiazoline causes long-lasting affective behavioral changes in female mice: Modulation by kappa opioid receptor signaling

The volatile compound 2,4,5-trimethylthiazoline (TMT, a synthetic predator scent) triggers fear, anxiety, and defensive responses in rodents that can outlast the encounter. The receptor systems underlying the development and persistence of TMT-induced behavioral changes remain poorly characterized, especially in females. Kappa opioid receptors regulate threat generalization and fear conditioning and alter basal anxiety, but their role in unconditioned fear responses in females has not been examined. Here, we investigated the effects of the long-lasting kappa opioid receptor antagonist, nor-binalthorphinmine dihydrochloride (nor-BNI; 10mg/kg), on TMT-induced freezing and conditioned place aversion in female mice. We also measured anxiety-like behavior in the elevated plus maze three days after TMT and freezing behavior when returned to the TMT-paired context ten days after the single exposure. We found that 35μl of 10% TMT elicited a robust freezing response during a five-minute exposure in female mice. TMT evoked persistent fear as measured by conditioned place aversion, reduced entries into the open arm of the elevated plus maze, and increased general freezing behavior long after TMT exposure. In line with the known role of kappa-opioid receptors in threat generalization, we found that kappa-opioid receptor antagonism increased basal freezing but reduced freezing during TMT presentation. Together, these findings indicate that a single exposure to TMT causes long-lasting changes in fear-related behavioral responses in female mice and highlights the modulatory role of kappa-opioid receptor signaling on fear-related behavioral patterns in females.

The Effect of KSK-94, a Dual Histamine H3 and Sigma-2 Receptor Ligand, on Adipose Tissue in a Rat Model of Developing Obesity.

Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H3/sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott's A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment. Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies. The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue. Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94.

The effects of killer cell immunoglobulin-like receptor (KIR) genes on susceptibility to severe COVID-19 in the Iranian population

BackgroundVariations in the innate and adaptive immune response systems are linked to variations in the severity of COVID-19. Natural killer cell (NK) function is regulated by sophisticated receptor system including Killer-cell immunoglobulin-like receptor (KIR) family. We aimed to investigate the impact of possessing certain KIR genes and genotypes on COVID19 severity in Iranians. KIR genotyping was performed on 394 age/sex matched Iranians with no underlying conditions who developed mild and severe COVID- 19. The presence and/or absence of 11 KIR genes were determined using the PCR with sequence specific primers (PCR-SSP).ResultsPatients with mild symptoms had higher frequency ofKIR2DS1 (p = 0.004) and KIR2DS2 (p = 0.017) genes compared to those with severe disease. While KIR3DL3 and deleted variant of KIR2DS4 occurred more frequently in patients who developed a severe form of the disease. In this study, a significant increase of and B haplotype was observed in the Mild group compared to the Severe group (respectively, p = 0.002 and p = 0.02). Also, the prevalence of haplotype A was significantly higher in the Severe group than in the Mild group (p = 0.02).ConclusionsThese results suggest that the KIR2DS1, KIR2DS, and B haplotype maybe have a protective effect against COVID-19 severity. The results also suggest the inhibitory gene KIR2DL3 and haplotype A are risk factors for the severity of COVID-19.

Sensing of an HIV-1-Derived Single-Stranded RNA-Oligonucleotide Induces Arginase 1-Mediated Tolerance.

Small synthetic oligodeoxynucleotides (ODNs) can mimic microbial nucleic acids by interacting with receptor systems and promoting immunostimulatory activities. Nevertheless, some ODNs can act differently on the plasmacytoid dendritic cell (pDC) subset, shaping their immunoregulatory properties and rendering them suitable immunotherapeutic tools in several clinical settings for treating overwhelming immune responses. We designed HIV-1-derived, DNA- and RNA-based oligonucleotides (gag, pol, and U5 regions) and assessed their activity in conferring a tolerogenic phenotype to pDCs in skin test experiments. RNA-but not DNA-oligonucleotides are capable of inducing tolerogenic features in pDCs. Interestingly, sensing the HIV-1-derived single-stranded RNA-gag oligonucleotide (RNA-gag) requires both TLR3 and TLR7 and the engagement of the TRIF adaptor molecule. Moreover, the induction of a suppressive phenotype in pDCs by RNA-gag is contingent upon the induction and activation of the immunosuppressive enzyme Arginase 1. Thus, our data suggest that sensing of the synthetic RNA-gag oligonucleotide in pDCs can induce a suppressive phenotype in pDCs, a property rendering RNA-gag a potential tool for therapeutic strategies in allergies and autoimmune diseases.

Topography of the GLP-1/GLP-1 receptor system in the spinal cord of male mice

Glucagon-like peptide-1 receptor (GLP-1R) agonists are now commonly used to treat type 2 diabetes and obesity. GLP-1R signaling in the spinal cord has been suggested to account for the mild tachycardia caused by GLP-1R agonists, and may also be involved in the therapeutic effects of these drugs. However, the neuroanatomy of the GLP-1/GLP-1R system in the spinal cord is still poorly understood. Here we applied in situ hybridization and immunohistochemistry to characterize this system, and its relation to cholinergic neurons. GLP-1R transcript and protein were expressed in neuronal cell bodies across the gray matter, in matching distribution patterns. GLP-1R-immunolabeling was also robust in dendrites and axons, especially in laminae II–III in the dorsal horn. Cerebrospinal fluid-contacting neurons expressed GLP-1R protein at exceedingly high levels. Only small subpopulations of cholinergic neurons expressed GLP-1R, including a subset of sympathetic preganglionic neurons at the rostral tip of the intermediolateral nucleus. GLP-1 axons innervated all regions where GLP-1R neurons were distributed, except laminae II–III. Scattered preproglucagon (Gcg) mRNA-expressing neurons were identified in the cervical and lumbar enlargements. The results will facilitate further studies on how GLP-1 regulates the sympathetic system and other autonomic and somatic functions via the spinal cord.

DIPG-15. NOVEL CNS SENSING SYNNOTCH-CAR T CELLS FOR TARGETING DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline glioma (DMG), including Diffuse intrinsic pontine glioma (DIPG), is an aggressive brain tumor in children with limited treatment options. Recent developments of phase 1 clinical trials have shown early promise for chimeric antigen receptor (CAR) T cells in patients with DMG/DIPG. However, several barriers such as the absence of tumor-specific antigens, restricted trafficking to the tumor site, and poor persistence hinder the full therapeutic potential of CAR T cell therapy in DMG/DIPG. METHODS To safely target the glioma-associated antigens (GAAs) without attacking nomal tissues expressing the same antigens, we adopted a novel synthetic Notch (synNotch) receptor system and engineered T cell circuits employing a “prime-and-kill” strategy. In this system, a synNotch receptor recognizing the priming antigen, Brevican (BCAN), exclusively expressed on cells in the central nervous system (CNS) but not on non-CNS cells, locally induces the expression of a tandem CAR against GAAs, ephrin type A receptor (EphA2) and interleukin-13 receptor a2 (IL13Ra2), there by homogenously eliminating DMG/DIPG cells. RESULTS The α-BCAN synNotch⋄α-EphA2/IL-13Rα2 CAR (B-SYNC) T cells efficiently killed DMG/DIPG (BT-245, SF8628, SU-DIPGXIII, and SU-DIPGXVII) cells in vitro in the presence of priming cells (K562 cells expressing BCAN). Moreover, a single intravenous infusion of B-SYNC T cells significantly (P&amp;lt; 0.001) prolonged the survival of immunodeficient mice bearing aggressive, orthotopic SF8628 DIPG xenografts and completely eradicated the tumor in more than 50% (4/7) of mice. Strikingly, we observed excellent homing, priming, activation, and persistence of B-SYNC T cells in the brain stem of mice bearing SF8628 xenografts. In contrast, constitutively active α-EphA2/IL-13Rα2 CAR T cells or untransduced T cells demonstrated a failure to migrate to the brain stem and improve the survival of mice. CONCLUSIONS Collectively, our findings strongly support the development of clinical trials evaluating the efficacy of B-SYNC T cells in DMG/DIPG patients.

Integration of IGZO-based memristor and Pt-based temperature sensor for enhanced artificial nociceptor system

A biological nociceptor functions as a sensory neuron receptor that detects external stimuli and transforms information to the central nervous system, prompting an appropriate response in the human body. In this study, we introduce and experimentally demonstrate a biological receptor system by integrating an IGZO-memristor with a temperature sensor to mimic the dynamics of biological thermoreceptors, including responses to innocuous and noxious stimuli. The IGZO-memristor exhibits a stable bipolar switching response with excellent endurance and retention properties, also revealing biological synaptic functionalities such as hyperalgesia and allodynia. Through our biological receptor system, we placed the temperature sensor on a hot plate and successfully emulated the biological responses of innocuous and noxious functions at different temperature levels 40 °C and 70 °C at the memristor end, respectively. This innovative approach introduces artificial nociceptor devices into artificial intelligence systems, providing a novel platform for the development of intelligent systems capable of mimicking human sensory responses.

Treatment-Resistant Depression and Medications

The management of treatment-resistant depression (TRD) is challenging. Researchers have identified novel targets, especially the glutamatergic system, in the pathogenesis of depressive disorder. N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine, have revolutionized the treatment of TRD due to their rapid antidepressant and antisuicidal effect. Various other receptor systems, including GABAergic, opioid receptors, the endogenous cannabinoid system, and cholinergic receptors, are novel targets to produce an antidepressant response. The US Food and Drug Administration (FDA) has approved intra-nasal ketamine as an add-on therapy to conventional antidepressants for TRD. Other compounds are in various stages of development. Identification and development of novel compounds by future research can help in overcoming the challenges of treating TRD. [ Psychiatr Ann . 2024;54(6):e177–e181.]

Artificial Tactile Receptor System for Sensitive Pressure-Neural Spike Conversion.

An artificial tactile receptor is crucial for e-skin in next-generation robots, mimicking the mechanical sensing, signal encoding, and preprocessing functionalities of human skin. In the neural network, pressure signals are encoded in spike patterns and efficiently transmitted, exhibiting low power consumption and robust tolerance for bit error rates. Here, we introduce a highly sensitive artificial tactile receptor system integrating a pressure sensor, axon-hillock circuit, and neurotransmitter release device to achieve pressure signal coding with patterned spikes and controlled neurotransmitter release. Owing to the heightened sensitivity of the axon-hillock circuit to pressure-mediated current signals, the artificial tactile receptor achieves a detection limit of 10 Pa that surpasses the human tactile receptors, with a wide response range from 10 to 5 × 105 Pa. Benefiting from the appreciable pressure-responsive performance, the potential application of an artificial tactile receptor in robotic tactile perception has been demonstrated, encompassing tasks such as finger touch and human pulse detection.

A "2-in-1" Bioanalytical System Based on Nanocomposite Conductive Polymers for Early Detection of Surface Water Pollution.

This work proposes an approach to the formation of receptor elements for the rapid diagnosis of the state of surface waters according to two indicators: the biochemical oxygen demand (BOD) index and toxicity. Associations among microorganisms based on the bacteria P. yeei and yeast S. cerevisiae, as well as associations of the yeasts O. polymorpha and B. adeninivorans, were formed to evaluate these indicators, respectively. The use of nanocomposite electrically conductive materials based on carbon nanotubes, biocompatible natural polymers-chitosan and bovine serum albumin cross-linked with ferrocenecarboxaldehyde, neutral red, safranin, and phenosafranin-has made it possible to expand the analytical capabilities of receptor systems. Redox polymers were studied by IR spectroscopy and Raman spectroscopy, the contents of electroactive components were determined by atomic absorption spectroscopy, and electrochemical properties were studied by electrochemical impedance and cyclic voltammetry methods. Based on the proposed kinetic approach to modeling individual stages of bioelectrochemical processes, the chitosan-neutral red/CNT composite was chosen to immobilize the yeast association between O. polymorpha (ks = 370 ± 20 L/g × s) and B. adeninivorans (320 ± 30 L/g × s), and a bovine serum albumin (BSA)-neutral composite was chosen to immobilize the association between the yeast S. cerevisiae (ks = 130 ± 10 L/g × s) and the bacteria P. yeei red/CNT (170 ± 30 L/g × s). After optimizing the composition of the receptor systems, it was shown that the use of nanocomposite materials together with associations among microorganisms makes it possible to determine BOD with high sensitivity (with a lower limit of 0.6 mg/dm3) and detect the presence of a wide range of toxicants of both organic and inorganic origin. Both receptor elements were tested on water samples, showing a high correlation between the results of biosensor analysis of BOD and toxicity and the results of standard analytical methods. The results obtained show broad prospects for creating sensitive and portable bioelectrochemical sensors for the early warning of environmentally hazardous situations based on associations among microorganisms and nanocomposite materials.

Radiolabeled peptides and their expanding role in clinical imaging and targeted cancer therapy.

There is an expanding body of evidence showing that synthetic peptides in combination with radioactive isotopes can be utilized for medical purposes. This area is of particular interest in oncology where applications in diagnosis and therapy are at different stages of development. We review the contributions in this area by the group originally founded by Carlo Pedone in Naples many years ago. We highlight the work of this group in the context of other developments in this area, focusing on three biologically relevant receptor systems: somatostatin, gastrin-releasing peptide, and cholecystokinin-2/gastrin receptors. We focus on key milestones, state of the art, and challenges in this area of research as well as the current and future outlook for expanding clinical applications.

Heart's Signaling Symphony: Exploring Cardiac Receptors

This overview delves into the intricate interplay between adrenergic and cholinergic receptors in regulating heart function. The sympathetic and parasympathetic nervous systems play a powerful role in controlling cardiac function by activating adrenergic and muscarinic receptors. In the human heart, there exist α1, β1, and β2- adrenoceptors and M2-muscarinic receptors and possibly also (prejunctional) α2-adrenoceptors. The human heart has a very uniform distribution of β1 and β2-adrenoceptors and a heterogeneous distribution of M2-receptors (more receptors in the atria than the ventricles). Heart rate and contraction force increase whenever β1 and β2-adrenoceptors are stimulated, while heart rate and contraction force fall when M2 receptors are stimulated (directly in the atria and indirectly in the ventricles). The distribution of β1 and β2-adrenoceptors in the human heart can be changed by pathological conditions (like heart failure) or pharmacological interventions (like -blocker medication), nevertheless, M2-receptors are much less influenced. The intricate relationships between these receptor systems offer possible cardiovascular disease therapy strategies. More research must be conducted, focused on the complex control mechanisms that regulate cardiac function and pathology, to fully comprehend the subtleties of these signalling pathways and how they affect heart health.

Affinity-Driven Aryl Diazonium Labeling of Peptide Receptors on Living Cells.

Peptide-receptor interactions play critical roles in a wide variety of physiological processes. Methods to link bioactive peptides covalently to unmodified receptors on the surfaces of living cells are valuable for studying receptor signaling, dynamics, and trafficking and for identifying novel peptide-receptor interactions. Here, we utilize peptide analogues bearing deactivated aryl diazonium groups for the affinity-driven labeling of unmodified receptors. We demonstrate that aryl diazonium-bearing peptide analogues can covalently label receptors on the surface of living cells using both the neurotensin and the glucagon-like peptide 1 receptor systems. Receptor labeling occurs in the complex environment of the cell surface in a sequence-specific manner. We further demonstrate the utility of this covalent labeling approach for the visualization of peptide receptors by confocal fluorescence microscopy and for the enrichment and identification of labeled receptors by mass spectrometry-based proteomics. Aryl diazonium-based affinity-driven receptor labeling is attractive due to the high abundance of tyrosine and histidine residues susceptible to azo coupling in the peptide binding sites of receptors, the ease of incorporation of aryl diazonium groups into peptides, and the relatively small size of the aryl diazonium group. This approach should prove to be a powerful and relatively general method to study peptide-receptor interactions in cellular contexts.

The limits of knowledge

The definition of knowledge encompasses various meanings, from the process by which we have the perception of the outside world, through the stimuli that we receive from this, when that perception becomes part of our system of awareness and experience. When awareness of ourselves and the outside world is acquired and recorded, we can define it as learning. In the broader, philosophical sense, knowledge consists in learning and retaining in the mind a notion, an information. In use, however, it has a more concrete semantic value, and can indicate the various degrees of knowledge, from the initial perception of the existence of a thing to the full cognition of its being, its modes and qualities. Whatever the subject, cell, organism, neuronal network, and so on, the process always takes place by the use of specific receptor systems, adapted to the reception of different stimuli from the environment. Because they are calibrated only on the stimuli they receive, the receptor systems have limited sensitivity. This limitation is extended to all living beings, who therefore have partial and incomplete knowledge of the world. In this work we are going to examine these limitations and invite scholars to become aware of them.