Glucocorticoid receptors orchestrate a convergence of host and cellular stress signals in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the nuclear steroid receptors that bind estrogens (ER) and progestogens (PRs) and does not exhibit HER2 (Human epidermal growth factor 2) receptor overexpression. Even in the face of initially effective chemotherapies, TNBC patients often relapse. One primary cause for therapy-resistant tumor progression is the activation of cellular stress signaling pathways. The glucocorticoid receptor (GR), a corticosteroid-activated transcription factor most closely related to PR, is a mediator of both endocrine/host stress and local tumor microenvironment (TME)-derived and cellular stress responses. Interestingly, GR expression is associated with a good prognosis in ER+ breast cancer but predicts poor prognosis in TNBC. Classically, GR's transcriptional activity is regulated by circulating glucocorticoids. Additionally, GR is regulated by ligand-independent signaling events. Notably, the stress-activated protein kinase, p38 MAP kinase, phosphorylates GR at serine 134 (Ser134) in response to TME-derived growth factors and cytokines, including HGF and TGFß1. Phospho-Ser134-GR (p-Ser134-GR) associates with cytoplasmic and nuclear signaling molecules, including 14-3-3ζ, aryl hydrocarbon receptors (AhR), and hypoxia-inducible factors (HIFs). Phospho-GR/HIF-containing transcriptional complexes upregulate gene sets whose protein products include the components of inducible oncogenic signaling pathways (PTK6) that further promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC. Recent studies have implicated liganded p-Ser134-GR (p-GR) in dexamethasone-mediated upregulation of genes related to TNBC cell motility and dysregulated metabolism. Herein, we review the tumor-promoting roles of GR and discuss how both ligand-dependent and ligand-independent/stress signaling-driven inputs to p-GR converge to orchestrate metastatic TNBC progression.

Bitter Taste Receptor 46 (hTAS2R46) Protects Monocytes/Macrophages from Oxidative Stress.

Bitter taste receptors (TAS2Rs) are not only responsible for taste perception in the oral cavity, but are spread throughout the body, generating a widespread chemosensory system. In humans, 25 subtypes have been identified and are differentially expressed in tissues and organs, including in the immune system. In fact, several TAS2R subtypes have been detected in neutrophils, lymphocytes, B and T cells, NK cells, and monocytes/macrophages, in which they regulate various protective functions of the innate immune system. Given its recognized anti-inflammatory and antioxidant activity, and the generally protective role of bitter taste receptors, in this work, we studied TAS2R46's potential in the protection of human monocyte/macrophage DNA from stress-induced damage. Through both direct and indirect assays and a single-cell gel electrophoresis assay, we demonstrated that absinthin, a specific TAS2R46 agonist, counteracts the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and reduces DNA damage in both cell types. Even though the release of ROS from monocytes/macrophages is fundamental for contrast pathogen agents, supraphysiological ROS production impairs their function, finally leading to cell death. Our results highlight TAS2R46 as a novel player involved in the protection of monocytes and macrophages from oxidative stress damage, while simultaneously supporting their antimicrobial activity.

Association of polymorphisms within P2RX4 with type 2 diabetes mellitus: a preliminary case-control study.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a complex heterogenic metabolic with a wide range of etiology. Purinergic receptors have pivotal roles in different processes and are hypothesized to have roles in the pathogenesis of T2DM. MATERIALS AND METHODS: Three hundred subjects affected by T2DM and 300 healthy subjects were genotyped by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). SPSS V16.0 was recruited for statistical analysis. RESULTS: The findings showed that the G allele of rs25644A > G increases the risk of T2DM in our population statistically (OR = 1.51, 95% CI = 1.14-1.99, p = 0.003). This allele in some genotype models, including the dominant model, caused an increase in the risk of T2DM. The interaction of genotypes between studied variants in the P2XR4 gene increased the risk of T2DM. Haplotype analysis showed that Ars1169727/Grs25644 haplotype caused an increase in the risk of T2DM. CONCLUSIONS: The findings suggest that rs25644A > G plays a role in our population's increased risk of T2DM.

An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II.

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and crosslinking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.

Δ 9 -Tetrahydrocannabinol alleviates hyperalgesia in a humanized mouse model of sickle cell disease.

People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of Δ9-tetrahydrocannabinol (THC), cannabis' intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1-3 mg-kg-1, intraperitoneal, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in HbSS, but not HbAA mice. In the tail-flick assay, THC (1 and 3 mg-kg-1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg-kg-1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-h novel object recognition). Subchronic THC treatment (1 and 3 mg-kg-1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. Significance Statement The study explores THC's efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC's potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.

Cannabinoid 2 receptor activation protects against diabetic cardiomyopathy through inhibition of AGE/RAGE-induced oxidative stress, fibrosis, and inflammasome activation.

Oxidative stress, fibrosis, and inflammasome activation from AGE-RAGE interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of ß-caryophyllene (BCP) on activating CB2 receptors against diabetes complications and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dosage of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance, insulin resistance, and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and SERCA2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NOX4 and activating PI3K/AKT/Nrf2 signaling. BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition (EndMT) in DCM mice by inhibiting TGF-ß/Smad signaling. Further, BCP treatment suppressed NLRP3 inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate CB2 receptor dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2 receptor antagonist AM630 and AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP showed the potential to protect the myocardium and pancreas of DCM mice mediating CB2 receptor dependent mechanisms. Significance Statement 1. ß-caryophyllene (BCP), a cannabinoid type 2 receptor (CB2R) agonist. 2. BCP attenuates diabetic cardiomyopathy via activating CB2R in mice 3. CB2R activation by BCP shows strong protection against fibrosis and inflammasome activation 4. It regulates AGE/RAGE and PI3K/Nrf2/Akt signaling in mice.

International Union of Basic and Clinical Pharmacology. CXV: The Class F of G Protein-Coupled Receptors.

The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD1-10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched (PTCH). The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to a rapid development of our knowledge about structure-function relationships providing a great starting point for drug development. Despite the progress questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. Significance Statement The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds.

The Effect of A2 Milk on Gastrointestinal Symptoms in Comparison to A1/A2 Milk: A Single-center, Randomized, Double-blind, Cross-over Study.

ß-Casein, a major protein in cow's milk, is divided into the A1 and A2 type variants. Digestion of A1 ß-casein yields the peptide ß-casomorphin-7 which could cause gastrointestinal (GI) discomfort but A2 milk containing only A2 ß-casein might be more beneficial than A1/A2 (regular) milk. The aim of this study was to evaluate the differences in GI discomfort after ingestion of A2 milk and A1/A2 milk. A randomized, double-blind, cross-over human trial was performed with 40 subjects who experienced GI discomfort following milk consumption. For each intervention period, either A2 milk first (A2→A1/A2) or A1/A2 milk was first consumed for 2 weeks (A1/A2→A2) following a 2-week washout period. GI symptom rating scale (GSRS) scores, questionnaire for digestive symptoms, and laboratory tests including fecal calprotectin were evaluated. For symptom analysis, generalized estimating equations gamma model was used. A2 milk increased bloating (P = 0.041) and loose stools (P = 0.026) compared to A1/A2 milk in GSRS. However, A2 milk caused less abdominal pain (P = 0.050), fecal urgency (P < 0.001) and borborygmus (P = 0.007) compared to A1/A2 milk in questionnaire for digestive symptoms. In addition, fecal calprotectin also decreased or less increased after consumption of A2 milk compared to A1/A2 milk (P = 0.030), and this change was more pronounced in males (P = 0.005) than in females. There were no significant adverse reactions during the trial. A2 milk alleviated digestive discomfort in Koreans following A2 milk consumption (ClinicalTrials.gov NCT06252636 and CRIS KCT0009301).

Sphingosine-1-phosphate signalling in the heart: exploring emerging perspectives in cardiopathology.

Cardiometabolic disorders contribute to the global burden of cardiovascular diseases. Emerging sphingolipid metabolites like sphingosine-1-phosphate (S1P) and its receptors, S1PRs, present a dynamic signalling axis significantly impacting cardiac homeostasis. S1P's intricate mechanisms extend to its transportation in the bloodstream by two specific carriers: high-density lipoprotein particles and albumin. This intricate transport system ensures the accessibility of S1P to distant target tissues, influencing several physiological processes critical for cardiovascular health. This review delves into the diverse functions of S1P and S1PRs in both physiological and pathophysiological conditions of the heart. Emphasis is placed on their diverse roles in modulating cardiac health, spanning from cardiac contractility, angiogenesis, inflammation, atherosclerosis and myocardial infarction. The intricate interplays involving S1P and its receptors are analysed concerning different cardiac cell types, shedding light on their respective roles in different heart diseases. We also review the therapeutic applications of targeting S1P/S1PRs in cardiac diseases, considering existing drugs like Fingolimod, as well as the prospects and challenges in developing novel therapies that selectively modulate S1PRs.

Systematic review and meta-analyses of cytisine to support tobacco cessation.

BACKGROUND AND AIMS: Cytisine (also known as cytisinicline) is a low-cost partial agonist of nicotinic acetylcholine receptors used to assist tobacco cessation. We aimed to review the effectiveness of cytisine for tobacco cessation and the effects of dose and co-use of behavioural or other pharmacological interventions on cessation outcomes. METHODS: We searched seven databases, Google Scholar, and reference lists of included publications for randomised controlled trials investigating use of cytisine as a tobacco cessation aid. Studies were eligible if participants were ≥15 years old and used tobacco upon study enrolment. We conducted four random effects meta-analyses and sensitivity analyses with fixed effects models. We used the Cochrane risk-of-bias tool for randomised trials version 2 to assess risk of bias in included studies, with adjustments recommended by the Cochrane Tobacco Addiction Group. RESULTS: Participants using cytisine were significantly more likely to quit tobacco than participants who received placebo/no intervention/usual care (risk ratio [RR] = 2.65, 95% confidence interval [CI] = 1.50-4.67, 6 trials, 5194 participants) or nicotine replacement therapy (RR = 1.36, 95% CI = 1.06-1.73, p = 0.0152, 2 trials, 1511 participants). The difference in cessation rates among participants receiving cytisine versus varenicline was not statistically significant (RR = 0.96, 95% CI 0.63-1.45, P = 0.8464, 3 trials, 2508 participants). Two trials examined longer versus shorter treatment duration, finding higher abstinence rates with longer treatment (RR = 1.29, 95% CI = 1.02-1.63, 2 trials, 1009 participants). The differences in the number of adverse events reported by participants who received cytisine versus placebo (RR = 1.19, 95% CI = 0.99-1.41, P = 0.0624; 6 trials; 4578 participants) or cytisine versus varenicline (RR = 1.37, 95% CI = 0.57-3.33, P = 0.4835; 2 trials; 1345 participants) were not statistically significant. Most adverse events were mild (e.g. abnormal dreams, nausea, headaches). CONCLUSIONS: Cytisine is an effective aid for tobacco cessation and appears to be more effective for tobacco cessation than placebo, no intervention, usual care and nicotine replacement therapy.

Mouse Models in Circadian Rhythm and Melatonin Research.

This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron-like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal-brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re-entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT-intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin-proficient strains are suited to investigate the circadian and melatoninergic systems.

A protocol to isolate, identify, and verify glucose- or carbohydrate-binding receptors.

Sensing, transport, and utilization of glucose is pivotal to the maintenance of energy homeostasis in animals. Although transporters involved in mobilizing glucose across different cellular compartments are fairly well known, the receptors that bind glucose to mediate its effects independently of glucose metabolism remain largely unrecognized. Establishing precise and reproducible methods to identify glucose receptors in the brain or other peripheral organs will pave the way for comprehending the role of glucose signaling pathways in maintaining, regulating, and reprogramming cellular metabolic needs. Identification of such potential glucose receptors will also likely lead to development of effective therapeutics for treatment of diabetes and related metabolic disorders. Commercially available biotin or radiolabeled glucose conjugates have low molecular weight; therefore, they do not provide enough sensitivity and density to isolate glucose receptors. Here, we describe a protocol to isolate, identify, and verify glucose-binding receptor/s using high molecular weight glucose (or other carbohydrate) conjugates. We have produced 30 kDa glucose- (or other carbohydrate-) biotin-polyacrylamide (PAA) conjugates with mole fractions of 80:5:15% respectively. These conjugates are used with biotin-streptavidin biochemistry, In-cell ELISA, and surface plasmon resonance (SPR) methods to isolate, identify, and verify glucose- or carbohydrate-binding receptors. We first demonstrate how streptavidin-coated magnetic beads are employed to immobilize glucose-biotin-PAA conjugates. Then, these beads are used to enrich and isolate glucose-binding proteins from tissue homogenates or from single-cell suspensions. The enriched or isolated proteins are subjected to mass spectrometry/proteomics to reveal the identity of top candidate proteins as potential glucose receptors. We then describe how the In-cell ELISA method is used to verify the interaction of glucose with its potential receptor through stable expression of the receptor in-vitro. We further demonstrate how a highly sensitive SPR method can be used to measure the binding kinetics of glucose with its receptor. In summary, we describe a protocol to isolate, identify, and verify glucose- or carbohydrate-binding receptors using magnetic beads, In-cell ELISA, and SPR. This protocol will form the future basis of studying glucose or carbohydrate receptor signaling pathways in health and in disease.

Increase Toll-like receptors 2 and 4 in apical periodontitis of rats with chronic liver disease.

The aim of this study was to evaluate the influence of liver fibrosis (LF) on the expression of Toll-like receptors (TLR) 2 and 4 in apical periodontitis (AP) in Wistar rats. Forty Wistar rats were allocated in the following groups (n = 10): C-control; AP-apical periodontitis; LF-liver fibrosis; AP + LF-rats with AP and LF. LF and AP were induced by established methodologies. Histological, bacteriological, and immunohistochemical analyses were performed according to pre-established scores. For comparisons between AP and AP + LF groups, the Mann-Whitney test was used (P < .05). The livers of the LF and AP + LF groups showed generalized portal inflammatory infiltrate and collagen fibers confirming the presence of LF. Histopathological analysis in the maxilla of the AP + LF group showed areas of necrosis comprising the entire dental pulp and periapical tissue surrounded by a more intense inflammatory infiltrate than observed in the AP group (P = 0.032). A significant number of specimens in the AP + LF group showed microorganisms beyond the apical foramen adhered to the extraradicular biofilm, demonstrating greater invasion compared to the AP group (P = .008). Immunohistochemical analysis showed a large number of cells immunoreactive for TLR2 and TLR4 in the AP + LF group, compared to the AP group (P < 0.05). Liver fibrosis favors the inflammation and contamination of microorganisms in apical periodontitis and triggers the expression of TLR2 and TLR4, modulating innate immunity response in periapical lesions.

Type 2 severe asthma: pathophysiology and treatment with biologics.

INTRODUCTION: The hallmark of most patients with severe asthma is type 2 inflammation, driven by innate and adaptive immune responses leading to either allergic or non-allergic eosinophilic infiltration of airways. The cellular and molecular pathways underlying severe type 2 asthma can be successfully targeted by specific monoclonal antibodies. AREAS COVERED: This review article provides a concise overview of the pathophysiology of type 2 asthma, followed by an updated appraisal of the mechanisms of action and therapeutic efficacy of currently available biologic treatments used for management of severe type 2 asthma. Therefore, all reported information arises from a wide literature search performed on PubMed. EXPERT OPINION: The main result of the recent advances in the field of anti-asthma biologic therapies is the implementation of a personalized medicine approach, aimed to achieve clinical remission of severe asthma. Today this accomplishment is made possible by the right choice of the most beneficial biologic drug for the pathologic traits characterizing each patient, including type 2 severe asthma and its comorbidities.

Class B1 GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease.

The secretin-like, class B1 sub-family of seven transmembrane-spanning G protein coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and utilize a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via a large N-terminal extracellular domain that forms a hydrophobic ligand binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogues of several class B1 ligands for therapeutic use. Among the most successful of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multi-functional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of poly-pharmacologic ligands. Further, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complex with either native ligands or multi-functional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

TurboID-mediated proximity labeling technologies to identify virus co-receptors.

Virus receptors determine the tissue tropism of viruses and have a certain relationship with the clinical outcomes caused by viral infection, which is of great importance for the identification of virus receptors to understand the infection mechanism of viruses and to develop entry inhibitor. Proximity labeling (PL) is a new technique for studying protein-protein interactions, but it has not yet been applied to the identification of virus receptors or co-receptors. Here, we attempt to identify co-receptor of SARS-CoV-2 by employing TurboID-catalyzed PL. The membrane protein angiotensin-converting enzyme 2 (ACE2) was employed as a bait and conjugated to TurboID, and a A549 cell line with stable expression of ACE2-TurboID was constructed. SARS-CoV-2 pseudovirus were incubated with ACE2-TurboID stably expressed cell lines in the presence of biotin and ATP, which could initiate the catalytic activity of TurboID and tag adjacent endogenous proteins with biotin. Subsequently, the biotinylated proteins were harvested and identified by mass spectrometry. We identified a membrane protein, AXL, that has been functionally shown to mediate SARS-CoV-2 entry into host cells. Our data suggest that PL could be used to identify co-receptors for virus entry.

The Relationship between Muscarinic and Cannabinoid Receptors in Neuronal Excitability and Epilepsy: A Review.

Background: Of the seventy million people who suffer from epilepsy, 40 percent of them become resistant to more than one antiepileptic medication and have a higher chance of death. While the classical definition of epilepsy was due to the imbalance between excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic signalling, substantial evidence implicates muscarinic receptors in the regulation of neural excitability. Summary: Cannabinoids have shown to reduce seizure activity and neuronal excitability in several epileptic models through the activation of muscarinic receptors with drugs which modulate their activity. Cannabinoids also have been effective in reducing antiepileptic activity in pharmaco-resistant individuals; however, the mechanism of its effects in temporal lobe epilepsy is not clear. Key Messages: This review seeks to elucidate the relationship between muscarinic and cannabinoid receptors in epilepsy and neural excitability.

Using the sympathetic system, beta blockers and alpha-2 agonists, to address acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) manifests as an acute inflammatory lung injury characterized by persistent hypoxemia, featuring a swift onset, high mortality, and predominantly supportive care as the current therapeutic approach, while effective treatments remain an area of active investigation. Adrenergic receptors (AR) play a pivotal role as stress hormone receptors, extensively participating in various inflammatory processes by initiating downstream signaling pathways. Advancements in molecular biology and pharmacology continually unveil the physiological significance of distinct AR subtypes. Interventions targeting these subtypes have the potential to induce specific alterations in cellular and organismal functions, presenting a promising avenue as a therapeutic target for managing ARDS. This article elucidates the pathogenesis of ARDS and the basic structure and function of AR. It also explores the relationship between AR and ARDS from the perspective of different AR subtypes, aiming to provide new insights for the improvement of ARDS.

GSH-responsive and folate receptor-targeted pyridine bisfolate-encapsulated chitosan nanoparticles for enhanced intracellular drug delivery in MCF-7 cells.

Folic acid receptor-targeted drug delivery system is a promising candidate for tumor-targeted delivery because its elevated expression specifically on tumor cells enables the selective delivery of cytotoxic cargo to cancerous tissue, thereby minimizing toxic side effects and increasing the therapeutic index. Pyridine bisfolate-chitosan (PyBFA@CS NPs) and folate-chitosan nanocomposite (FA@CS NPs) were synthesized with suitable particle size (256.0 ± 15.0 and 161.0 ± 5.0 nm), high stability (ζ = -27.0 ± 0.1 and -30.0 ± 0.2 mV), respectively, and satisfactory biocompatibility to target cells expressing folate receptors and try to answer the question: Is the metal center always important for activity? Since almost all pharmaceuticals work by binding to specific proteins or DNA, the in vitro binding of human serum albumin (HSA) to PyBFA@CS NPs and FA@CS NPs has been investigated and compared with PyBFA. Strong affinity to HSA is shown by quenching and binding constants in the range of 105 and 104 M-1, respectively with PyBFA@CS NPs showing the strongest. The compounds-HSA kinetic stability, affinity, and association constants were investigated using a stopped-flow method. The findings showed that all formulations bind by a static quenching mechanism that consists of two reversible steps: rapid second-order binding and a more slowly first-order isomerization reaction. The overall coordination affinity of HSA to PyBFA@CS NPs (6.6 × 106 M-1), PyBFA (4.4 × 106 M-1), and FA@CS NPs (1.3 × 106 M-1) was measured and The relative reactivity is roughly (PyBFA@CS NPs)/(PyBFA)/(FA@CS NPs) = 5/3/1. Additionally, in vitro cytotoxicity revealed that, consistent with the binding constants and coordination affinity, active-targeting formulations greatly inhibited FR-positive MCF-7 cells in compared to FRs-negative A549 cells in the following trend: PyBFA@CS NPs > PyBFA > FA@CS NPs. Furthermore, in vitro drug release of PyBFA@CS NPs was found to be stable in PBS at pH 7.4, however, the in pH 5.4 and in pH 5.4 containing 10 mM glutathione (GSH) (mimicking the tumor microenvironment) reached 43 % and 73 %, respectively indicating that the PyBFA@CS NPs system is sensitive to GSH. Folate-modified nanoparticles, PyBFA@CS NPs, are a promising therapeutic for MCF-7 therapy because they not only showed a greater affinity for HSA, but also showed higher cleavage efficiency toward the minor groove of pBR322 DNA via the hydrolytic way, as well as effective antibacterial activity that avoids the usage of extra antibiotics.‬‬‬‬‬‬‬‬‬‬‬‬ ‬‬‬‬‬‬‬‬‬‬‬‬‬‬.