Guanosine Monophosphate Research Articles

Vinpocetine, a Phosphodiesterase Type 1 Inhibitor, Mitigates Locomotor Hyperactivity in Female Mice Exposed to Lead During Development

Background/Objectives Studies in rodents indicate that disruptions in both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways are involved in the development of hyperactive behavior. We examined whether vinpocetine, a phosphodiesterase type 1 inhibitor that enhances brain cAMP and cGMP levels, could mitigate locomotor hyperactivity in mice exposed to lead during early development. Methods Swiss mice were exposed to 90 ppm of lead in their drinking water throughout gestation and the first ten postnatal days. At postnatal day 10 (PN10), blood lead levels (BLLs) were about 30 µg/dL. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or a vehicle 4 h before the evaluation of locomotor activity in the open field. Results Lead-exposed males did not display differences in locomotor activity compared to controls, while lead-exposed females showed a significant increase in locomotion. Vinpocetine treatment significantly reversed the lead-induced hyperactivity in females. Conclusions These findings suggest that the cAMP and cGMP signaling pathways play a role in the hyperactivity induced by lead exposure.

Unveiling the interplay between soluble guanylate cyclase activation and redox signalling in stroke pathophysiology and treatment.

Soluble guanylate cyclase (sGC) stands as a pivotal regulatory element in intracellular signalling pathways, mediating the formation of cyclic guanosine monophosphate (cGMP) and impacting diverse physiological processes across tissues. Increased formation of reactive oxygen species (ROS) is widely recognized to modulate cGMP signalling. Indeed, oxidatively damaged, and therefore inactive sGC, contributes to poor vascular reactivity and more severe neurological damage upon stroke. However, the specific involvement of cGMP in redox signalling remains elusive. Here, we demonstrate a significant cGMP-dependent reduction of reactive oxygen and nitrogen species upon sGC activation under hypoxic conditions, independent of any potential scavenger effects. Importantly, this reduction is directly mediated by downregulating NADPH oxidase (NOX) 4 and 5 during reperfusion. Using an in silico simulation approach, we propose a mechanistic link between increased cGMP signalling and reduced ROS formation, pinpointing NF-κB1 and RELA/p65 as key transcription factors regulating NOX4/5 expression. In vitro studies revealed that p65 translocation to the nucleus was reduced in hypoxic human microvascular endothelial cells following sGC activation. Altogether, these findings unveil the intricate regulation and functional implications of sGC, providing valuable insights into its biological significance and ultimately therapeutic potential.

C-di-GMP phosphodiesterase ProE interacts with quorum sensing protein PqsE to promote pyocyanin production in Pseudomonas aeruginosa.

The universal bacterial second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) plays critical roles in regulating a variety of bacterial functions such as biofilm formation and virulence. The metabolism of c-di-GMP is inversely controlled by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs). Recently, increasing studies suggested that the protein-protein interactions between DGCs/PDEs and their partners appear to be a common way to achieve specific regulation. In this work, we showed that the PDE ProE can interact with PQS quorum sensing protein PqsE to regulate pyocyanin production in Pseudomonas aeruginosa. Our bacterial two-hybrid assay demonstrated that ProE directly interacts with PqsE, and isothermal titration calorimetry and surface plasmon resonance assay further confirmed that the binding affinity of ProE with PqsE is at micromolar level. Both ProE and PqsE negatively regulate intracellular c-di-GMP levels. Furthermore, our transcriptomic study showed that co-expression of ProE and PqsE significantly changes the gene expression profiles in P. aeruginosa, especially with increased expression of pyocyanin genes, and the qPCR and phenotypic results confirmed the transcriptome data. Taken together, our study suggested that the interaction between ProE and PqsE plays a critical role in regulation of pyocyanin production and highlights the importance of protein-protein interaction mediated c-di-GMP signaling in P. aeruginosa.IMPORTANCEc-di-GMP is pivotal in orchestrating various bacterial functions. In Pseudomonas aeruginosa, the nuanced balance of intracellular c-di-GMP is maintained by approximately 41 diguanylate cyclases (DGCs) and phosphodiesterases (PDEs). Emerging studies indicate that the c-di-GMP metabolic DGCs and PDEs may be involved in the signal transduction process by directly binding to the target protein, thus influencing downstream function. Despite their known importance, the precise functions of these proteins, especially their interacting partners, remain unclear. In this study, we identified that PQS quorum sensing system protein PqsE is a binding partner of c-di-GMP phosphodiesterase ProE; further analysis suggested that the ProE specifically interacts with PqsE to promote pyocyanin production. Our study extended the regulatory mechanism of the c-di-GMP signal transduction and quorum sensing in governing bacterial physiology.

Molecular mechanisms of angiotensin type 2 receptor-mediated nitric oxide pathway in angiotensin II-induced vasorelaxation: Roles of potassium channels.

A variety of biological functions is attributed to the renin-angiotensin system (RAS). One of them is regulating vascular tone through its final effector Angiotensin II (Ang II). Ang II action is mediated by the Angiotensin type 1 receptor (AT1-R) which plays a role in vasoconstriction, and Angiotensin type 2 receptor (AT2-R) which may result in vascular relaxation through the releasing of endothelium mediates relaxation factors such as Nitric Oxide (NO). Therefore, this study investigated the role of AT2-R in vasodilation after blocking the effect of AT1-R in the rat aorta. Furthermore, it is to determine whether or not Ang II through NO has a role in rat aorta dilation via using valsartan. For control isolated aortic rings were preincubated with Valsartan (AT1- R inhibitor) and then stimulated with angiotensin II dose-dependent. For treating aortic rings different blockers and inhibitors were used. Pd123177 (AT2- R inhibitor) (20 µM), an inhibitor of PKA H-89 (10 µM), eNOS inhibitor L-NAME (0.3 mM), with group of K channel blockers such as TEA (1 mM), 4-AP (1 mM), BaCl2 (1 mM), clotrimazole (0.03 mM) and GLIB (0.01 mM). Our analysis demonstrates vasodilation in aortic rings induced by Ang II after blocking ATI-R and this response was highly reliant on PKA/eNOS and cyclic guanosine monophosphate (cGMP). The data from this investigation provided evidence that Ca2 + activated K+ channels (KCa) and Voltage-dependent K channel (KV) mediated Ang II vasorelaxation. Finally, these results indicate that angiotensin II primarily induces dilatation AT2-R after inhibiting the angiotensin AT1 receptor through a cascade of signaling pathways involving many enzymes and plasma membrane protein channels.

Acid-Triggered Dual-Functional Hydrogel Platform for Enhanced Bone Regeneration.

Stem cell implantation holds promise for enhancing bone repair, but risks of pathogen transmission and malignant cell transformation should not be ignored. Compared to stem cell implantation, recruitment of endogenous stem cells to injured sites is more critical for in situ bone regeneration. In this study, based on the acidic microenvironment of bone injury, an HG-AA1:1-SDF-1α composite hydrogel with a dual-control intelligent switch function is developed by incorporating stromal cell-derived factor (SDF-1α), arginine carbon dots (Arg-CDs), and calcium ions (Ca2+) into the oxidized hyaluronic acid/gelatin methacryloyl (HG) hydrogel. The acidic microenvironment triggers the first switch (Schiff base bond is broken between HG-AA1:1 and SDF-1α) of HG-AA1:1-SDF-1α composite hydrogel to continuously release SDF-1α. Compared to the neutral (pH 7.4) media, the cumulative release of SDF-1α in acidic (pH 5.5) media is ≈2.5 times higher, which enhances the migration and recruitment of endogenous mesenchymal stem cells (MSCs). The recruited MSCs immediately initiate the second switch and metabolize Arg-CDs into the bioactive nitric oxide (NO) in the presence of Ca2+, activating NO/cyclic guanosine monophosphate (cGMP) signaling pathway to promote angiogenesis. Therefore, the engineered HG-AA1:1-SDF-1α composite hydrogel shows promising potential to achieve "coupling osteogenesis and angiogenesis" for bone regeneration.

Protective Effects of Monoacylglycerol Lipase Inhibition in Rats with Severe Acute Pancreatitis and Its Possible Mechanism.

In the context of gastrointestinal diseases, the role of monoacylglycerol lipase (MAGL) is significant. Therefore, the objective of this study was to examine the protective effects of MAGL inhibition using JZL184 in rat models of severe acute pancreatitis (SAP) and to explore its mechanism. In this study, a rat model of SAP was established, and the rats were divided into three groups for treatment: the Control group (CON), the SAP group (SAP), and the SAP group treated with JZL184 (JZL184). The serum levels of amylase (AMS), alanine aminotransferase (ALT), creatinine (Cr), nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and phosphodiesterase (PDE) were measured using enzyme-linked immunosorbent detection kits. The ascites volume was determined using the cotton ball weighing method. The levels of reactive oxygen species (ROS) were detected using the ROS Kit. Additionally, histological tissue changes were assessed through hematoxylin and eosin staining. The SAP group showed increased levels of AMS, ALT, Cr, ROS, and ascites volume compared to the CON group. Additionally, the SAP group exhibited congested and edematous lung and pancreatic tissues with inflammation. However, the JZL184 group, when compared to the SAP group, showed decreased levels of AMS, ALT, Cr, and ROS, reduced ascites volume, and significantly reduced lung tissue and pancreatic histopathology scores. In the NO/cGMP/PDE system, compared with the CON group, the levels of NO and PDE in the SAP group were higher and the levels of cGMP were lower. Compared with the SAP group, the JZL184 group decreased NO and PDE levels and increased cGMP levels. Indeed, the inhibition of MAGL with JZL184 has been found to have a protective effect on rats with SAP. Specifically, it has shown significant improvement in the pathological damage of lung and pancreatic tissues. Furthermore, JZL184 has also exhibited protective effects on the liver and kidney. The mechanism may be related to the effect of JZL184 on the NO/cGMP/ PDE signaling pathway.

Vericiguat improves cardiac remodelling and function in rats with doxorubicin-induced cardiomyopathy.

Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has been demonstrated effective in improving prognosis of patients with heart failure with reduced ejection fraction. However, there are limited data concerning the effect of vericiguat in patients with doxorubicin (DOX)-induced cardiomyopathy (DIC). In this study, we investigated the effects of vericiguat on cardiac structure and function in rats with DIC as well as their potential mechanisms of action. DIC rats were established by intraperitoneal injection of DOX (1mg/kg) twice a week for 6weeks, followed by intragastric administration of vericiguat 1mg/kg/day or an equal volume of normal saline for 8weeks. Cardiac histology and function, circulating levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP), nitric oxide (NO), and oxidative indices, as well as myocardial cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling, oxidative and apoptosis-associated protein were measured. Compared with the control group, rats treated with DOX exhibited significantly increased heart size, reduced systolic function and elevated plasma levels of NT-proBNP. Histological findings revealed myocardial cell atrophy, fibrosis and apoptosis. Vericiguat treatment effectively reversed DOX-induced cardiac remodelling and improved systolic function. Mechanistically, Vericiguat attenuated the inhibitory effects of DOX on the myocardial cGMP-PKG axis and nuclear factor erythroid 2-related factor 2 (Nrf2) protein, thereby alleviating oxidative stress and apoptosis. Vericiguat improved cardiac remodelling and contractile function in rats with DIC through upregulation of cGMP-PKG signalling and inhibition of oxidative stress and myocardial apoptosis.

Ratiometric luminescence detection of Bi(III) ions in water using a europium coordination polymer

A ratiometric luminescent probe for detecting Bi(III) in water using a functionalized Eu(III) coordination polymer was developed. The raw materials guanosine monophosphate (GMP), Eu(III), and 2,6-pyridine dicarboxylic acid (DPA) were used to synthesize the GMP-Eu-DPA polymer, which contained Eu(III) coordinated with GMP and DPA and gave red emission at a wavelength of 614 nm when excited at a wavelength of 282 nm. Adding Bi(III) decreased the intensity of luminescence of the GMP-Eu-DPA coordination polymer at 614 nm and caused a GMP–Bi complex that strongly luminesced at 373 nm under excitation at 282 nm to form. Under optimal conditions, the luminescence intensity ratio I 373/I 614 had a good linear relationship with the Bi(III) concentration in the range 1.0–230 μM, and the detection limit was low (0.6 μM). The dual emission reverse rate of change luminescent probe can eliminate environmental influences, making the proposed detection method highly selective. This method has been successfully used to detect Bi(III) in water samples.

Potential beneficial impacts of tadalafil on cardiovascular diseases.

Tadalafil is a selective phosphodiesterase type 5 (PDE5) inhibitor commonly used for the treatment of erectile dysfunction and benign prostatic hyperplasia. Its mechanism of action involves the inhibition of PDE5, leading to increased levels of nitric oxide and cyclic guanosine monophosphate in the corpus cavernosum, which facilitates smooth muscle relaxation. This article reviews studies using tadalafil in the treatment of cardiovascular diseases and emphasizes its potential advantages in conditions such as pulmonary arterial hypertension, atherosclerosis, coronary artery disease, myocardial infarction, heart failure, stroke, diabetic ulcers, and cardiomyopathy. Although tadalafil shows potential efficacy in treating cardiovascular disease, further experimental studies are needed to clarify its pharmacological effects on cardiovascular protection beyond PDE5 inhibition.

Modulation of Second Messenger Signaling in the Brain Through PDE4 and PDE5 Inhibition: Therapeutic Implications for Neurological Disorders.

Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer's, Parkinson's, and Huntington's diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions.

The Influence of Cell Isolation and Culturing on Natriuretic Peptide Receptors in Aortic Vascular Smooth Muscle Cells.

Vascular smooth muscle cell (SMC) relaxation by guanylyl cyclases (GCs) and cGMP is mediated by NO and its receptor soluble GC (sGC) or natriuretic peptides (NPs) ANP/BNP and CNP with the receptors GC-A and GC-B, respectively. It is commonly accepted that cultured SMCs differ from those in intact vessels. Nevertheless, cell culture often remains the first step for signaling investigations and drug testing. Previously, we showed that even popular reference genes changed dramatically after SMC isolation from aorta. Regarding NP receptors, a substantial amount of data relies on cell culture. We hypothesize that the NP/cGMP system in intact aortic tunica media differs from isolated and cultured aortic SMCs. Therefore, we studied isolation and culturing effects on the expression of NP receptors GC-A, GC-B, and NP clearance receptor (NPRC) compared to sGC. We investigated intact tunica media and primary SMCs from the longitudinal halves of the same rat aorta. GC activity was monitored by cyclic guanosine monophosphate (cGMP). In addition, we hypothesize that there are sex-dependent differences in the NP/cGMP cascade in both intact tissue and cultured cells. We, therefore, analyzed a male and female cohort. Expression was quantified by RT-qPCR comparing aortic media and SMCs with our recently validated reference gene (RG) small nuclear ribonucleoprotein 2 (U2). Only GC-A was stably expressed. In intact media, GC-A exceeded GC-B and NPRC. However, GC-B, NPRC, and sGC were dramatically upregulated in cultured SMCs of the same aortae different from the stable GC-A. The expression was mirrored by NP-induced GC activity. In cultured cells, changes in GC activity were delayed compared to receptor expression. Minor differences between both sexes could also be revealed. Thus, isolation and culture fundamentally alter the cGMP system in vascular SMCs with potential impact on drug testing and scRNAseq. Especially, the dramatic increase in the clearance receptor NPRC in culture might distort all physiological ANP, BNP, and CNP effects.

Study on the mechanism of regulating micromolar Fe utilization and promoting denitrification by guanosine monophosphate (GMP) based multi-signal functional material Hematin@Fe/GMP

A novel multi-signal functional material consisting of Hematin, Fe, and guanosine monophosphate (GMP) was successfully constructed (Hematin@Fe/GMP) to enhance denitrification efficiency based on the signal network regulation of electron transfer, micromolar Fe utilization, and microbial community. Hematin@Fe/GMP enhanced nitrate reduction rate by 2.33-fold with a 9.9 mg L-1 h-1 reduction rate. The mechanisms of accelerated denitrification were elaborated deeply from the electrochemical experiments, microbial metabolism activity, key enzyme activity, gene expression, and microbial community. Specifically, electrochemical experiments and X-ray photoelectron spectroscopy demonstrated that the released redox signal (Fe2+/Fe3+) promoted the increased redox substances (extracellular polymeric substances, cytochrome c, and riboflavin) to accelerate electron transfer efficiency. Metagenomic analysis suggested the released Fe utilization signal modulated siderophores genes (fhuB, fhuC, and fhuD) to promote the uptake and utilization of micromolar Fe, which was more conducive to synthesizing cytochrome c. Moreover, extracellular polymeric substances (EPS) stripping experiments demonstrated that the membrane-anchored cyt-c could shuttle in EPS and bind with Hematin@Fe/GMP to form an electrical conduit for accelerating denitrification efficiency. In inhibition experiments, Hematin@Fe/GMP could break down electron transfer barriers and restore/compensate for the electron transfer chain. Meanwhile, Hematin@Fe/GMP could restore the electrical signal disruption and synergize with the enriched signaling-capable microorganisms (Stutzerimonas and Thauera) to regulate quorum sensing. This research introduced multi-signal modulation of Hematin@Fe/GMP on denitrification and provided strategies for accelerating the biological transformation process and effectively utilizing micromolar Fe in practical applications.

Relationship between physicochemical properties, non-volatile substances, and microbial diversity during the processing of dry-cured Spanish mackerel.

To meet the demand of consumers for high-quality dry-cured fish. This study investigates the relationship between microbial diversity and the changes in physicochemical properties and non-volatile flavor compounds of dry-cured Spanish mackerel (DCSM) throughout the curing process. Our findings demonstrate that moisture content significantly decreased during curing, while NaCl generally increased. The nitrite level of 1.52mg/kg, meeting national safety standards. Additionally, there was a significant increase in hardness and chewiness. The synergistic effect of glutamic acid (Glu), alanine (Ala), and histidine (His) with inosine monophosphate (IMP), adenosine monophosphate (AMP) and guanosine monophosphate (GMP) enhanced the umami taste. Proteobacteria and Photobacteria are the main microorganisms of DCSM at the phylum and genus levels. Proteobacteria and Photobacteria are the main microorganisms of DCSM at the phylum and genus levels. Photobacterium, Moritella, and Pseudomonas were positively correlated with AMP, GMP, Ala, and Glu. And negatively correlated with nitrite and TBARS. These findings suggest that specific microorganisms positively influence the quality of DCSM through their metabolic activities. This research enhances our understanding of flavor formation mechanisms and provides critical insights for optimizing DCSM processing and quality control.

Construction of a circularly polarized luminescence sensor based on self-assembly of carbon dots and G-quartet chiral nanofibers.

Circularly polarized luminescence (CPL) is a fascinating luminescence phenomenon that has garnered significant research attention for chiroptical applications. In this study, we developed a highly sensitive chiroptical sensor by co-assembling G-quartet nanofibers and nonchiral nitrogen sulfur-doped carbon dots (N-S-CDs) for dual ion detection. The N-S-CDs were synthesized using the one-step microwave method, and a helical G-quartet-based nanofiber structure (g-fiber) was simultaneously formed from guanosine 5'-monophosphate (GMP) in the presence of Sr2+. An adjustable helical G-quartet-based nanofiber provided an optimal chiral environment for CPL emission, with a dissymmetry factor (glum) reaching ±0.02. Notably, the left-handed (L-) and right-handed (R-) helical chirality of the complex was determined by switching between kinetic trap states and thermodynamic equilibrium during the reaction process. An optimized CPL sensor was developed based on chiral CDs/g-fiber composite materials, utilizing sensitive CPL as the signal output of dual detection for Hg2+ and I-. Similar limits of detection (LODs) were achieved for both L-/R-nanocomposites, with the best results being 83.5 nM for Hg2+ and 142.8 nM for I-. These values are comparable with or even better than those obtained with other optical analytical methods. Since CPL biosensors are relatively rare to date, our work presents a new horizon for the application of chiral CPL composites in biological assays.

The difference between young and older ducks: Amino acid, free fatty acid, nucleotide compositions and breast muscle proteome.

Duck meat has a unique taste and nutritional value, but age probably affects meat quality. In this study, ducks of different ages (60-day-old, D60; 900-day-old, D900) were chosen, and the odor, taste, amino acid, nucleotide, and free fatty acid components of breast meat were evaluated to investigate the differences. The results showed that the amino acid contents of breast muscle in D900 ducks, especially in Asp (umami) and Thr (sweet), were richer than those in D60 ducks. In addition, the levels of guanosine-5'-monophosphate (GMP), inosine-5'-monophosphate (IMP), monounsaturated fatty acid (MUFA; C18:1t), and polyunsaturated fatty acid (PUFA; C18:2) in D900 ducks were higher than those in D60 ducks. Proteomic approach was further performed to analyze the difference of breast muscle between young and older ducks in protein level. We found that 496 differentially expressed proteins (DEPs) were screened. GO and KEGG analysis mainly enriched in glycine, serine, and threonine metabolism, tyrosine metabolism, and pyruvate metabolism. Moreover, correlation analysis revealed that BPGM, ADH5, ME2, ME3, GLO1, and PDHB, were specifically correlated with amino acids, nucleotides, and free fatty acids in meat from D60 ducks, whereas only two proteins, GRHPR and COMT, showed specific correlations with amino acids, nucleotides, and free fatty acids in meat from D900 ducks. This study proposes several candidate protein biomarkers for older duck meat that should be evaluated in the future.

Soluble guanylyl cyclase stimulators and activators: promising drugs for the treatment of hypertension?

Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD.The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand.In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.

HDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAFV600E-mutant microsatellite stable colorectal cancer

BackgroundB-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF...

Understanding the structural and functional diversity of ATP-PPases using protein domains and functional families in the CATH database.

ATP-pyrophosphatases (ATP-PPases) are the most primordial lineage of the large and diverse HUP (high-motif proteins, universal stress proteins, ATP-pyrophosphatase) superfamily. There are four different ATP-PPase substrate-specificity groups (SSGs), and members of each group show considerable sequence variation across the domains of life despite sharing the same catalytic function. Owing to the expansion in the number of ATP-PPase domain structures from advances in protein structure prediction by AlphaFold2 (AF2), we have characterized the two most populated ATP-PPase SSGs, the nicotinamide adenine dinucleotide synthases (NADSs) and guanosine monophosphate synthases (GMPSs). Local structural and sequence comparisons of NADS and GMPS identified taxonomic-group-specific functional motifs. As GMPS and NADS are potential drug targets of pathogenic microorganisms including Mycobacterium tuberculosis, bacterial GMPS and NADS specific functional motifs reported in this study, may contribute to antibacterial-drug development.

Structure-based method for the discovery of selective inhibitors of PED 5 in erectile dysfunction therapy from the Pacific oyster peptides (Crassostrea gigas): Peptidomic analysis, molecular docking, and activity validation.

Erectile dysfunction (ED) is a male sexual disorder mainly caused by a reduction in the cellular concentration of cyclic guanosine monophosphate (cGMP), which is degraded by phosphodiesterase type-5 (PDE-5). Oyster protein (OP) and its hydrolysates have been used for centuries to address male erectile dysfunction, however the mechanisms and evidence supporting their efficacy remain unclear. In this study, OP was hydrolyzed using trypsin to produce peptides that inhibit PDE-5. Following separation by ultrafiltration and Sephadex G-25, a total of 3202 peptides were identified. Virtual screening and molecular docking were employed to identify PDE-5 inhibitory peptides and elucidate their interaction mechanisms with PDE-5. Five peptides with the sequences FLF, LMF, LLW, FGPF, and IPW demonstrated strong interactions with PED5. The results indicated that the key binding sites critical for docking included Phe820, Gln817 and Val782 of the target receptor PED-5. The highest inhibition rate observed for FGPF was 94.6 %, while the inhibition rates for IPW and FLF were 89.0 % and 87.6 %, respectively. The lowest inhibition rate was recorded for LLW at 68 %. These findings suggest that these five peptides have the potential to serve as PDE-5 inhibitors in the health food industry and medicine.

A Clinical Study to Evaluate the Anti-inflammatory Effect of Lactoferrin + Disodium Guanosine Monophosphate Therapy in the Patients with Chronic Kidney Disease.

India is impacted by the increasing burden of chronic kidney disease (CKD) and end-stage renal disease (ESRD), necessitating efficient management and therapy. CKD is characterized by elevated levels of inflammatory biomarkers, specifically IL-1β, IL-1RA, IL-6, TNF-α, TGF-β, and fibrinogen. The aim of this research is to determine the antiinflammatory effects of lactoferrin + disodium guanosine monophosphate therapy in CKD patients. The objective of this study is to examine the efficacy of this therapy versus conservative CKD management alone in reducing inflammation. This study intends to examine the possible benefits of study drug in treating inflammation associated with CKD by analyzing its effect on inflammatory markers including IL-6 and TNF-α. This randomized, open-label, parallel group, two-arm clinical study, comprising of 40 patients with CKD, with 20 patients in each group. The groups were well-matched in terms of demographic characteristics. Conception, screening, randomization, and follow-up visits including physical examinations, laboratory investigations, and medication dispensation were all carried out over a 29-week period. Creatinine clearance, estimated glomerular filtration rate (eGFR), estimated urine urea nitrogen, and inflammatory markers (IL-6, IL-10, TNF-α, CRP) were analyzed at time of screening and at 3 and 6-month postrandomization. The study found a significant decrease in inflammatory markers, including TNF-α, IL-6, and IL-10, in the group receiving study drug, indicating its potential as an antiinflammatory intervention for managing CKD. Secondary endpoints, including hemoglobin (Hb) and e-GFR levels, showed nonsignificant improvements in the study group compared to the control group. No significant adverse events were reported during the study. The study highlights the potential antiinflammatory effects of the lactoferrin + disodium guanosine monophosphate therapy in individuals with CKD. The findings suggest that study drug may be a viable intervention for managing inflammation in CKD patients. Further research is needed to validate these results and explore its long-term effects in CKD management.