Cyclic Monophosphate Research Articles

Discovery of Selenium-Containing Derivatives as Potent and Orally Bioavailable GLP-1R Agonists.

Glucagon-like peptide-1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. The development of orally bioavailable and long-acting small-molecule GLP-1R agonists is a pursuit in both academia and industry. Herein, new selenium (Se)-containing compounds were designed using a Se-oxygen bioisostere strategy on the danuglipron scaffold. Among these, compound 21 was orally bioavailable and exhibited full agonistic efficacy in promoting cyclic adenosine monophosphate (cAMP) accumulation. In hGLP-1R knock-in mice, 21 effectively reduced blood glucose levels and food intake, with the duration of action slightly extended compared to that of danuglipron. Importantly, no significant adverse effects were observed in mice treated with 21 during the subacute toxicity studies. This study delineates the potential of Se-containing compounds as orally bioavailable GLP-1R agonists, with compound 21 emerging as a promising candidate for T2DM and obesity treatment.

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.

Connecting dots: Preclinical foundations to clinical realities of PDE4 inhibitors in Alzheimer's disease.

Alzheimer's Disease (AD), a progressive and age-associated neurodegenerative disorder, is primarily characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Despite advances in targeting Aβ-mediated neuronal damage with anti-Aβ antibodies, these treatments provide only symptomatic relief and fail to address the multifactorial pathology of the disease. This necessitates the exploration of novel therapeutic approaches and a deeper understanding of molecular signaling mechanisms underlying AD. Phosphodiesterases (PDEs), particularly Phosphodiesterase 4 (PDE4), play a pivotal role in regulating cyclic adenosine monophosphate (cAMP), a key molecule involved in memory consolidation and cognitive function. PDE4 inhibitors have demonstrated potential in enhancing memory and cognition in preclinical models of AD by modulating cAMP signaling. However, their clinical translation has been limited due to challenges such as adverse effects, narrow therapeutic windows, and low specificity in mechanism of action. This review bridges the gap between preclinical discoveries and clinical applications of PDE4 inhibitors in AD. It highlights preclinical evidence supporting the neuroprotective and anti-inflammatory effects of PDE4 inhibitors while addressing challenges in their clinical development, including issues of safety, efficacy, and disease-specific targeting. By integrating findings from both preclinical and clinical studies, we provide a comprehensive understanding of the therapeutic potential of PDE4 inhibitors in AD. Furthermore, this review outlines future research directions aimed at optimizing PDE4 inhibition strategies for AD treatment, offering a roadmap to translate foundational insights into clinical realities.

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.

Tandem GGDEF-EAL Domain Proteins Pleiotropically Modulate c-di-GMP Metabolism Enrolled in Bacterial Cellulose Biosynthesis.

Cyclic diguanosine monophosphate (c-di-GMP) is a crucial secondary messenger that regulates bacterial cellulose (BC) synthesis. It is synthesized by diguanylate cyclase (DGC) containing a Gly-Gly-Asp/Glu-Glu-Phe (GGDEF) domain and degraded by phosphodiesterase (PDE) with a Glu-Ala-Leu (EAL) domain. In this work, a systematic analysis of ten GGDEF-EAL tandem domain proteins from Komagataeibacter xylinus CGMCC 2955 assessed their c-di-GMP metabolic functions and effects on BC titer and structure. Of these, five proteins exhibited DGC activity, and five exhibited PDE activity in vitro. GE03 was identified as a bifunctional protein. Most mutant strains deficient in GGDEF-EAL protein showed changes in BC metabolism, motility, and c-di-GMP levels. The combined knockout of identified PDE proteins increased the BC titer by 48.1% compared to the wild type. Overall, our findings advance our understanding of c-di-GMP signaling and its role in BC synthesis, introducing novel concepts and effective strategies for enhancing industrial BC production.

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.

Thymol and Carvacrol as Potential Tocolytic and Anti-inflammatory Agents in Pregnant Rat Uterus.

This work aimed to evaluate the anti-inflammatory and myorelaxant effect of thymol (TM) and carvacrol (CAR) in the pregnant rat uterus. Both compounds exhibit considerable antimicrobial, antispasmodic, and anti-inflammatory effects and due to these properties, they were studied in this in vitro model of premature birth induced by infection. All uterine tissues were studied in uterine contraction tests to determine the inhibitory effect of TM, CAR (10, 56, 100, 150, and 230 μM), and nifedipine (a calcium channel antagonist) on phasic and tonic contraction induced by electro- and pharmacomechanical stimuli. The quantitative determination of cyclic adenosine monophosphate (cAMP) induced by TM and CAR in the uterine lysate was carried out by ELISA. For the determination of the anti-inflammatory effect of TM, the pro-inflammatory cytokine, interleukin (IL)-1β, in uterine samples stimulated with lipopolysaccharide (LPS) was measured. Forskolin (FSK) was used as a positive control to evaluate the cAMP and cytokine levels. TM, CAR, and nifedipine inhibited the uterine contractions at the highest concentration level, however, nifedipine was the most equipotent (p<0.05). In addition, TM and CAR did not increase the intracellular cAMP production in comparison with FSK (p<0.05). However, both compounds were able to decrease the LPS-induced production in a concentration-dependent manner that was considered statistically significant (p>0.05). Finally, both the anti-inflammatory and uterine relaxing effects induced by TM and CAR were neither associated with the increase in cAMP levels nor with the production of IL-1β in pregnant rat uterine samples. Therefore, TM and CAR can be considered as alternative adjuvants for the treatment of infection-induced preterm labor. Before the in vitro experiments, an in-silico analysis was conducted using the Expaisy online server to evaluate the biological effects of thymol on uterine contraction. It is crucial to know the interaction and identification of genes encoding the Voltage-dependent L-type calcium channel subunit alpha-1C proteins, because of the functional relationship it may have in the inhibition of the uterine contraction. These properties place TM as a potentially safe and effective adjuvant agent in cases of preterm birth, an area of pharmacological treatment that requires urgent improvement.

Stimulator of Interferon Genes Signal in Lung Cancer Regulates Differentiation of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment Via the Interferon Regulatory Factor 3/NF-κB Pathway.

Background: This study was designed to explore the action mechanism of stimulator of interferon genes (STING) on the differentiation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment of lung cancer. Methods: Bioinformatics analysis yielded a potential pathway for STING to regulate MDSC differentiation, the interferon regulatory factor 3 (IRF3)/NF-κB axis. The transfection efficiency of STING overexpression plasmid and small interfering RNA against IRF3 (siIRF3) was examined by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection, A9 cells were co-cultured with extracted bone marrow cells (BMCs). MDSC differentiation, protein expression of the IRF3/NF-κB pathway, and changes in nuclear translocation of NF-κB were analyzed by flow cytometry, Western blot, and immunofluorescence staining experiments. A transplanted tumor mouse model was used for invivo experiments. After cyclic diadenyl monophosphate (CDA; STING agonist) treatment, changes in MDSC differentiation and protein expression of the IRF3/NF-κB axis in transplanted tumors were verified by immunohistochemical staining, qRT-PCR, and Western blot. Results: Coculture of A9 cells and BMCs promoted MDSC differentiation, inhibited activation of IRF3/NF-κB signal in A9 cells, and boosted nuclear translocation of NF-κB. However, after the upregulation of STING, IRF3/NF-κB signal was activated, while MDSC differentiation and nuclear translocation of NF-κB were inhibited. SiIRF3 reversed the effects of STING overexpression. In vivo, CDA dampened MDSC differentiation and promoted protein expression of the IRF3/NF-κB axis. Conclusion: STING signal in lung cancer cells inhibits MDSC differentiation through activation of the IRF3/NF-κB pathway.

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.

Effects of tryptophan-selective lipidated GLP-1 peptides on the GLP-1 receptor.

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) are widely used as antidiabetic and anti-obesity agents. Although conventional GLP-1 RAs such as liraglutide and semaglutide are acylated with fatty acids to delay their degradation by dipeptidylpeptidase-4 (DPP-4), the manufacturing process is challenging. We previously developed selectively lipidated GLP-1 peptides at their only tryptophan residue (peptide A having one 8-amino-3,6-dioxaoctanoic acid (miniPEG) linker and peptide B having three miniPEG linkers). In this study, we evaluated their effects on the GLP-1 receptor in vitro and in vivo. Both novel peptides were shown to increase cyclic adenosine monophosphate (cAMP) production and insulin secretion similarly to that by GLP-1(7-37) and liraglutide in vitro. In addition, these novel peptides lowered blood glucose levels by increasing insulin levels after oral administration of glucose and they suppressed gastrointestinal motility as effectively as liraglutide. The effects of peptide A on activation of satiety-promoting neurons in the arcuate nucleus and the consequent suppression of food intake and body weight were also similar to those of liraglutide, while the effects of peptide B were less than those of liraglutide. Under high-fat diet feeding, both long-term administration of peptide A and peptide B improved glucose tolerance and insulin sensitivity similarly to liraglutide. Thus, tryptophan-selective lipidated GLP-1 peptides are as effective as conventional GLP-1 RAs in reducing plasma glucose levels and body weight and may represent a less demanding method of manufacture of GLP-1 RAs.

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...

Exploring the Analgesic Effect of Acupuncture on Knee Osteoarthritis Based on MLT/cAMP/PKA/CREB Signaling Pathway.

Acupuncture is an effective treatment for knee osteoarthritis (KOA), reducing pain and improving function. While melatonin (MLT) has notable pain relief benefits, the analgesic mechanism of acupuncture in KOA and its relationship with melatonin are still unknown. This study aims to explore this mechanism. In this work, the KOA rabbit model was constructed using the traditional Hulth method, and the therapeutic effect was assessed by the Lequesne MG score and Pain assessment by hot plate test. The pathological alterations of cartilage tissue were observed using hematoxylin and eosin (H&E) staining, Safranin O-fast green and MASSON staining to observe the pathological changes in cartilage tissue, and the efficacy was evaluated according to the principles of Mankin score and Osteoarthritis Research Society International (OARSI) score. Meanwhile, MLT in serum, cyclic adenosine monophosphate (cAMP) in cartilage, and matrix metalloproteinase-3 (MMP-3) in joint fluid were detected by enzyme-linked immunosorbent assay. In addition, the expression of aromatic L-amino acid N-acetyltransferase (AANAT), melatonin receptor 1 (MT1) and 2 (MT2) mRNAs in cartilage was determined by real-time quantitative reverse transcription-polymerase chain reaction, and the levels of proteins related to PKA/CREB signaling pathway were detected by Western blotting. Based on the results of Lequesne MG score and Pain assessment by hot plate test experimental data, the treatment group presented significant improvements in knee pain and overall function relative to OA (Osteoarthritis) group. Besides, according to results of histologic staining, Mankin and OARSI scores, articular cartilage degeneration of treatment group remarkably improved. In addition, acupuncture significantly reduced the expression of the inflammatory factor MMP-3 in knee joint fluid and significantly increased the levels of MLT, AANAT, MT1, MT2, cAMP, PKA and CREB. By regulating sympathetic excitability, acupuncture may activate the MLT/cAMP/PKA/CREB signaling pathway, decrease inflammatory factor expression and slow down degradation of articular cartilage, resulting in the relief of knee pain.

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.

Upregulation of cAMP/PKA/CREB signaling mediated by GABABR might contribute to the amelioration effects of sea cucumber peptides (Acaudina leucoprocta) on cognitive dysfunction in mice

This study aimed to determine the effects and underlying mechanisms of sea cucumber peptides (SCP) obtained from Acaudina leucoprocta in mitigating induced by D-galactose cognitive dysfunction in mice. Additionally, it aimed to validate the cognitive-enhancing potential of peptides identified via in silico and peptidomics using SH-SY5Y cells. The results demonstrated significant improvement in behavioral performance with oral administration of SCP. Additionally, SCP normalized oxidative stress and neurotransmitter imbalances (especially gamma-aminobutyric acid, GABA). Also, SCP effectively rectified gut microbiota dysbiosis. Mechanistically, SCP activated the γ-aminobutyric acid type B receptors (GABABR)/ cyclic adenosine monophosphate (cAMP)/ cAMP-dependent protein kinase A (PKA)/ cAMP response element-binding protein (CREB) axis to promote GABA release and alleviate neuronal and oxidative stress damage, which subsequently ameliorated cognitive dysfunction. Furthermore, docking analysis predicted the binding of fourteen peptides with high abundance and PeptideRanker scores to GABABR. Notably, Lys-Gly-Phe-Pro (KGFP) had the strongest binding affinities and actively interacted with GABABR sites through hydrogen bonds, van der Waals, hydrophobic, and electrostatic interactions. The capacity of KGFP to improve cognitive function was further demonstrated when the SH-SY5Y cells were subjected to D-galactose. These results imply that the implementation of SCP intervention could be a useful tactic for improving cognitive function.

ZBED3 exacerbates hyperglycemia by promoting hepatic gluconeogenesis through CREB signaling

BackgroundElevated hepatic glucose production (HGP) is a prominent manifestation of impaired hepatic glucose metabolism in individuals with diabetes. Increased hepatic gluconeogenesis plays a pivotal role in the dysregulation of hepatic glucose metabolism and contributes significantly to fasting hyperglycemia in diabetes. Previous studies have identified zinc-finger BED domain-containing 3 (ZBED3) as a risk gene for type 2 diabetes (T2DM), and its single nucleotide polymorphism (SNPs) is closely associated with the fasting blood glucose level, suggesting a potential correlation between ZBED3 and the onset of diabetes. This study primarily explores the effect of ZBED3 on hepatic gluconeogenesis and analyzes the relevant signaling pathways that regulate hepatic gluconeogenesis. MethodsThe expression level of ZBED3 was assessed in the liver of insulin-resistant (IR)-related disease. RNA-seq and bioinformatics analyses were employed to examine the ZBED3-related pathway that modulated HGP. To investigate the role of ZBED3 in hepatic gluconeogenesis, the expression of ZBED3 was manipulated by upregulation or silencing using adeno-associated virus (AAV) in mouse primary hepatocytes (MPHs) and HHL-5 cells. In vivo, hepatocyte-specific ZBED3 knockout mice were generated. Moreover, AAV8 was employed to achieve hepatocyte-specific overexpression and knockdown of ZBED3 in C57BL/6 and db/db mice. Immunoprecipitation and mass spectrometry (IP-MS) analyses were employed to identify proteins that interacted with ZBED3. Co-immunoprecipitation (co-IP), glutathione S-transferase (GST) - pulldown, and dual-luciferase reporter assays were conducted to further elucidate the underlying mechanism of ZBED3 in regulating hepatic gluconeogenesis. ResultsThe expression of ZBED3 in the liver of IR-related disease models was found to be increased. Under the stimulation of glucagon, ZBED3 promoted the expression of hepatic gluconeogenesis-related genes PGC1A, PCK1, G6PC, thereby increasing HGP. Consistently, the rate of hepatic gluconeogenesis was found to be elevated in mice with hepatocyte-specific overexpression of ZBED3 and decreased in those with ZBED3 knockout. Additionally, the knockdown of ZBED3 in the liver of db/db mice resulted in a reduction in hepatic gluconeogenesis. Moreover, the study revealed that ZBED3 facilitated the nuclear translocation of protein arginine methyltransferases 5 (PRMT5) to influence the regulation of PRMT5-mediated symmetrical dimethylation of arginine (s-DMA) of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), which in turn affects the phosphorylation of CREB and ultimately promotes HGP. ConclusionsThis study indicates that ZBED3 promotes hepatic gluconeogenesis and serves as a critical regulator of the progression of diabetes.

Improved bioavailability of polydatin and its protective effect against cisplatin induced nephrotoxicity through self-assembled fucoidan and carboxymethyl chitosan delivery system.

Cisplatin induced acute kidney injury (AKI) is clinically prevalent, with a complex pathogenesis and a lack of effective therapeutic drugs. Polydatin (Po) has excellent biological activity, but its low solubility and bioavailability limit its application. In this study, fucoidan (Fu) and carboxymethyl chitosan (Cs) self-assembled into nanoparticles through electrostatic interactions/hydrogen bonding and loaded Po (Fu/Cs Po NPs). In vitro studies found that Fu/Cs Po NPs protected human renal tubular epithelial (HK-2) cells from cisplatin induced damage and accumulation of reactive oxygen species (ROS). Mechanistic studies showed that Fu/Cs Po NPs inhibited cisplatin induced DNA damage and activation of cyclic guanosine monophosphate synthase (cGAS) and intron gene stimulator (STING) pathways. In vivo studies showed that Fu/Cs Po NPs treatment alleviated cisplatin induced AKI symptoms, including elevated blood urea nitrogen (BUN) and serum creatinine (SCr), as well as pathological damage to kidney tissues. In vivo mechanism studies also showed that Fu/Cs Po NPs treatment inhibited cisplatin induced DNA damage and activation of the cGAS-STING pathway. The pharmacokinetic and tissue distribution results demonstrated that the Fu/Cs delivery system enhanced the bioavailability and kidney accumulation of Po in vivo. In summary, our study provided potential drugs for the treatment of cisplatin induced AKI.

Impact of Lysine to Methionine Ratios on Antioxidant Capacity and Immune Function in the Rumen of Tibetan Sheep: An RNA-Seq Analysis.

With global protein prices on the rise, lowering protein levels in animal feed, together with balancing diet composition and reducing nitrogen emissions, can both reduce the environmental impact of agriculture and save on feed costs. However, the formulation of an ideal amino acid (AA) composition is crucial for better protein utilization by livestock. This study aimed to investigate the effects of different lysine to methionine ratios on the antioxidant capacity and immune function of the rumen in Tibetan sheep. Ninety male Tibetan sheep, weaned at 2 months of age, were randomly divided into three groups (1:1, 2:1 and 3:1 lysine ratios) and subjected to a 100-day feeding trial. RNA sequencing (RNA-seq) was utilized to analyse the impact of different AA ratios on gene expression in rumen tissue, whereas the levels of antioxidant enzymes (total antioxidant capacity [T-AOC], superoxide dismutase [SOD], glutathione peroxidase [GSH-Px] and catalase [CAT]) and immunoglobulins (immunoglobulin A [IgA], immunoglobulin G [IgG] and immunoglobulin M [IgM]) were evaluated. The results indicated that the 1:1 group significantly upregulated the expression of PTGS2, PLA2G12A and PLA2G4 genes, enhancing antioxidant enzyme activity, reducing free radical production and modulating systemic immune responses. COL16A1 and KCNK5 were highly expressed in the protein digestion and absorption pathway, maintaining the structural integrity and function of the rumen epithelium. BMP4 and TGFBR2 were significantly enriched in the cytokine-cytokine receptor interaction pathway and positively correlated with CAT and T-AOC. ITGA8 was upregulated in the 1:1 group, participating in the regulation of various cellular signalling pathways. ATP2B1 was enriched in the cyclic guanosine monophosphate (cGMP)- protein kinase G (PKG) signalling and mineral absorption pathways, primarily influencing oxidative stress and immune responses by regulating intracellular calcium ion concentration. This study demonstrates that a 1:1 lysine to methionine ratio is most beneficial for enhancing the antioxidant capacity and immune function of the rumen in Tibetan sheep.

The formation of aggregated chromatin/chromosomes in mouse oocytes treated with high concentration of IBMX as a model for a chromosome transfer in human

The presence of cyclic adenosine monophosphate (cAMP) has been considered to be a fundamental factor in ensuring meiotic arrest prior to ovulation. cAMP is regarded as a key molecule in the regulation of oocyte maturation. However, it has been reported that increased levels of intracellular cAMP can result in abnormal cytokinesis, with some MI oocytes leading to symmetrically cleaved 2-cell MII oocytes. Consequently, we aimed to investigate the effects of elevated intracellular cAMP levels on abnormal cytokinesis and oocyte maturation during the meiosis of mouse oocytes. This study found that a high concentration of isobutylmethylxanthine (IBMX) also caused chromatin/chromosomes aggregation (AC) after the first meiosis. The rates of AC increased the greater the concentration of IBMX. In addition, AC formation was found to be reversible, showing that the re-formation of the spindle chromosome complex was possible after the IBMX was removed. In human oocytes, the chromosomes aggregate after the germinal vesicle breakdown and following the first and second polar body extrusions (the AC phase), while mouse oocytes do not have this AC phase. The results of our current study may indicate that the AC phase in human oocytes could be related to elevated levels of intracytoplasmic cAMP.

Impact of Long-Term Cold Storage on the Physicochemical Properties, Volatile Composition, and Sensory Attributes of Dried Jujube (Zizyphus jujuba Mill.).

Grey jujube (Zizyphus jujuba Mill. cv. Huizao), a prominent cultivar from Xinjiang, China, is well known for its high nutritional value and medicinal benefits. This study investigates the effects of long-term storage on the quality attributes of grey jujube, focusing on color, texture, physicochemical properties, bioactive ingredients, amino acid profiles, sensory characteristics, and volatile compounds. Over a three-year storage period, significant changes were observed, including a decline in lightness and redness of the peel, accompanied by textural modifications such as increased hardness and chewiness, primarily attributed to moisture loss. Physicochemical analyses revealed significant reductions in moisture content, sugars (particularly reducing sugars), and bioactive compounds such as vitamin C, total flavonoids, and cyclic adenosine monophosphate (cAMP). In contrast, total acidity showed a significant increase over time. Sensory evaluation indicated a substantial loss of fresh aroma and flavor, with the development of off-flavors over time. Additionally, a comprehensive analysis of volatile compounds highlighted significant transformations in aroma profiles, with notable reductions in desirable esters and increases in acetic acid concentrations. This study investigates the quality changes of grey jujubes during storage from sensory and physicochemical perspectives, aiming to provide a novel approach for differentiating between newly harvested and aged grey jujubes. Furthermore, these findings provide theoretical support for improving and optimizing storage conditions. Future research should focus on elucidating the underlying mechanisms of these changes, identifying key markers for quality control during grey jujube storage, and providing a scientific basis for distinguishing between newly harvested and aged grey jujubes, while improving storage quality.