Mesenchymal stromal cells restrain the Th17 cell response via L-amino-acid oxidase within lymph nodes.

Mesenchymal stromal/stem cells (MSC) have emerged as a promising therapeutic avenue for treating autoimmune diseases, eliciting considerable interest and discussion regarding their underlying mechanisms. This study revealed the distinctive ability of human umbilical cord MSC to aggregate within the lymph nodes of mice afflicted with autoimmune diseases, but this phenomenon was not observed in healthy mice. The specific distribution is driven by the heightened expression of the CCL21-CCR7 axis in mice with autoimmune diseases, facilitating the targeted homing of MSC to the lymph nodes. Within the lymph nodes, MSC exhibit a remarkable capacity to modulate Th17 cell function, exerting a pronounced anti-inflammatory effect. Transplanted MSC stimulates the secretion of L-amino-acid oxidase (LAAO), a response triggered by elevated levels of tumor necrosis factor-α (TNF-α) in mice with autoimmune diseases through the NF-κB pathway. The presence of LAAO is indispensable for the efficacy of MSC, as it significantly contributes to the inhibition of Th17 cells. Furthermore, LAAO-derived indole-3-pyruvic acid (I3P) serves as a potent suppressor of Th17 cells by activating the aryl hydrocarbon receptor (AHR) pathway. These findings advance our understanding of the global immunomodulatory effects exerted by MSC, providing valuable information for optimizing therapeutic outcomes.

Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges.

Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.

Chemometric-based analysis and bioassay guided identification of potent compounds with intestinal motility promoting effects from Dalitong Granules.

ETHNOPHARMACOLOGICAL RELEVANCE: Dalitong Granules (DLT), a potent Traditional Chinese Medicine known for its ability to promote gastrointestinal motility, is widely used in clinical practice for the treatment of Functional Dyspepsia (FD). Despite the remarkable clinical efficacy of DLT, the specific components responsible for its effectiveness remains unclear. AIM OF THE STUDY: The study aimed to identify potential active ingredients of DLT for treating FD through spectrum-effect relationship analysis, multivariate statistical analysis and network pharmacology analysis. The efficacy of these identified compounds was subsequently validated using the zebrafish intestinal peristalsis model. MATERIALS AND METHODS: The fingerprints of various solvent-extracted DLT were analyzed using high performance liquid chromatography coupled with tandem high-resolution mass spectrometry. The intestinal motility-promoting activities of DLT extracted by different solvents were evaluated through an intestinal propulsion test in mice. Potential therapeutic substances in DLT for treating FD were screened via chemometric analysis based on spectrum-effect relationship analysis. The correlation between the intensity of common peaks in the total ion chromatogram and the pharmacodynamic indices was assessed using multivariate statistical analysis. Additionally, given the complexity of Traditional Chinese Medicine, which comprises multiple components and targets, a network pharmacology analysis was performed to investigate the potential active ingredients in DLT. Finally, the pharmacological effects of these compounds in DLT were validated using a zebrafish intestinal motility model. RESULTS: Through spectral-effect relationships analysis and network pharmacology analysis, it was determined that ten ingredients in DLT contribute to the promotion of intestinal motility. In a zebrafish intestinal motility model, it was observed that eight chemicals (excluding tetrahydropalmatine) demonstrate favorable activity of promoting gastrointestinal motility. These findings suggest that these ingredients may serve as potential therapeutic agents for improving gastric motility disorders. CONCLUSIONS: This study employed spectral-effect relationship and network pharmacology analysis to identify the active ingredients in DLT. The findings were then validated using a zebrafish intestinal peristalsis model. These results provide a scientific foundation for the clinical application of DLT as a key traditional herbal formula for managing FD.

Mesenteric lymph nodes: a critical site for the up-regulatory effect of hUC-MSCs on Treg cells by producing TGF-ß1 in colitis treatment.

BACKGROUND: Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects. METHODS: First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-ß1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD. RESULTS: The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-ß1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-ß1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis. CONCLUSIONS: MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-ß1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.

All-Solution-Processed Electronics with Sub-Microscale Resolution and Nanoscale Fidelity Fabricated Via a Humidity-Controlled, Surface Energy-Directed Assembly Process.

Solution-based processes have received considerable attention in the fabrication of electronics and sensors owing to their merits of being low-cost, vacuum-free, and simple in equipment. However, the current solution-based processes either lack patterning capability or have low resolution (tens of micrometers) and low pattern fidelity in terms of line edge roughness (LER, several micrometers). Here, we present a surface energy-directed assembly (SEDA) process to fabricate metal oxide patterns with up to 2 orders of magnitude improvement in resolution (800 nm) and LER (16 nm). Experiment results show that high pattern fidelity can be achieved only at low relative humidities of below 30%. The reason for this phenomenon lies in negligible water condensation on the solution droplet. Employing the SEDA process, all-solution-processed metal oxide thin film transistors (TFTs) are fabricated by using indium oxide as channel layers, indium tin oxide as source/drain electrodes and gate electrodes, and aluminum oxide as gate dielectrics. TFT-based logic gate circuits, including NOT, NOR, NAND, and AND are fabricated as well, demonstrating the applicability of the SEDA process in fabricating large area functional electronics.

Intestinal Metabolism of Crocin and a Pharmacokinetics and Pharmacodynamics Study in the Chronic Social Defeat Stress Mouse Model.

Orally administered crocin rapidly and efficiently rescues depressive-like behaviors in depression models; however, crocin levels in the circulatory and central nervous systems are rather low. The underlying mechanism responsible for the inconsistency between pharmacokinetics and pharmacodynamics is unknown. To identify the active metabolites and clarify the underlying mechanisms, the pharmacokinetics and metabolic effects of the gut flora and hepatic and intestinal microsomes on crocin were examined, and the pharmacodynamics of crocin and its major metabolite, crocetin, were also evaluated in both normal and pseudo germ-free mice subjected to chronic social defeat stress. The results showed that oral administration of 300 mg/kg crocin significantly improved the depression-like behaviors of chronic social defeat stress mice, although the levels of crocin in the circulatory system were rather low (Cmax = 43.5 ± 8.6 µg/L; AUC = 151 ± 20.8 µg·h/L). However, the primary metabolite of crocetin was much more abundant in vivo (Cmax = 4662.5 ± 586.1 µg/L; AUC = 33,451.9 ± 3323.6 µg·h/L). Orally administered crocin was primarily metabolized into crocetin by the gut flora instead of hepatic or intestinal microsomal enzymes, and less than 10% of crocin was transformed into crocetin in the liver or intestinal microsomes. Inhibition of the gut flora dramatically reduced the production of and in vivo exposure to crocetin, and the rapid antidepressant effect of crocin disappeared. Moreover, crocetin showed rapid antidepressant effects similar to those of crocin, and the effects were independent of the gut flora. In conclusion, the metabolic transformation of crocin to crocetin primarily contributes to the rapid antidepressant effects of crocin and is dependent on the gut flora.

Gastrodin Ameliorates the Inflammation, Oxidative Stress, and Extracellular Matrix Degradation of IL-1ß-Mediated Fibroblast-Like Synoviocytes via Suppressing the Gremlin-1/NF-κB Pathway.

BACKGROUND: Synovial inflammation plays a crucial role in osteoarthritis (OA). Gastrodin (GAS), an active ingredient derived from the Gastrodia elata Blume rhizome, possesses antioxidant and anti-inflammatory pharmacological effects. This research aimed to evaluate the function and molecular mechanism of GAS on human fibroblast-like synoviocytes of osteoarthritis (HFLS-OA) induced by interleukin (IL)-1ß. METHODS: The impact of GAS on the viability of IL-1ß-treated HFLS-OA cells was assessed using the cell counting kit-8 (CCK-8). Quantitative real-time reverse transcription PCR (qRT-PCR) was employed to detect changes in IL-8, IL-6, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor (TNF)-α, and Gremlin-1 mRNA expression in each group. Corresponding kits were utilized to measure the catalase (CAT) and superoxide dismutase (SOD) activities, as well as the nitric oxide (NO) level. Western blot analysis was conducted to examine the expression of extracellular matrix degradation-associated proteins and nuclear factor kappa-B (NF-κB) pathway-correlated proteins in each group. RESULTS: GAS significantly promoted the proliferation of IL-1ß-induced HFLS-OA cells and concurrently down-regulated Gremlin-1 mRNA expression (p < 0.05). Through the down-regulation of Gremlin-1 expression, GAS exhibited the following effects: decreased IL-8, IL-6, and TNF-α mRNA expression, as well as NO levels (p < 0.05); increased SOD and CAT activities (p < 0.05); down-regulated matrix metallopeptidase 13 (MMP-13) and MMP-1 protein expression levels (p < 0.01); and up-regulated collagen II protein expression level (p < 0.01) in IL-1ß-treated HFLS-OA cells. Additionally, GAS decreased phospho-inhibitory kappa B (p-IκB)/IκB, phospho-inhibitory kappa B kinase (p-IKK)/IKK, and p-p65/p65 ratios in IL-1ß-induced HFLS-OA cells by inhibiting Gremlin-1 expression (p < 0.01). CONCLUSION: GAS demonstrates a positive impact on inflammation, oxidative stress, and extracellular matrix degradation in IL-1ß-mediated HFLS-OA cells. This effect is achieved by suppressing Gremlin-1 expression and reducing NF-κB pathway activity.

A multi-modality imaging strategy to determine the multiple in vivo fates of human umbilical cord mesenchymal stem cells at different periods of acute liver injury treatment.

Human umbilical cord mesenchymal stem cells (HUCMSCs) are applied for disease therapy as a new type of drug in many countries. Their effects are not only presented by live cells, but also apoptotic bodies or cell fragments of dead cells. Therefore, it is meaningful to determine the multiple fates of HUCMSCs in vivo. Although various probes combining different imaging modalities have been developed to label and trace transplanted HUCMSCs in vivo, the status of the cells (live, dead, or apoptotic) was not distinguished, and a thorough understanding of the multiple fates of HUCMSCs after transplantation in vivo is lacking. Therefore, a magnetic resonance (MR)/near infrared fluorescent (NIRF)/bioluminescence (BI) multi-modality imaging strategy was developed. Iron oxide nanoparticles (IONPs) were assembled into 100 nm nanoparticles using epigallocatechin gallate as a chemical linker to increase the MR signal and reduce the exocytosis of IONPs for direct cell labeling and longitudinal MR imaging tracking. Fluorescent probes for apoptosis (DEVD-Cy-OH) were also loaded in the above assemblies to monitor the cell status. Meanwhile, the cell surface was labeled with the fluorescent dye Cy7 via bioorthogonal reactions to visualize the NIRF signal. Luciferase was lentivirally transfected into live cells to generate bioluminescence. Such labeling did not affect either the viability, proliferation, migration, differentiation characteristics of HUCMSCs or their therapeutic effects on acute liver injury mice in vivo. The in vivo fates of HUCMSCs were monitored via MR/NIRF/BI multi-modality imaging in acute liver injury mice. Although MR and Cy7 signals aggregated in injured liver for 7 days, the BI signals persisted for less than 24 hours. There was an increase in DEVD-Cy-OH signals in the injured liver, but they were almost at the basal level. That means that HUCMSCs survive in mice for a short time, and the dead form of HUCMSCs accumulated in a large quantity and sustained for a long time, which might contribute to their therapeutic effect.

Carnosol prevents cardiac remodeling and ventricular arrhythmias in pressure overload-induced heart failure mice.

Cardiac remodeling is a commonly observed pathophysiological phenomenon associated with the progression of heart failure in various cardiovascular disorders. Carnosol, a phenolic compound extracted from rosemary, possesses noteworthy pharmacological properties including anti-inflammatory, antioxidant, and anti-apoptotic activities. Considering the pivotal involvement of inflammation, oxidative stress, and apoptosis in cardiac remodeling, the present study aims to assess the effects of carnosol on cardiac remodeling and elucidate the underlying mechanisms. In an in vivo model, cardiac remodeling was induced by performing transverse aortic constriction (TAC) surgery on mice, while an in vitro model was established by treating neonatal rat cardiomyocytes (NRCMs) with Ang II. Our results revealed that carnosol treatment effectively ameliorated TAC-induced myocardial hypertrophy and fibrosis, thereby attenuating cardiac dysfunction in mice. Moreover, carnosol improved cardiac electrical remodeling and restored connexin 43 expression, thereby reducing the vulnerability to ventricular fibrillation (VF). Furthermore, carnosol significantly reduced Ang II-induced cardiomyocyte hypertrophy in NRCMs and alleviated the upregulation of hypertrophy and fibrosis markers. Both in vivo and in vitro models of cardiac remodeling exhibited the anti-inflammatory, anti-oxidative, and anti-apoptotic effects of carnosol. Mechanistically, these effects were mediated through the Sirt1/PI3K/AKT pathway, as the protective effects of carnosol were abrogated upon inhibition of Sirt1 or activation of the PI3K/AKT pathway. In summary, our study suggests that carnosol prevents cardiac structural and electrical remodeling by regulating the anti-inflammatory, anti-oxidative, and anti-apoptotic effects mediated by Sirt1/PI3K/AKT signaling pathways, thereby alleviating heart failure and VF.

Feasibility exploration of GSH in the treatment of acute hepatic encephalopathy from the aspects of pharmacokinetics, pharmacodynamics, and mechanism.

Our previous study highlighted the therapeutic potential of glutathione (GSH), an intracellular thiol tripeptide ubiquitous in mammalian tissues, in mitigating hepatic and cerebral damage. Building on this premise, we posited the hypothesis that GSH could be a promising candidate for treating acute hepatic encephalopathy (AHE). To verify this conjecture, we systematically investigated the feasibility of GSH as a therapeutic agent for AHE through comprehensive pharmacokinetic, pharmacodynamic, and mechanistic studies using a thioacetamide-induced AHE rat model. Our pharmacodynamic data demonstrated that oral GSH could significantly improve behavioral scores and reduce hepatic damage of AHE rats by regulating intrahepatic ALT, AST, inflammatory factors, and homeostasis of amino acids. Additionally, oral GSH demonstrated neuroprotective effects by alleviating the accumulation of intracerebral glutamine, down-regulating glutamine synthetase, and reducing taurine exposure. Pharmacokinetic studies suggested that AHE modeling led to significant decrease in hepatic and cerebral exposure of GSH and cysteine. However, oral GSH greatly enhanced the intrahepatic and intracortical GSH and CYS in AHE rats. Given the pivotal roles of CYS and GSH in maintaining redox homeostasis, we investigated the interplay between oxidative stress and pathogenesis/treatment of AHE. Our data revealed that GSH administration significantly relieved oxidative stress levels caused by AHE modeling via down-regulating the expression of NADPH oxidase 4 (NOX4) and NF-κB P65. Importantly, our findings further suggested that GSH administration significantly regulated the excessive endoplasmic reticulum (ER) stress caused by AHE modeling through the iNOS/ATF4/Ddit3 pathway. In summary, our study uncovered that exogenous GSH could stabilize intracerebral GSH and CYS levels to act on brain oxidative and ER stress, which have great significance for revealing the therapeutic effect of GSH on AHE and promoting its further development and clinical application.

The regulation of GSH/GPX4-mediated lipid accumulation confirms that schisandra polysaccharides should be valued equally as lignans.

ETHNOPHARMACOLOGICAL RELEVANCE: Acetaminophen (APAP) induced liver injury (AILI) is a common cause of clinical hepatic damage and even acute liver failure. Our previous research has shown that Schisandra chinensis lignan extract (SLE) can exert a hepatoprotective effect by regulating lipid metabolism. Although polysaccharides from Schisandra chinensis (S. chinensis), like lignans, are important components of S. chinensis, their pharmacological activity and target effects on AILI have not yet been explored. AIM OF THE STUDY: This study aims to quantitatively reveal the role of SCP in the pharmacological activity of S. chinensis, and further explore the pharmacological components, potential action targets and mechanisms of S. chinensis in treating AILI. MATERIALS AND METHODS: The therapeutic effect of SCP on AILI was systematically determined via comparing the efficacy of SCP and SLE on in vitro and in vivo models. Network pharmacology, molecular docking and multi-omics techniques were then used to screen and verify the action targets of S. chinensis against AILI. RESULTS: SCP intervention could significantly improve AILI, and the therapeutic effect was comparable to that of SLE. Notably, the combination of SCP and SLE did not produce mutual antagonistic effects. Subsequently, we found that both SCP and SLE could significantly reverse the down-regulation of GPX4 caused by the APAP modeling, and then further improving lipid metabolism abnormalities. CONCLUSIONS: Hepatoprotective effects of SCP and SLE is most correlated with their regulation of GSH/GPX4-mediated lipid accumulation. This is the first exploration of the hepatoprotective effect and potential mechanism of SCP in treating AILI, which is crucial for fully utilizing S. chinensis and developing promising AILI therapeutic agents.

Retracted: MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling Pathway.

This publication has been retracted by the Editor due to the identification of non-original figure images and manuscript content that raise concerns regarding the credibility and originality of the study and the manuscript. Reference: Ying-Jun Zhang, He Huang, Yu Liu, Bin Kong, Guangji Wang. MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-kappaB) Signaling Pathway. Med Sci Monit, 2019; 25: 7898-7907. DOI: 10.12659/MSM.919861.

Desorption Electrospray Ionization Mass Spectrometry Imaging Techniques Depict a Reprogramming of Energy and Purine Metabolism in the Core Brain Regions of Chronic Social Defeat Stress Mice.

Depression is associated with pathological changes and metabolic abnormalities in multiple brain regions. The simultaneous comprehensive and in situ detection of endogenous molecules in all brain regions is essential for a comprehensive understanding of depression pathology, which is described in this paper. A method based on desorption electrospray ionization mass spectrometry imaging (DESI-MSI) technology was developed to classify mouse brain regions using characteristic lipid molecules and to detect the metabolites in mouse brain tissue samples simultaneously. The results showed that characteristic lipid molecules can be used to clearly distinguish each subdivision of the mouse brain, and the accuracy of this method is higher than that of the conventional staining method. The cerebellar cortex, medial prefrontal cortex, hippocampus, striatum, nucleus accumbens-core, and nucleus accumbens-shell exhibited the most significant differences in the chronic social defeat stress model. An analysis of metabolic pathways revealed that 13 kinds of molecules related to energy metabolism and purine metabolism exhibited significant changes. A DESI-MSI method was developed for the detection of pathological brain sections. We found, for the first time, that there are characteristic changes in the energy metabolism in the cortex and purine metabolism in the striatum, which is highly important for obtaining a deeper and more comprehensive understanding of the pathology of depression and discovering regulatory targets.

Compound Shouwu Jiangzhi Granule regulates triacylglyceride synthesis to alleviate hepatic lipid accumulation.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with few therapeutic options currently available. Traditional Chinese medicine has been used for thousands of years and exhibited remarkable advantages against such complicated disease for its "multi-component, multi-target and multi-pathway" characteristics. Compound Shouwu Jiangzhi Granule (CSJG) is a clinical empirical prescription for the treatment of NAFLD, but its pharmacological mechanism remains unknown. METHODS: The clinical efficacy of CSJG was retrospectively analyzed in NAFLD patients by comparing blood biomarkers levels and liver MR images before and after CSJG treatment. Then, high-fat/high-fructose (HFHF) diet-induced NAFLD mice were used to further confirm CSJG's effect against hepatic lipid accumulation through hepatic lipid determination and histopathological staining of liver samples. Next, the ingredients of CSJG were determined, and network pharmacology analysis was performed to predict potential targets of CSJG, followed by quantitative PCR (qPCR) and western blotting for verification. Then, lipidomics study was carried out to further explore the anti-NAFLD mechanism of CSJG from the perspective of triacylglyceride (TAG) synthesis but not free fatty acid (FFA) synthesis. The enzymes involved in this process were assayed by qPCR and western blotting. The potential interactions between the key enzymes of TAG synthesis and the active ingredients of CSJG were analyzed by molecular docking. RESULTS: CSJG attenuated blood lipid levels and hepatic fat accumulation in both NAFLD patients and mice. Although network pharmacology analysis revealed the FFA synthesis pathway, CSJG only slightly affected it. Through lipidomics analysis, GSJG was found to significantly block the synthesis of diglycerides (DAGs) and TAGs in the liver, with decreased DGAT2 and increased PLD1 protein expression, which diverted DAGs from the synthesis of TAGs to the production of PEs, PCs and PAs and thus lowed TAGs level. Molecular docking suggested that rhein, luteolin and liquiritigenin from CSJG might be involved in this regulation. CONCLUSION: Clinical and experimental evidence demonstrated that CSJG is a promising agent for the treatment of NAFLD. CSJG regulated TAGs synthesis to alleviate hepatic lipid accumulation. Rhein, luteolin and liquiritigenin from CSJG might play a role in it.

Exacerbating effects of circadian rhythm disruption on the systemic lupus erythematosus.

OBJECTIVE: Circadian rhythm disruption (CRD) has been associated with inflammation and immune disorders, but its role in SLE progression is unclear. We aimed to investigate the impact of circadian rhythms on immune function and inflammation and their contribution to SLE progression to lupus nephritis (LN). METHODS: This study retrospectively analysed the clinical characteristics and transcriptional profiles of 373 samples using bioinformatics and machine-learning methods. A flare risk score (FRS) was established to predict overall disease progression for patients with lupus. Mendelian randomisation was used to analyse the causal relationship between CRD and SLE progression. RESULTS: Abnormalities in the circadian pathway were detected in patients with SLE, and lower enrichment levels suggested a disease state (normalised enrichment score=0.6714, p=0.0062). The disruption of circadian rhythms was found to be closely linked to lupus flares, with the FRS showing a strong ability to predict disease progression (area under the curve (AUC) of 5-year prediction: 0.76). The accuracy of disease prediction was improved by using a prognostic nomogram based on FRS (AUC=0.77). Additionally, Mendelian randomisation analysis revealed an inverse causal relationship between CRD and SLE (OR 0.6284 (95% CI 0.3630 to 1.0881), p=0.0485) and a positive causal relationship with glomerular disorders (OR 0.0337 (95% CI 1.634e-3 to 6.934e-1), p=0.0280). CONCLUSION: Our study reveals that genetic characteristics arising from CRD can serve as biomarkers for predicting the exacerbation of SLE. This highlights the crucial impact of CRD on the progression of lupus.

Plasma metabolomics reveals risk factors for lung adenocarcinoma.

Background: Metabolic reprogramming plays a significant role in the advancement of lung adenocarcinoma (LUAD), yet the precise metabolic changes remain incompletely understood. This study aims to uncover metabolic indicators associated with the progression of LUAD. Methods: A total of 1083 subjects were recruited, including 670 LUAD, 135 benign lung nodules (BLN) and 278 healthy controls (HC). Gas chromatography-mass spectrometry (GC/MS) was used to identify and quantify plasma metabolites. Odds ratios (ORs) were calculated to determine LUAD risk factors, and machine learning algorithms were utilized to differentiate LUAD from BLN. Results: High levels of oxalate, glycolate, glycine, glyceric acid, aminomalonic acid, and creatinine were identified as risk factors for LUAD (adjusted ORs>1.2, P<0.03). Remarkably, oxalate emerged as a distinctive metabolic risk factor exhibiting a strong correlation with the progression of LUAD (adjusted OR=5.107, P<0.001; advanced-stage vs. early-stage). The Random Forest (RF) model demonstrated a high degree of efficacy in distinguishing between LUAD and BLN (accuracy = 1.00 and 0.73, F1-score= 1.00 and 0.79, and AUC = 1.00 and 0.76 in the training and validation sets, respectively). TCGA and GTEx gene expression data have shown that lactate dehydrogenase A (LDHA), a crucial enzyme involved in oxalate metabolism, is increasingly expressed in the progression of LUAD. High LDHA expression levels in LUAD patients are also linked to poor prognoses (HR=1.66, 95% CI=1.34-2.07, P<0.001). Conclusions: This study reveals risk factors associated with LUAD.

In pursuit of feedback activation: New insights into redox-responsive hydropersulfide prodrug combating oxidative stress.

Redox-responsive hydropersulfide prodrugs are designed to enable a more controllable and efficient hydropersulfide (RSSH) supply and to thoroughly explore their biological and therapeutic applications in oxidative damage. To obtain novel activation patterns triggered by redox signaling, we focused on NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1), a canonical antioxidant enzyme, and designed NQO1-activated RSSH prodrugs. We also performed a head-to-head comparison of two mainstream structural scaffolds with solid quantitative analysis of prodrugs, RSSH, and metabolic by-products by LC-MS/MS, confirming that the perthiocarbamate scaffold was more effective in intracellular prodrug uptake and RSSH production. The prodrug was highly potent in oxidative stress management against cisplatin-induced nephrotoxicity. Strikingly, this prodrug possessed potential feedback activation properties by which the delivered RSSH can further escalate the prodrug activation via NQO1 upregulation. Our strategy pushed RSSH prodrugs one step further in the pursuit of efficient release in biological matrices and improved druggability against oxidative stress.

Deep Learning-Driven Exploration of Pyrroloquinoline Quinone Neuroprotective Activity in Alzheimer's Disease.

Alzheimer's disease (AD) is a pressing concern in neurodegenerative research. To address the challenges in AD drug development, especially those targeting Aß, this study uses deep learning and a pharmacological approach to elucidate the potential of pyrroloquinoline quinone (PQQ) as a neuroprotective agent for AD. Using deep learning for a comprehensive molecular dataset, blood-brain barrier (BBB) permeability is predicted and the anti-inflammatory and antioxidative properties of compounds are evaluated. PQQ, identified in the Mediterranean-DASH intervention for a diet that delays neurodegeneration, shows notable BBB permeability and low toxicity. In vivo tests conducted on an Aß1₋42-induced AD mouse model verify the effectiveness of PQQ in reducing cognitive deficits. PQQ modulates genes vital for synapse and anti-neuronal death, reduces reactive oxygen species production, and influences the SIRT1 and CREB pathways, suggesting key molecular mechanisms underlying its neuroprotective effects. This study can serve as a basis for future studies on integrating deep learning with pharmacological research and drug discovery.

Implementation of field-programmable Gate array-based clock synchronization in the fiber channel communication system.

A sub-nanosecond clock synchronization scheme based on the field programmable gate array (FPGA) is proposed for the Fiber Channel (FC) communication system in this paper. The counter value of the slave node is synchronized to that of the master node through the embedded IEEE 1588 protocol over the communication link. In order to ensure the counter clocks have the same frequency in both nodes, which is recovered from the FC communication link, the clock phase difference is measured by the digital dual mixer time difference technique and the data recovery technique in the Gigabyte Transceiver, and then it is compensated by the mixed-mode clock manager in FPGAs. The proposed clock synchronization approach is evaluated with an FC communication system that has a serial rate of 12.5 Gbps, and the reported experimental results show that the proposed clock synchronization module can achieve a time difference lower than 1 ns.