Effects of fucoidan and synbiotics supplementation during bismuth quadruple therapy of Helicobacter pylori infection on gut microbial homeostasis: an open-label, randomized clinical trial.

Background: The eradication regimen for Helicobacter pylori (H. pylori) infection can induce gut dysbiosis. In this open-label, prospective, and randomized clinical trial, we aimed to assess the effects of fucoidan supplementation on the eradication rate and gut microbial homeostasis in the context of quadruple therapy, as well as to investigate the combined effects of fucoidan and synbiotics supplementations. Methods: Eighty patients with H. pylori infection were enrolled and randomly assigned to one of four treatment groups: the QT (a 2-week quadruple therapy alone), QF (quadruple therapy plus a 6-week fucoidan supplementation), QS (quadruple therapy plus a 6-week synbiotics supplementation), and QFS (quadruple therapy with a 6-week fucoidan and synbiotics supplementation), with 20 patients in each group. The QT regimen included rabeprazole, minocycline, amoxicillin, and bismuth potassium citrate. The synbiotics supplementation contained three strains of Bifidobacterium, three strains of Lactobacillus, along with three types of dietary fiber. All of the patients underwent 13C-urea breath test (13C-UBT) at baseline and at the end of the 6th week after the initiation of the interventions. Fresh fecal samples were collected at baseline and at the end of the 6th week for gut microbiota analysis via 16S rRNA gene sequencing. Results: The eradication rates among the four groups showed no significant difference. In the QT group, a significant reduction in α-diversity of gut microbiota diversity and a substantial shift in microbial composition were observed, particularly an increase in Escherichia-Shigella and a decrease in the abundance of genera from the Lachnospiraceae and Ruminococcaceae families. The Simpson index was significantly higher in the QF group than in the QT group. Neither the QS nor QFS groups exhibited significant changes in α-diversity or ß-diversity. The QFS group was the only one that did not show a significant increase in the relative abundance of Escherichia-Shigella, and the relative abundance of Klebsiella significantly decreased in this group. Conclusion: The current study provided supporting evidence for the positive role of fucoidan and synbiotics supplementation in the gut microbiota. The combined use of fucoidan and synbioticss might be a promising adjuvant regimen to mitigate gut dysbiosis during H. pylori eradication therapy.

Pathwise synchronization of global coupled system with linear multiplicative rough noise.

This paper focuses on achieving pathwise synchronization in stochastic differential equations with linear multiplicative rough noises, which are fractional Brownian rough paths with Hurst parameter H∈(13,12). Using rough paths theory, a useful transformation is introduced to convert the equations into random differential equations. Stability and dynamical behavior of the solutions to the equations are discussed, and pathwise synchronization of the solutions to the coupled system is proven. Also we have verified the synchronization results in Hölder space. And at the end, two alternative forms of noises are considered, and synchronization results are presented. Moreover, numerical simulations are provided to illustrate the results.

Machine Learning for Early Discrimination Between Lung Cancer and Benign Nodules Using Routine Clinical and Laboratory Data.

BACKGROUND: Lung cancer poses a global health threat necessitating early detection and precise staging for improved patient outcomes. This study focuses on developing and validating a machine learning-based risk model for early lung cancer screening and staging, using routine clinical data. METHODS: Two medical center, observational, retrospective studies were conducted, involving 2312 lung cancer patients and 653 patients with benign nodules. Machine learning techniques, including differential analysis and feature selection, were employed to identify key factors for modeling. The study focused on variables such as nodule density, carcinoembryonic antigen (CEA), age, and lifestyle habits. The Logistic Regression model was utilized for early diagnoses, and the XGBoost model was utilized for staging based on selected features. RESULTS: For early diagnoses, the Logistic Regression model achieved an area under the curve (AUC) of 0.716 (95% confidence interval [CI] 0.607-0.826), with 0.703 sensitivity and 0.654 specificity. The XGBoost model excelled in distinguishing late-stage from early-stage lung cancer, exhibiting an AUC of 0.913 (95% CI 0.862-0.963), with 0.909 sensitivity and 0.814 specificity. These findings highlight the model's potential for enhancing diagnostic accuracy and staging in lung cancer. CONCLUSION: This study introduces a novel machine learning-based risk model for early lung cancer screening and staging, leveraging routine clinical information and laboratory data. The model shows promise in enhancing accuracy, mitigating overdiagnosis, and improving patient outcomes.

A xenograft model of Kaposiform hemangioendothelioma in nude mice recapitulates Kasabach-Merritt phenomenon.

BACKGROUND: Kasabach-Merritt phenomenon (KMP) is characterized by profound thrombocytopenia and consumptive coagulopathy associated with vascular tumors, such as Kaposiform hemangioendothelioma (KHE). The pathogenesis of KMP remains unclear and its treatment is challenging. In this study, we tried to establish an animal model of KMP, which may facilitate the research on the etiology and new treatment. METHODS: A fresh sample of KHE from a one-month-old female infant with KMP was scissored into pieces and transplanted subcutaneously into the back of the nude mice. Blood routine examination was performed before the transplantation and 2, 4, 8, 12, and 16 weeks after the transplantation. Transplanted tumors were harvested 2, 4, 8, 12, and 16 weeks after the transplantation. H-E staining, immunohistochemistry staining of CD31 and α-SMA, and ultrastructural observation were performed on the plugs. RESULTS: Blood test showed a significant decrease in the number of platelets 2 weeks after transplantation. The number of platelets showed an overall trend of recovery from 2 weeks despite a slight decrease at 12 weeks after transplantation. There was no significant difference in the platelet count at 16 weeks after transplantation compared with the original state. H-E staining showed abundant irregular blood sinuses in the transplanted tumors with plenty of blood cells 2 weeks after the transplantation. 4, 8, and 12 weeks after transplantation, the density of blood sinuses decreased progressively. 16 weeks after transplantation, the plugs involuted into fibrous tissue. Immunohistochemistry staining showed the positive expression of CD31 in the endothelial cells and α-SMA in the perivascular cells. Ultrastructural observation also showed the features of KHE and progressive evolution of the tumors. CONCLUSIONS: We successfully established an experimental model of KMP by the xenograft of KHE in nude mice, which manifested profound thrombocytopenia and typical pathological structure.

A nanofluidic spiking synapse.

Currently, the nanofluidic synapse can only perform basic neuromorphic pulse patterns. One immediate problem that needs to be addressed to further its capability of brain-like computing is the realization of a nanofluidic spiking device. Here, we report the use of a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate membrane to achieve bionic ionic current-induced spiking. In addition to the simulation of various electrical pulse patterns, our synapse could produce transmembrane ionic current-induced spiking, which is highly analogous to biological action potentials with similar phases and excitability. Moreover, the spiking properties could be modulated by ions and neurochemicals. We expect that this work could contribute to biomimetic spiking computing in solution.

Differential expression of ADRB1 causes different responses to norepinephrine in adipocytes of Duroc-Landrace-Yorkshire pigs and min pigs.

Research has shown that pigs from different regions exhibit varying responses to cold stimuli. Typically, cold stimuli induce browning of white adipose tissue mediated by adrenaline, promoting non-shivering thermogenesis. However, the molecular mechanisms underlying differential response of pig breeds to norepinephrine are unclear. The aim of this study was to investigate the differences and molecular mechanisms of the effects of norepinephrine (NE) treatment on adipocytes of Min pigs (a cold-resistant pig breed) and Duroc-Landrace-Yorkshire (DLY) pigs. Real time-qPCR, western blot, and immunofluorescence were performed following NE treatment on cell cultures of adipocytes originating from Min pigs (n = 3) and DLY pigs (n = 3) to assess the expressions of adipogenesis markers, beige fat markers, and mitochondrial biogenesis markers. The results showed that NE did not affect browning of adipocytes in DLY pigs, whereas promoted browning of adipocytes in Min pigs. Further, the expression of ADRB1 (Adrenoceptor Beta 1, ADRB1) was higher in subcutaneous adipose tissue and adipocytes of Min pigs than those of DLY pigs. Overexpression of ADRB1 in DLY pig adipocytes enhanced sensitivity to NE, exhibiting decreased adipogenesis markers, upregulated beige fat markers, and increased mitochondrial biogenesis. Conversely, adipocytes treated with ADRB1 antagonist in Min pigs resulted in decreased cellular sensitivity to NE. Further studies revealed differential CpG island methylation in ADRB1 promoter region, with lower methylation levels in Min pigs compared to DLY pigs. In conclusion, differential methylation of the ADRB1 promoter region leads to different ADRB1 expression, resulting in varying responsiveness to NE in adipocytes of two pig breeds. Our results provide new insights for further analysis of the differential cold responsiveness in pig breeds from different regions.

Impact of dietary n-6/n-3 fatty acid ratio of atherosclerosis risk: A review.

Atherosclerosis is a causative factor associated with cardiovascular disease (CVD). Over the past few decades, extensive research has been carried out on the relationship between the n-6/n-3 fatty acid ratio of ingested lipids and the progression of atherosclerosis. However, there are still many uncertainties regarding the precise nature of this relationship, which has led to challenges in providing sound dietary advice to the general public. There is therefore a pressing need to review our current understanding of the relationship between the dietary n-6/n-3 fatty acid ratio and atherosclerosis, and to summarize the underlying factors contributing to the current uncertainties. Initially, this article reviews the association between the n-6/n-3 fatty acid ratio and CVDs in different countries. A summary of the current understanding of the molecular mechanisms of n-6/n-3 fatty acid ratio on atherosclerosis is then given, including inflammatory responses, lipid metabolism, low-density lipoprotein cholesterol oxidation, and vascular function. Possible reasons behind the current controversies on the relationship between the n-6/n-3 fatty acid ratio and atherosclerosis are then provided, including the precise molecular structures of the fatty acids, diet-gene interactions, the role of fat-soluble phytochemicals, and the impact of other nutritional factors. An important objective of this article is to highlight areas where further research is needed to clarify the role of n-6/n-3 fatty acid ratio on atherosclerosis.

Phenotypic subgroup in serologically active clinically quiescent systemic lupus erythematosus: A cluster analysis based on CSTAR cohort.

BACKGROUND: Serologically active clinically quiescent (SACQ) is a state within systemic lupus erythematosus (SLE) characterized by elevated serologic markers without clinical activity. The heterogeneity in SACQ patients poses challenges in disease management. This multicenter prospective study aimed to identify distinct SACQ subgroups and assess their utility in predicting organ damage. METHODS: SACQ was defined as a sustained period of at least 6 months with persistent serologic activity, marked by positive anti-double-stranded DNA (dsDNA) antibodies and/or hypocomplementemia, and without clinical activity. Cluster analysis was employed, utilizing 16 independent components to delineate phenotypes. FINDINGS: Among the 4,107 patients with SLE, 990 (24.1%) achieved SACQ within 2.0 ± 2.3 years on average. Over a total follow-up of 7,105.1 patient years, 340 (34.3%) experienced flares, and 134 (13.5%) developed organ damage. Three distinct SACQ subgroups were identified. Cluster 1 (n = 219, 22.1%) consisted predominantly of elderly males with a history of major organ involvement at SLE diagnosis, showing the highest risk of severe flares (16.4%) and organ damage (27.9%). Cluster 2 (n = 279, 28.2%) was characterized by milder disease and a lower risk of damage accrual (5.7%). Notably, 86 patients (30.8%) in cluster 2 successfully discontinued low-dose glucocorticoids, with 49 of them doing so without experiencing flares. Cluster 3 (n = 492, 49.7%) featured the highest proportion of lupus nephritis and a moderate risk of organ damage (11.8%), with male patients showing significantly higher risk of damage (hazard ratio [HR] = 4.51, 95% confidence interval [CI], 1.82-11.79). CONCLUSION: This study identified three distinct SACQ clusters, each with specific prognostic implications. This classification could enhance personalized management for SACQ patients. FUNDING: This work was funded by the National Key R&D Program (2021YFC2501300), the Beijing Municipal Science & Technology Commission (Z201100005520023), the CAMS Innovation Fund (2021-I2M-1-005), and National High-Level Hospital Clinical Research Funding (2022-PUMCH-D-009).

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Catalytic properties of trivalent rare-earth oxides with intrinsic surface oxygen vacancy.

Oxygen vacancy (Ov) is an anionic defect widely existed in metal oxide lattice, as exemplified by CeO2, TiO2, and ZnO. As Ov can modify the band structure of solid, it improves the physicochemical properties such as the semiconducting performance and catalytic behaviours. We report here a new type of Ov as an intrinsic part of a perfect crystalline surface. Such non-defect Ov stems from the irregular hexagonal sawtooth-shaped structure in the (111) plane of trivalent rare earth oxides (RE2O3). The materials with such intrinsic Ov structure exhibit excellent performance in ammonia decomposition reaction with surface Ru active sites. Extremely high H2 formation rate has been achieved at ~1 wt% of Ru loading over Sm2O3, Y2O3 and Gd2O3 surface, which is 1.5-20 times higher than reported values in the literature. The discovery of intrinsic Ov suggests great potentials of applying RE oxides in heterogeneous catalysis and surface chemistry.

Abnormal static and dynamic brain network connectivity associated with chronic tinnitus.

In order to comprehensively understand the changes of brain networks in patients with chronic tinnitus, this study combined static and dynamic analysis methods to explore the abnormalities of brain networks. Thirty-two patients with chronic tinnitus and 30 age-, sex- and education-matched healthy controls (HC) were recruited. Independent component analysis was used to identify resting-state networks (RSNs). Static and dynamic functional network connectivity (FNC) were performed. The temporal properties of brain network including mean dwell time (MDT), fraction time (FT) and numbers of transitions (NT) were calculated. Two-sample t test and Spearman's correlation were used for group compares and correlation analysis. Four RSNs showed abnormal FNC including auditory network (AUN), default mode network (DMN), attention network (AN) and sensorimotor network (SMN). For static analysis, tinnitus patients showed significantly decreased FNC in AUN-DMN, AUN-AN, DMN-AN, and DMN-SMN than HC [p < 0.05, false discovery rate (FDR) corrected]. For dynamic analysis, tinnitus patients showed significantly decreased FNC in DMN-AN in state 3 (p < 0.05, FDR corrected). MDT in state 3 was significantly decreased in tinnitus patients (t = 2.039, P = 0.046). In the tinnitus group, the score of tinnitus functional index (TFI) was negatively correlated with MDT and FT in state 4, and the duration of tinnitus was positively correlated with FT in state 1 and NT. Chronic tinnitus causes abnormal brain network connectivity. These abnormal brain networks help to clarify the mechanism of tinnitus generation and chronicity, and provide a potential basis for the treatment of tinnitus.

A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori.

Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25-0.5 µg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer.

BACKGROUND: Gastric cancer is one of the most common malignant tumors in the world, and its occurrence and development involve complex biological processes. Iron death, as a new cell death mode, has attracted wide attention in recent years. However, the regulatory mechanism of iron death in gastric cancer and its effect on lipid peroxidation metabolism remain unclear. AIM: To explore the role of iron death in the development of gastric cancer, reveal its relationship with lipid peroxidation, and provide a new theoretical basis for revealing the molecular mechanism of the occurrence and development of gastric cancer. METHODS: The process of iron death in gastric cancer cells was simulated by cell culture model, and the occurrence of iron death was detected by fluorescence microscopy and flow cytometry. The changes of gene expression related to iron death and lipid peroxidation metabolism were analyzed by high-throughput sequencing technology. In addition, a mouse model of gastric cancer was established, and the role of iron death in vivo was studied by histology and immunohistochemistry, and the level of lipid peroxidation was detected. These methods comprehensively and deeply reveal the regulatory mechanism of iron death on lipid peroxidation metabolism in the occurrence and development of gastric cancer. RESULTS: Iron death was significantly activated in gastric cancer cells, and at the same time, associated lipid peroxidation levels increased significantly. Through high-throughput sequencing analysis, it was found that iron death regulated the expression of several genes related to lipid metabolism. In vivo experiments demonstrated that increased iron death in gastric cancer mice was accompanied by a significant increase in lipid peroxidation. CONCLUSION: This study confirmed the important role of iron death in regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer. The activation of iron death significantly increased lipid peroxidation levels, revealing its regulatory mechanism inside the cell.

A Λ-Ir(iii)-phenylquinazolinone complex enhances ferroptosis by selectively inhibiting metallothionein-1.

Chirality plays an indispensable role in various biological processes, and interactions between chiral enantiomers and biomolecular targets provide new perspectives in precision drug development. While ferroptosis has received increasing attention as a novel pathway to reverse drug resistance, work on the design of precise ferroptosis-targeting molecules through chiral programming was limited. In this work, we designed and synthesized a pair of chirality-dependent ferroptosis-inducing Ir(iii)-phenylquinazolinone complexes (Δ-IrPPQ and Λ-IrPPQ) by inhibiting ferroptosis suppressor protein-1 (FSP1), while the pair of IrPPQ complexes induced extremely different ferroptosis effects as well as distinct photodynamic therapy (PDT) responses toward pancreatic cancer cells. Interestingly, this chirality-dependent biological mechanism through proteomic analysis and molecular simulation revealed that the specific binding and inhibition of metallothionein-1 (MT1) by Λ-IrPPQ sensitized cancer cells to ferroptosis, inducing a burst of reactive oxygen species, lipid peroxidation, glutathione depletion, and inactivation of FSP1. While in comparison, Δ-IrPPQ induced mild ferroptotic cell death. Through simple chiral resolution, the obtained Λ-IrPPQ achieved precise regulation of ferroptosis in pancreatic cancer cells. This work provides new insights into the design of chiral ferroptosis-inducing metallodrugs for future pancreatic cancer therapy.

In-depth understanding the synergisms of Cu atomic clusters on Cu single atoms for highly effective electrocatalytic oxygen reduction reaction and Zn-Air battery.

In this paper, a novel, simple and mild soft template assisted strategy and further carbonization approach has been constructed to the size-tunable preparation of porous Cu-N-C/Surfactant catalysts successfully. Note that the pluronic F127 has a significant influence on the synthesis of porous Cu-N-C/F127 with the atomically dispersed Cu-N4 and adjacent Cu atomic clusters (ACs) than other surfactants owing to their particular non-ionic structure. By combining a series of experimental analysis and density functional theory (DFT) calculations, the synergistic effects between the adjacent Cu ACs and atomically dispersed Cu-N4 are favorable for manipulating the binding energy of O2 adsorption and intermediates desorption at the atomic interface of catalysts, resulting in an excellent electrocatalytic ORR performance with a faster kinetics for Cu-N-C/F127 than those of the Cu-N-C, Cu-N-C/CTAB, Cu-N-C/SDS, and comparable with the commercial Pt/C catalyst. This method not only provides a novel approach for synthesizing highly effective copper based single atom catalysts toward ORR, but also offers an in-depth understanding of the synergisms of adjacent ACs on the Cu single atoms (SAs) for highly effective electrocatalytic ORR and Zn-air Battery.

Activation of the cGAS-STING-IRF3 Axis by Type I and II Interferons Contributes to Host Defense.

Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (ß) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-ß and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-ß and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-ß- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.

Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications.

Acute kidney injury (AKI) is a frequent and severe complication of sepsis and is characterized by significant mortality and morbidity. However, the pathogenesis of septic acute kidney injury (S-AKI) remains elusive. Metabolic reprogramming, which was originally referred to as the Warburg effect in cancer, is strongly related to S-AKI. At the onset of sepsis, both inflammatory cells and renal parenchymal cells, such as macrophages, neutrophils and renal tubular epithelial cells, undergo metabolic shifts toward aerobic glycolysis to amplify proinflammatory responses and fortify cellular resilience to septic stimuli. As the disease progresses, these cells revert to oxidative phosphorylation, thus promoting anti-inflammatory reactions and enhancing functional restoration. Alterations in mitochondrial dynamics and metabolic reprogramming are central to the energetic changes that occur during S-AKI. In this review, we summarize the current understanding of the pathogenesis of metabolic reprogramming in S-AKI, with a focus on each cell type involved. By identifying relevant key regulatory factors, we also explored potential metabolic reprogramming-related therapeutic targets for the management of S-AKI.

Exploring the Regulatory Effect of LPJZ-658 on Copper Deficiency Combined with Sugar-Induced MASLD in Middle-Aged Mice Based on Multi-Omics Analysis.

Globally, metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), is one of the most common liver disorders and is strongly associated with copper deficiency. To explore the potential effects and mechanisms of Lactiplantibacillus plantarum LPJZ-658, copper deficiency combined with a high-sugar diet-induced MASLD mouse model was utilized in this study. We fed 40-week-old (middle-aged) male C57BL/6 mice a copper-deficient and high-sugar diet for 16 weeks (CuDS), with supplementary LPJZ-658 for the last 6 weeks (CuDS + LPJZ-658). In this study, we measured body weight, liver weight, and serum biochemical markers. Lipid accumulation, histology, lipidomics, and sphingolipid metabolism-related enzyme expression were investigated to analyze liver function. Untargeted metabolomics was used to analyze the serum and the composition and abundance of intestinal flora. In addition, the correlation between differential liver lipid profiles, serum metabolites, and gut flora at the genus level was measured. The results show that LPJZ-658 significantly improves abnormal liver function and hepatic steatosis. The lipidomics analyses and metabolic pathway analysis identified sphingolipid, retinol, and glycerophospholipid metabolism as the most relevant metabolic pathways that characterized liver lipid dysregulation in the CuDS group. Consistently, RT-qPCR analyses revealed that the enzymes catalyzing sphingolipid metabolism that were significantly upregulated in the CuDS group were downregulated by the LPJZ-658 treatment. In addition, the serum metabolomics results indicated that the linoleic acid, taurine and hypotaurine, and ascorbate and aldarate metabolism pathways were associated with CuDS-induced MASLD. Notably, we found that treatment with LPJZ-658 partially reversed the changes in the differential serum metabolites. Finally, LPJZ-658 effectively regulated intestinal flora abnormalities and was significantly correlated with differential hepatic lipid species and serum metabolites. In conclusion, we elucidated the function and potential mechanisms of LPJZ-658 in alleviating copper deficiency combined with sugar-induced middle-aged MASLD and hope this will provide possible treatment strategies for improving MASLD.

AC-ModNet: Molecular Reverse Design Network Based on Attribute Classification.

Deep generative models are becoming a tool of choice for exploring the molecular space. One important application area of deep generative models is the reverse design of drug compounds for given attributes (solubility, ease of synthesis, etc.). Although there are many generative models, these models cannot generate specific intervals of attributes. This paper proposes a AC-ModNet model that effectively combines VAE with AC-GAN to generate molecular structures in specific attribute intervals. The AC-ModNet is trained and evaluated using the open 250K ZINC dataset. In comparison with related models, our method performs best in the FCD and Frag model evaluation indicators. Moreover, we prove the AC-ModNet created molecules have potential application value in drug design by comparing and analyzing them with medical records in the PubChem database. The results of this paper will provide a new method for machine learning drug reverse design.