The complex roles of m 6 A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases.

N6-methyladenosine (m 6 A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m 6 A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m 6 A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m 6 A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m 6 A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m 6 A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m 6 A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m 6 A's role in neurodegenerative processes. The roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the time-specific nature of m 6 A and its varying effects on distinct brain regions and in different environments.

Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis.

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP. We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models. We also found that allopurinol and febuxostat, as purine-like and non-purine XO inhibitors, respectively, exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points. Moreover, we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity. Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha (HIF-1α)-regulated lactate dehydrogenase A (LDHA) and NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways and reduced the enrichment of 13C6-glucose to 13C3-lactate. Lastly, we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels, while pancreatic XO and urate were also increased in severe AP patients. These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

Structural characterization and hypolipidemic activity of a natural polysaccharide from Suaeda salsa L.

Herein, the identification and analysis of a newly discovered hypolipidemic polysaccharide extracted from Suaeda salsa L., SS3-N1, is reported. The weight-average molecular weight (Mw), number-average molecular weight (Mn), and dispersity (Ð) of SS3-N1 were determined to be 45.50 kDa, 34.21 kDa, and 1.33, respectively. This polysaccharide primarily consists of galactose (50.80 %) and arabinose (30.70 %), with lower proportions of xylose, mannose, guluronic acid, rhamnose, glucuronic acid, ribose, and fucose. Methylation and NMR analyses indicated that its backbone was primarily composed of R → 3,6)-ß-D-Galp-(1 → R and R → 5)-α-L-Araf-(1→ residues. The sugar units at the reducing and nonreducing ends were identified as R → 4)-ß-D-Xylp-(1 → R and R → 3)-ß-D-Galp-(1 → R, respectively. In addition, α-L-Araf (1 → R side branches were incorporated at the C-3 position of R → 3,6)-ß-D-Galp-(1 → R. At 100 µg/mL, SS3-N1 surpassed the lipid-lowering efficacy of the positive control, atorvastatin (0.4 µM), in an egg yolk powder (EYP)-induced hyperlipidemic zebrafish model. This effect may be attributed to the modulation of cholesterol metabolism due to the upregulation of nrf2, ho-1, ampk, ppara, and cyp7a1 gene expression and the downregulation of acaca and hmgcr gene expression. Such dual gene regulation inhibits fatty acid and cholesterol synthesis, suggesting potential applications for the natural hypolipidemic polysaccharide derived from S. salsa L.

The discriminatory capability of anthropometric measures in predicting reproductive outcomes in Chinese women with PCOS.

OBJECTIVE: Obesity is a common feature in women with polycystic ovary syndrome (PCOS) and potentially significantly influences reproductive function. However, opinions are divided as to which factor is a more appropriate obesity predictor of reproductive outcomes. The aim of this study was to investigate the discriminatory capability of anthropometric measures in predicting reproductive outcomes in Chinese women with PCOS. METHODS: A total of 998 women with PCOS from PCOSAct were included. Logistic regression models were used to compute the odds ratios (ORs) and 95% confidence interval (95% CIs) to assess the effect of anthropometric measures, including body mass index (BMI), waist circumference (WC), hip circumference (HC), the waist‒hip ratio (WHR) and the waist‒height ratio (WHtR), on reproductive outcomes. The discrimination abilities of the models were assessed and compared based on the area under the receiver operating characteristic curve (AUC), Akaike's information criterion (AIC) and integrated discrimination improvement (IDI). RESULTS: Among PCOS women, there was a graded association between anthropometric measures and predicted reproductive outcomes across quintiles of anthropometric measures, including a linear association among WHR, BMI and reproductive outcomes and among waist circumference, WHtR and live birth, pregnancy, and ovulation. However, only a linear association was noted between the hip and ovulation. C-statistic comparisons and IDI analyses revealed a trend towards a significant superiority of BMI for ovulation and WHR for live birth, pregnancy and conception in the models. Combining obesity variables improved discrimination in the multivariable models for reproductive outcomes. CONCLUSIONS: Our findings support that BMI is a better predictor of ovulation and that the WHR is a better predictor of live birth, pregnancy and conception, whereas the combination of obesity variables contributes to the discrimination of reproduction.

Design, Synthesis, Antifungal Evaluation, and Three-Dimensional Quantitative Structure-Activity Relationship of Novel 5-Sulfonyl-1,3,4-thiadiazole Flavonoids.

Plant pathogenic fungi frequently disrupt the normal physiological and biochemical functions of plants, leading to diseases, compromising plant health, and ultimately reducing crop yield. This study aimed to address this challenge by identifying antifungal agents with innovative structures and novel mechanisms of action. We designed and synthesized a series of flavonoid derivatives substituted with 5-sulfonyl-1,3,4-thiadiazole and evaluated their antifungal activity against five phytopathogenic fungi. Most flavonoid derivatives demonstrated excellent antifungal activity against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Rhizoctorzia solani (R. solani), Fusarium graminearum (F. graminearum), and Colletotrichum orbiculare (C. orbiculare). Specifically, the EC50 values of 38 target compounds against R. solani were below 4 µg/mL, among which the compounds C13 (EC50 = 0.49 µg/mL), C15 (EC50 = 0.37 µg/mL), and C19 (EC50 = 0.37 µg/mL) had the most prominent antifungal activity, superior to that of the control drug carbendazim (EC50 = 0.52 µg/mL). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of the cellular ultrastructures of R. solani mycelia and cells after treatment with the compound C19 revealed sprawling growth of hyphae, a distorted outline of their cell walls, and reduced mitochondrial numbers. Studying the 3D-QSAR between the molecular structure and antifungal activity of 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoid derivatives could significantly improve conventional drug molecular design pathways and facilitate the development of novel antifungal leads.

Postpartum depression and autoimmune disease: a bidirectional Mendelian randomization study.

Purpose: The rising prevalence of postpartum depression (PPD) is harmful to women and families. While there is a growing body of evidence suggesting an association between PPD and autoimmune diseases (ADs), the direction of causality remains uncertain. Therefore, Mendelian randomization (MR) study was employed to investigate the potential causal relationship between the two. Methods: This study utilized large-scale genome-wide association study genetic pooled data from two major databases: the IEU OpenGWAS project and the FinnGen databases. The causal analysis methods used inverse variance weighting (IVW). The weighted median, MR-Egger method, MR-PRESSO test, and the leave-one-out sensitivity test have been used to examine the results' robustness, heterogeneity, and horizontal pleiotropy. Results: A total of 23 ADs were investigated in this study. In the IVW model, the MR study showed that PPD increased the risk of type 1 diabetes (OR , = 1.15 (1.05-1.26),p<0.01),Hashimoto's thyroiditis((OR) = 1.21 (1.09-1.34),p<0.0001),encephalitis((OR) = 1.66 (1.06-2.60),p<0.05). Reverse analysis showed that ADs could not genetically PPD. There was no significant heterogeneity or horizontal pleiotropy bias in this result. Conclusion: Our study suggests that PPD is a risk factor for type 1 diabetes, Hashimoto's thyroiditis, and encephalitis from a gene perspective, while ADs are not a risk factor for PPD. This finding may provide new insights into prevention and intervention strategies for ADs according to PPD patients.

Combined knockdown of CD151 and MMP9 may inhibit the malignant biological behaviours of triple-negative breast cancer through the GSK-3ß/ß-catenin-related pathway.

Triple-negative breast cancer (TNBC) represents a significant health concern for women worldwide, and the overproduction of MMP9 and CD151 is associated with various cancers, influencing tumour growth and progression. This study aimed to investigate how CD151 and MMP9 affect TNBC cell migration, apoptosis, proliferation, and invasion. Immunohistochemical experiments revealed that CD151 and MMP9 were positively expressed in triple-negative breast cancer, and lymph node metastasis, the histological grade, and CD151 and MMP9 expression were found to be independent prognostic factors for the survival of patients with triple-negative breast cancer. Cytological experiments indicated that the knockdown of CD151 or MMP9 slowed triple-negative breast cancer cell growth, migration, and invasion and increased the apoptosis rate. Compared with CD151 knockdown, double MMP9 and CD151 knockdown further promoted cell death and inhibited TNBC cell proliferation, migration, and invasion. Moreover, ß-catenin and p-GSK-3ß were significantly downregulated. In summary, simultaneously silencing CD151 and MMP9 further suppressed the proliferation, migration and invasion of TNBC cells and promoted their apoptosis. One possible strategy for inducing this effect is to block the GSK-3ß/ß-catenin pathway.

Chaiqin chengqi decoction treatment mitigates hypertriglyceridemia-associated acute pancreatitis by modulating liver-mediated glycerophospholipid metabolism.

BACKGROUND: The incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing globally and more so in China. The characteristics of liver-mediated metabolites and related key enzymes are rarely reported in HTG-AP. Chaiqin chengqi decoction (CQCQD) has been shown to protect against AP including HTG-AP in both patients and rodent models, but the underlying mechanisms in HTG-AP remain unexplored. PURPOSE: To assess the characteristics of liver-mediated metabolism and the therapeutic mechanisms of CQCQD in HTG-AP. METHODS: Male human apolipoprotein C3 transgenic (hApoC3-Tg; leading to HTG) mice or wild-type littermates received 7 intraperitoneal injections of cerulein (100 µg/kg) to establish HTG-AP and CER-AP, respectively. In HTG-AP, some mice received CQCQD (5.5 g/kg) gavage at 1, 5 or 9 h after disease induction. AP severity and related liver injury were determined by serological and histological parameters; and underlying mechanisms were identified by lipidomics and molecular biology. Molecular docking was used to identify key interactions between CQCQD compounds and metabolic enzymes, and subsequently validated in vitro in hepatocytes. RESULTS: HTG-AP was associated with increased disease severity indices including augmented liver injury compared to CER-AP. CQCQD treatment reduced severity and liver injury of HTG-AP. Glycerophospholipid (GPL) metabolism was the most disturbed pathway in HTG-AP in comparison to HTG alone. In HTG-AP, the mRNA level of GPL enzymes involved in phosphocholine (PC) and phosphatidylethanolamine (PE) synthesis (Pcyt1a, Pcyt2, Pemt, and Lpcat) were markedly upregulated in the liver. Of the GPL metabolites, lysophosphatidylethanolamine LPE(16:0) in serum of HTG-AP was significantly elevated and positively correlated with the pancreas histopathology score (r = 0.65). In vitro, supernatant from Pcyt2-overexpressing hepatocytes co-incubated with LPE(16:0) or phospholipase A2 (a PC- and PE-hydrolyzing enzyme) alone induced pancreatic acinar cell death. CQCQD treatment downregulated PCYT1a and PCYT2 enzyme levels in the liver. Hesperidin and narirutin were identified top two CQCQD compounds with highest affinity docking to PCYT1a and PCYT2. Both hesperidin and narirutin reduced the level of some GPL metabolites in hepatocytes. CONCLUSION: Liver-mediated GPL metabolism is excessively activated in HTG-AP with serum LPE(16:0) level correlating with disease severity. CQCQD reduces HTG-AP severity partially via modulating key enzymes in GPL metabolism pathway.

Examination tolerance, pre-examination anxiety, knowledge needs and cooperation in gastroscopic examinees: A prospective, correlational analysis in a health screening population.

AIM: To explore the correlations between examination tolerance and anxiety, knowledge needs and examination cooperation in sedation-free gastroscopy examinees. DESIGN: Cross-sectional survey using convenience sampling. METHODS: A total of 170 healthy adults who underwent sedation-free gastroenteroscopy were asked to complete a visual analogue scale (VAS) to rate their examination tolerance, the state anxiety questionnaire (S-AI), a newly designed knowledge needs questionnaire and a cooperation questionnaire. RESULTS: The VAS score was 4.47 ± 1.96, the state anxiety score was 39.46 ± 9.81, the total score for knowledge needs was 44.89 ± 11.02, and the average cooperation score was 2.47 ± 0.38. The VAS score during the examination positively correlated with the pretest state anxiety score and pretest knowledge needs score and negatively correlated with the examination cooperation score. The results of multiple linear regression analysis showed that after undergoing the examination for the first time, anxiety, body position and swallowing control were the main factors influencing the examination tolerance of sedation-free gastroscopy examinees. PATIENT OR PUBLIC CONTRIBUTION: We would like to thank the staff and patients of the participating hospital for their assistance and cooperation in performing the current study.

Effects of Different Test Positions on Quantitative Muscle Strength of Wrist and Finger Flexor Muscle Groups and Its Standardization.

OBJECTIVES: To explore the effects of different test positions on quantitative muscle strength of wrist and finger flexor muscle groups and to establish a standardized muscle strength test protocol for each muscle group. METHODS: Forty healthy subjects (12 males and 28 females) were recruited. A portable digital quantitative muscle strength tester, Micro FET2TM, was used to measure the flexor muscle strength of each finger and the wrist joint at the 30° extension, 0° neutral, and 30° flexion, respectively. Palmar abduction strength of the thumb was measured at 30° and 60°, respectively. Ten subjects were randomly selected from the 40 subjects, and the quantitative muscle strength of each muscle group was tested again by the same operator after an interval of 10 to 15 days. RESULTS: Except for the fact that in males, there was no significant difference in flexor muscle strength of thumb and wrist joint between 30° of wrist extension and neutral 0° position, the muscle strength of the other fingers flexion and wrist palmar flexor showed the following characteristics：30° of wrist extension > neutral 0° position > 30° of flexion, and the PAST was 30°>60°; The flexor muscle strength of all the subjects was thumb > index finger > middle finger > ring finger > little finger; All muscle strength values of male were greater than those of female, and the difference was statistically significant (P<0.05); There was no significant difference between the left and right side muscle strength values of all subjects (P>0.05). The reliability of muscle strength values measured at different times in 10 subjects was good. CONCLUSIONS: The quantitative muscle strength of each muscle group of the hand and wrist is affected by the test position, and a standardized and uniformed test position should be adopted in the actual identification. Micro FET2TM has good reliability for hand and wrist quantitative muscle strength testing. The 30° extension of the wrist can be used as the best standardized test position for the flexion muscle strength of each finger and wrist joint. The 30° position can be used as the best standardized test position for PAST.

Construction of an IFNAR1 knockout MDBK cell line using CRISPR/Cas9 and its effect on bovine virus replication.

The type I interferon (IFN) pathway is important for eukaryotic cells to resist viral infection, as well as an impediment to efficient virus replication. Therefore, this study aims to create an IFNAR1 knockout (KO) Madin-Darby bovine kidney (MDBK) cell line using CRISPR/Cas9 and investigate its application and potential mechanism in increasing viral replication of bovines. The IFNAR1 KO cells showed increased titers of bovine viral diarrhea virus (BVDV) (1.5 log10), with bovine enterovirus and bovine parainfluenza virus type 3 (0.5-0.8 log10). RNA-seq revealed reduced expression of the genes related IFN-I pathways including IFNAR1, STAT3, IRF9, and SOCS3 in IFNAR1 KO cells compared with WT cells. In WT cells, 306 differentially expressed genes (DEGs) were identified between BVDV-infected and -uninfected cells. Of these, 128 up- and 178 down-regulated genes were mainly associated with growth cycle and biosynthesis, respectively. In IFNAR1 KO cells, 286 DEGs were identified, with 82 up-regulated genes were associated with signaling pathways, and 204 down-regulated genes. Further, 92 DEGs were overlapped between WT and IFNAR1 KO cells including ESM1, IL13RA2, and SLC25A34. Unique DEGs in WT cells were related to inflammation and immune regulation, whereas those unique in IFNAR1 KO cells involved in cell cycle regulation through pathways such as MAPK. Knocking down SLC25A34 and IL13RA2 in IFNAR1 KO cells increased BVDV replication by 0.3 log10 and 0.4 log10, respectively. Additionally, we constructed an IFNAR1/IFNAR2 double-knockout MDBK cell line, which further increased BVDV viral titers compared with IFNAR1 KO cells (0.6 log10). Overall, the IFNAR1 KO MDBK cell line can support better replication of bovine viruses and therefore provides a valuable tool for bovine virus research on viral pathogenesis and host innate immune response.

Does the Angulation of the Screws in the Zero-P Implant Affect the Clinical and Radiological Outcomes of Patients?

OBJECTIVE: When implanting the Zero-P device, the screws of Zero-P form a bone wedge with a 40 ± 5° cranial and caudal angle (CCA). However, no study has been performed in the optimal CCA of the Zero-P implant. To investigate whether the cranial/caudal angles (CCA) of the screws affect the clinical and radiological outcomes in patients undergoing ACDF with the Zero-P implant. METHODS: From January 2016 to December 2023, we retrospectively analyzed 186 patients who underwent 1-level ACDF with the Zero-P device. The patients were divided into four groups: group A (cranial angle ≤40°, caudal angle ≤40°); group B (cranial angle ≤40°, caudal angle >40°); group C (cranial angle >40°, caudal angle ≤40°); and group D (cranial angle >40°, caudal angle >40°). The clinical outcomes, including Japanese Orthopaedic Association (JOA), neck disability index (NDI), and visual analogue scale (VAS) scores, the radiological parameters, including cervical lordosis (CL), cervical lordosis of operated segments (OPCL), intervertebral space height (ISH) and fusion rate (FR), and the complications, were evaluated and compared. Parametric tests, non-parametric tests, and chi-square tests were conducted to analyze the data. RESULTS: The OPCL of group A was significantly less than that of the other groups at the final follow-up (p < 0.05). The ISH of group D was significantly less than that of group A at the final follow-up (p < 0.05). The subsidence rate of group A was significantly less than that of group D at the final follow-up (p < 0.05). At the final follow-up, the upper adjacent-level degeneration (ASD) of group D was significantly less severe than that of groups A and B (p < 0.05). The clinical outcomes do not differ among groups (p > 0.05). CONCLUSION: A larger CCA of the screws (cranial angle >40°, caudal angle >40°) was better for maintaining OPCL and reducing the incidence of ASD. A smaller CCA of the screws (cranial angle ≤40°, caudal angle ≤40°) was better for maintaining ISH and reducing the rate of subsidence.

Click-free imaging of carbohydrate trafficking in live cells using an azido photothermal probe.

Real-time tracking of intracellular carbohydrates remains challenging. While click chemistry allows bio-orthogonal tagging with fluorescent probes, the reaction permanently alters the target molecule and only allows a single snapshot. Here, we demonstrate click-free mid-infrared photothermal (MIP) imaging of azide-tagged carbohydrates in live cells. Leveraging the micromolar detection sensitivity for 6-azido-trehalose (TreAz) and the 300-nm spatial resolution of MIP imaging, the trehalose recycling pathway in single mycobacteria, from cytoplasmic uptake to membrane localization, is directly visualized. A peak shift of azide in MIP spectrum further uncovers interactions between TreAz and intracellular protein. MIP mapping of unreacted azide after click reaction reveals click chemistry heterogeneity within a bacterium. Broader applications of azido photothermal probes to visualize the initial steps of the Leloir pathway in yeasts and the newly synthesized glycans in mammalian cells are demonstrated.

Subway Fine Particles (PM2.5)-Induced Pro-Inflammatory Response Triggers Airway Epithelial Barrier Damage Through the TLRs/NF-κB-Dependent Pathway In Vitro.

Subways are widely used in major cities around the world, and subway fine particulate matter (PM2.5) is the main source of daily PM2.5 exposure for urban residents. Exposure to subway PM2.5 leads to acute inflammatory damage in humans, which has been confirmed in mouse in vivo studies. However, the concrete mechanism by which subway PM2.5 causes airway damage remains obscure. In this study, we found that subway PM2.5 triggered release of pro-inflammatory cytokines such as interleukin 17E, tumor necrosis factor α, transforming growth factor ß, and thymic stromal lymphopoietin from human bronchial epithelial cells (BEAS-2B) in a dose-effect relationship. Subsequently, supernatant recovered from the subway PM2.5 group significantly increased expression of the aforementioned cytokines in BEAS-2B cells compared with the subway PM2.5 group. Additionally, tight junctions (TJs) of BEAS-2B cells including zonula occludens-1, E-cadherin, and occludin were decreased by subway PM2.5 in a dose-dependent manner. Moreover, supernatant recovered from the subway PM2.5 group markedly decreased the expression of these TJs compared with the control group. Furthermore, inhibitors of toll-like receptors (TLRs) and nuclear factor-kappa B (NF-κB), as well as chelate resins (e.g., chelex) and deferoxamine, remarkably ameliorated the observed changes of cytokines and TJs caused by subway PM2.5 in BEAS-2B cells. Therefore, these results suggest that subway PM2.5 induced a decline of TJs after an initial ascent of cytokine expression, and subway PM2.5 altered expression of both cytokines and TJs by activating TLRs/NF-κB-dependent pathway in BEAS-2B cells. The metal components of subway PM2.5 may contribute to the airway epithelial injury.

A metabolomics perspective reveals the mechanism of the uric acid-lowering effect of Prunus salicina Lindl. cv. "furong" polyphenols in hypoxanthine and potassium oxybate-induced hyperuricemic mice.

The incidence of hyperuricemia (HUA) shows a gradually increasing trend towards affecting younger individuals, and it can significantly harm the overall health status of the body. Based on a metabolomics perspective, this study reveals the mechanism of the uric acid-lowering action of Prunus salicina Lindl. cv. "furong" polyphenols (PSLP) on a hyperuricemia mouse model induced by hypoxanthine and potassium oxybutyrate. The results demonstrate that PSLP comprise an effective treatment strategy for reducing the levels of serum uric acid (SUA), serum creatinine (SCr) and blood urea nitrogen (BUN) in HUA mice (p < 0.05), wherein the maximum decrease rates are up to 44.50%, 29.46%, and 32.95%, respectively. PSLP are observed to exert a pronounced inhibitory effect on the activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) in the livers of HUA mice, with reductions of up to 16.36% and 20.13%, respectively. These findings illustrate that PSLP exert a significant uric acid-lowering effect. Subsequent metabolomic analysis of mouse serum identified 28 potential biomarkers for hyperuricemia, whose levels were markedly diminished by PSLP. This process involved alterations in purine, glycine, the pentose phosphate pathway, and galactose metabolism. Twenty-eight potential biomarkers were identified for hyperuricemia by subsequent metabolomic analysis of mouse serum, whose levels were markedly reversed by PSLP intervention. The regulation of HUA by PSLP involved alterations in purine metabolism, glycerolipid metabolism, the pentose phosphate pathway, and galactose metabolism. The mechanism of PSLP ameliorated hyperuricemia might be attributed to reduction of the level of the uric acid precursor ribose-5-phosphate in the pentose phosphate pathway, the inhibition of the activities of uric acid synthase XOD and ADA in purine metabolism, and reduction of the synthesis of the end product uric acid. This study provides a theoretical basis for the development of functional foods based on PSLP, which can potentially reduce uric acid levels.

The Clinical Characteristics and Outcomes of Acute Pancreatitis Are Different in Elderly Patients: A Single-Center Study over a 6-Year Period.

Objectives: This study aims to analyze the clinical characteristics of elderly patients with acute pancreatitis (AP) and investigate the effects of age on the clinical outcomes of AP. Methods: Patients aged ≥ 18 years with AP admitted within 72 h from 1 September 2013 to 31 August 2019 were included. Patients were divided into elderly (≥60 years) and non-elderly (<60 years) groups. Clinical data and outcomes were compared. Results: A total of 756 elderly and 4896 non-elderly patients with AP were included. The elderly patients had different etiological distributions and more severe clinical markers and scores. Age was an independent risk factor for mortality [odds ratio (OR): 2.911, 95% CI: 1.801-4.706, p < 0.001], intensive care unit admission (OR: 1.739, 95% CI: 1.126-2.685, p = 0.013), persistent organ failure (OR: 1.623, 95% CI: 1.326-1.987, p < 0.001), multiple organ failure (OR: 1.757, 95% CI: 1.186-2.604, p = 0.005), and infection (OR: 2.451, 95% CI: 1.994-3.013, p < 0.001). Adjusted multiple logistic regression and trend analysis confirmed the risk of the age for the outcomes. The deaths of elderly patients showed a biphasic pattern with peaks in the first and fifth weeks, in contrast to the single peak in the first week in the non-elderly patients. Conclusions: Elderly patients with AP were associated with worse clinical outcomes. It is crucial to devote considerable attention to the optimization of therapeutic approaches to reduce late mortality in this group of patients.

Kaempferol inhibited invasion and metastasis of gastric cancer cells by targeting AKT/GSK3ß pathway based on network pharmacology and molecular docking.

This study aims to explore the mechanisms of the inhibitory effect of kaempferol on the invasion and metastasis of gastric cancer (GC) cells through network pharmacology prediction and experimental verification. It identifies core targets via PPI network analysis and finds that kaempferol binds to these targets well. In vitro experiments showed that kaempferol could inhibit the proliferation, colony formation, migration and invasion of GC cells. Western blotting indicated kaempferol may reduce AKT and GSK3ß phosphorylation, leading to lower expression of invasion-related genes SRC, MMP9, CXCR4, KDR, and MMP2. Overall, kaempferol may prevent migration and invasion of GC cells via the AKT/GSK3ß signaling pathway.

Nicotinamide Suppresses Hyperactivation of Dendritic Cells to Control Autoimmune Disease through PARP Dependent Signaling.

Dendritic cells (DCs) are crucial in initiating and shaping both innate and adaptive immune responses. Clinical studies and experimental models have highlighted their significant involvement in various autoimmune diseases, positioning them as promising therapeutic targets. Nicotinamide (NAM), a form of vitamin B3, with its anti-inflammatory properties, has been suggested, while the involvement of NAM in DCs regulation remains elusive. Here, through analyzing publicly available databases, we observe substantial alterations in NAM levels and NAM metabolic pathways during DCs activation. Furthermore, we discover that NAM, but not Nicotinamide Mononucleotide (NMN), significantly inhibits DCs over-activation in vitro and in vivo. The suppression of DCs hyperactivation effectively alleviates symptoms of psoriasis. Mechanistically, NAM impairs DCs activation through a Poly (ADP-ribose) polymerases (PARPs)-NF-κB dependent manner. Notably, phosphoribosyl transferase (NAMPT) and PARPs are significantly upregulated in lipopolysaccharide (LPS)-stimulated DCs and psoriasis patients; elevated NAMPT and PARPs expression in psoriasis patients correlates with higher psoriasis area and severity index (PASI) scores. In summary, our findings underscore the pivotal role of NAM in modulating DCs functions and autoimmune disorders. Targeting the NAMPT-PARP axis emerges as a promising therapeutic approach for DC-related diseases.

Enzymatic synthesis of N-formylated sialosides via a five-enzyme cascade.

Here we report an enzymatic approach to synthesize N-formylneuraminic acid (Neu5Fo) containing sialosides, through a five-enzyme cascade. This method stands as an alternative to traditional chemical syntheses, aiming for precision and efficiency in generating sialosides with a tailored N-formyl group generated directly from formic acid. The newly synthesized Neu5Fo was characterized using various NMR techniques revealing a conformational equilibrium at the amide bond of the formyl group in slow exchange on the NMR time scale with a trans : cis ratio of ∼2 : 1. This work not only suggests potential for exploring the biological roles of sialosides but also points to the possibility of developing novel therapeutic agents.