Investigating a novel surrogate indicator of adipose accumulation in relation to erectile dysfunction.

INTRODUCTION: Although previous studies have linked obesity and erectile dysfunction, the novel surrogate indicators of adipose accumulation are more essential and dependable factors to consider. Therefore, the primary objective of the current investigation was to examine and clarify the association between metabolic score for visceral fat (METS-VF) and erectile dysfunction. METHODS: Firstly, multivariate logistic regression analysis, smoothed curve fitting, and threshold effect analysis were employed to investigate the association between METS-VF and erectile dysfunction. Mediation analysis was also performed to evaluate the mediating role of homocysteine and inflammation. After that, subgroup analysis was carried out to examine the stability of the correlation of METS-VF with erectile dysfunction in various population settings. Furthermore, the area under the receiver operating characteristic (ROC) curve and eXtreme Gradient Boosting (XGBoost) algorithm were utilized to assess the capability of identifying METS-VF in comparison to the other four obesity-related indicators in identifying erectile dysfunction. RESULTS: After adjusting for all confounding factors, METS-VF was strongly and favourablely correlated with erectile dysfunction. With each additional unit rise in METS-VF, the prevalence of erectile dysfunction increased by 141%. A J-shaped relationship between METS-VF and erectile dysfunction was discovered through smoothed curve fitting. Marital status, physical activity, and smoking status can potentially modify this association. This finding of the ROC curve suggests that METS-VF had a powerful identifying capacity for erectile dysfunction (AUC = 0.7351). Homocysteine and inflammation mediated 4.24% and 2.81%, respectively. CONCLUSION: The findings of the current investigation suggest that METS-VF can be considered a dependable identifying indicator of erectile dysfunction.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Primary pulmonary meningioma and minute pulmonary meningothelial-like nodules: Rare pulmonary nodular lesions requiring more awareness in clinical practice.

In this editorial, we comment on an article by Ruan et al published in a recent issue of the World Journal of Clinical Case. Pulmonary meningothelial proliferative lesions, including primary pulmonary meningiomas, minute pulmonary meningothelial-like nodules, and metastatic pulmonary meningiomas are rare pulmonary lesions. These lesions are difficult to differentiate from lung cancers based on clinical and imaging manifestations. Herein, we briefly introduce the clinical, imaging, and pathological characteristics of these lesions and discuss their pathogenesis to strengthen the current understanding of pulmonary meningothelial proliferative lesions in clinical diagnosis and therapy.

Risk factors associated with false negative rate of sentinel lymph node biopsy in endometrial cancer: a systematic review and meta-analysis.

Objective: Currently, sentinel lymph node biopsy (SLNB) is increasingly used in endometrial cancer, but the rate of missed metastatic lymph nodes compared to systemic lymph node dissection has been a concern. We conducted a systematic review and meta-analysis to evaluate the false negative rate (FNR) of SLNB in patients with endometrial cancer and to explore the risk factors associated with this FNR. Data sources: Three databases (PubMed, Embase, Web of Science) were searched from initial database build to January 2023 by two independent reviewers. Research eligibility criteria: Studies were included if they included 10 or more women diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I or higher endometrial cancer, the study technique used sentinel lymph node localization biopsy, and the reported outcome metrics included false negative and/or FNR. Study appraisal and synthesis methods: Two authors independently reviewed the abstracts and full articles. The FNR and factors associated with FNR were synthesized through random-effects meta-analyses and meta-regression. The results: We identified 62 eligible studies. The overall FNR for the 62 articles was 4% (95% CL 3-5).There was no significant difference in the FNR in patients with high-risk endometrial cancer compared to patients with low-risk endometrial cancer. There was no difference in the FNR for whether frozen sections were used intraoperatively. The type of dye used intraoperatively (indocyanine green/blue dye) were not significantly associated with the false negative rate. Cervical injection reduced the FNR compared with alternative injection techniques. Indocyanine green reduced the FNR compared with alternative Tc-99m. Postoperative pathologic ultrastaging reduced the FNR. Conclusions: Alternative injection techniques (other than the cervix), Tc-99m dye tracer, and the absence of postoperative pathologic ultrastaging are risk factors for a high FNR in endometrial cancer patients who undergo SLNB; therefore, we should be vigilant for missed diagnosis of metastatic lymph nodes after SLNB in such populations. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023433637.

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

Efficacy and safety of perioperative therapy for locally resectable gastric cancer: A network meta-analysis of randomized clinical trials.

BACKGROUND: Gastric cancer (GC) is the fifth most commonly diagnosed malignancy worldwide, with over 1 million new cases per year, and the third leading cause of cancer-related death. AIM: To determine the optimal perioperative treatment regimen for patients with locally resectable GC. METHODS: A comprehensive literature search was conducted, focusing on phase II/III randomized controlled trials (RCTs) assessing perioperative chemotherapy and chemoradiotherapy in treating locally resectable GC. The R0 resection rate, overall survival (OS), disease-free survival (DFS), and incidence of grade 3 or higher nonsurgical severe adverse events (SAEs) associated with various perioperative regimens were analyzed. A Bayesian network meta-analysis was performed to compare treatment regimens and rank their efficacy. RESULTS: Thirty RCTs involving 8346 patients were included in this study. Neoadjuvant XELOX plus neoadjuvant radiotherapy and neoadjuvant CF were found to significantly improve the R0 resection rate compared with surgery alone, and the former had the highest probability of being the most effective option in this context. Neoadjuvant plus adjuvant FLOT was associated with the highest probability of being the best regimen for improving OS. Owing to limited data, no definitive ranking could be determined for DFS. Considering nonsurgical SAEs, FLO has emerged as the safest treatment regimen. CONCLUSION: This study provides valuable insights for clinicians when selecting perioperative treatment regimens for patients with locally resectable GC. Further studies are required to validate these findings.

Intermittent tourniquet compared to throughout tourniquet use during Total Knee Arthroplasty in patients with Body Mass Index of 30 or more: A retrospective cohort study.

Background: Tourniquet use during total knee arthroplasty (TKA) reduces bleeding which optimises bone-cement interface for prosthesis stability and improves surgical field visualisation. However, prolonged usage can lead to complications and poorer outcomes. Some surgeons advocate for intermittent tourniquet application. Limited literature exists for patients with high body mass index (BMI). This study aims to compare the outcomes of intermittent tourniquet (IT) to throughout tourniquet (TT) use among obese patients undergoing primary TKA for knee osteoarthritis. Methods: This was a retrospective cohort study. In the TT group, tourniquet was inflated from the beginning and released once the bone cement has hardened. In the IT group, tourniquet was inflated at the beginning, released after initial incision and haemostasis, then inflated again during cementation. Tourniquet was released once the bone cement had set. Categorical outcome measures were analysed using Chi-squared or Fisher's exact test. T-test or Kruskal-Wallis test were used for continuous data. Results: When comparing IT to TT among patients with BMI≥30 (IT n = 48, TT n = 47), the mean duration of surgery was shorter in the TT group (p < 0.05). The difference in haemoglobin drop between the two groups was not statistically significant from post-operative day three onwards. There was no difference in transfusion rate (p > 0.05). ROM was greater in the IT group up to three weeks post-operatively (p < 0.05). When comparing patients with BMI <30 (n = 71) and BMI≥30 (n = 48) with IT use, there was no statistically significant difference in ROM and LOS. Conclusion: Patients with BMI≥30 in the IT group had greater ROM in the initial post-operative period. Although operative time and blood loss were greater among the IT group, there was no difference in transfusion rate. Outcomes of TKA performed with IT were similar for patients with BMI≥30 and BMI <30. The authors recommend intermittent tourniquet use during TKA for patients with BMI≥30. Level of evidence: 3.

Tumor necrosis factor α1 decreases mucosal immune and antioxidant response in the midgut of hybrid fish (white crucian carp ♀ × red crucian carp ♂).

Tumor necrosis factor α1 (TNFα) is a pleiotropic cytokine involved in immune regulation and cellular homeostasis, but the crucial role of TNFα in fish gut remained unclear. The current study aimed to evaluate the immunoregulatory function of TNFα1 on gut barrier in a novel hybrid fish (WR), which was produced by crossing white crucian carp (Carassius cuvieri, ♀) with red crucian carp (Carassius auratus red var, ♂). In this study, WR-tnfα1 sequence was identified, and a high-level expression was detected in the intestine. Elevated levels of WR-tnfα1 expressions were detected in immune-related tissues and cultured fish cells on stimulation. The appearance of vacuolization and submucosal rupture was observed in TNFα1-treated midgut of WR, along with elevated levels of goblet cell atrophy, whereas no significant changes were detected in most expressions of tight-junction genes and mucin genes. In contrast, WR receiving gut perfusion with WR-TNFα1 showed a remarkable decrease in antioxidant status in midgut, whereas the expression levels of apoptotic genes and redox responsive genes increased sharply. These results suggested that TNFα1 could exhibit a detrimental effect on antioxidant defense and immune regulation in the midgut of WR.

Added value of DCER-features to clinicopathologic model for predicting metachronous metastases in rectal cancer patients.

RATIONALE AND OBJECTIVES: The study aimed to investigate whether dynamic contrast-enhanced MRI parameters and preoperative radiological features (DCER-Features) add value to the clinicopathologic model for predicting metachronous metastases in rectal cancer patients. MATERIALS AND METHODS: From January 2014 to December 2020, 859 patients in the PACS system were retrospectively screened. Of the initial 722 patients with surgically confirmed rectal cancer and no synchronous metastases, 579 patients were excluded for various reasons such as lack of clinicopathological or radiological information. 143 patients were finally included in this study. And 73 Patients of them developed metachronous metastasis within five years. After stepwise multiple regression analyses, we constructed three distinct models. Model 1 was developed solely based on clinicopathological factors, and model 2 incorporated clinicopathological characteristics along with DCE-MRI parameters. Finally, model 3 was built on all available factors, including clinicopathological characteristics, DCE-MRI parameters, and radiological features based on rectal magnetic resonance imaging. The radiological features assessed in this study encompass tumor imaging staging, location, and circumferential resection margin (CRM) for primary tumors, as well as the number of visible lymph nodes and suspected metastatic lymph nodes. Receiver operating characteristic (ROC) and decision curve analysis (DCA) were conducted to evaluate whether the diagnostic efficiency was improved. RESULTS: The performance of model 3 (including clinicopathologic characteristics and DCER-Features) was the best (AUC: 0.856, 95% CI 0.778-0.886), whereas it was 0.796 (95% CI 0.720-0.828) for model 2 and 0.709 (95% CI 0.612-0.778) for model 1 (DeLong test: model 1 vs model 2, p = 0.004; model 2 vs model 3, p = 0.037; model 1 vs model 3, p < 0.001). The decision curves indicated that the net benefit of model 3 was higher than the other two models at each referral threshold. The calibration plot of the three models revealed an excellent predictive accuracy. CONCLUSION: This study suggests that DCER-Features have added value for the clinicopathological model to predict metachronous metastasis in patients with rectal cancers.

The evaluation of cystatin protein vaccines based on the stress response of ticks triggered by low-temperature and toxin stress in Haemaphysalis doenitzi.

BACKGROUND: Ticks, which are obligate blood-feeding parasites, transmit a wide range of pathogens during their hematophagic process. Certain enzymes and macromolecules play a crucial role in inhibition of several tick physiological processes, including digestion and reproduction. In the present study, genes encoding type 2 cystatin were cloned and characterized from Haemaphysalis doenitzi, and the potential role of cystatin in tick control was further assessed. RESULTS: Two cystatin genes, HDcyst-1 and HDcyst-2, were successfully cloned from the tick H. doenitzi. Their open reading frames are 390 and 426 base pairs, and the number of coding amino acids are 129 and 141, respectively. In the midgut, salivary glands, Malpighian tubules and ovaries of ticks, the relative expression of HDcyst-1 was higher in the midgut and Malpighian tubules, and HDcyst-2 was higher in the salivary glands of H. doenitzi, respectively. Lipopolysaccharide (LPS) injection and low-temperature stress elevated cystatin expression in ticks. Enzyme-linked immunosorbent assay showed that both rHDcyst-1 and rHDcyst-2 protein vaccines increased antibody levels in immunized rabbits. A vaccination trial in rabbits infected with H. doenitzi showed that both recombinant cystatin proteins significantly reduced tick engorgement weights and egg mass weight, in particular, rHDcyst-1 significantly prolonged tick engorgement time by 1 day and reduced egg hatching rates by 16.9%. In total, rHDcyst-1 and rHDcyst-2 protein vaccinations provided 64.1% and 51.8% protection to adult female ticks, respectively. CONCLUSION: This is the first report on the immunological characterization of the cystatin protein and sequencing of the cystatin gene in H. doenitzi. Cystatin proteins are promising antigens that have the potential to be used as vaccines for infestation of H. doenitzi control. © 2024 Society of Chemical Industry.

Cadmium toxicity to and accumulation in a soil collembolan (Folsomia candida): major factors and prediction using a back-propagation neural network model.

Accurate prediction of cadmium (Cd) ecotoxicity to and accumulation in soil biota is important in soil health. However, very limited information on Cd ecotoxicity on naturally contaminated soils. Herein, we investigated soil Cd ecotoxicity using Folsomia candida, a standard single-species test animal, in 28 naturally Cd-contaminated soils, and the back-propagation neural network (BPNN) model was used to predict Cd ecotoxicity to and accumulation in F. candida. Soil total Cd and pH were the primary soil properties affecting Cd toxicity. However, soil pH was the main factor when the total Cd concentration was < 3 mg kg-1. Interestingly, correlation analysis and the K-spiked test confirmed nutrient potassium (K) was essential for Cd accumulation, highlighting the significance of studying K in Cd accumulation. The BPNN model showed greater prediction accuracy of collembolan survival rate (R2 = 0.797), reproduction inhibitory rate (R2 = 0.827), body Cd concentration (R2 = 0.961), and Cd bioaccumulation factor (R2 = 0.964) than multiple linear regression models. Then the developed BPNN model was used to predict Cd ecological risks in 57 soils in southern China. Compared to multiple linear regression models, the BPNN models can better identify high-risk regions. This study highlights the potential of BPNN as a novel and rapid tool for the evaluation and monitoring of Cd ecotoxicity in naturally contaminated soils.

[Tetramethylpyrazine regulates angiogenesis of endothelial cells in cerebral ischemic stroke injury via SIRT1/VEGFA signaling pathway].

This study aims to investigate whether tetramethylpyrazine(TMP) can stimulate angiogenesis in cerebral microvascular endothelial cells and alleviate cerebral ischemic stroke(CIS) and to explore the underlying mechanisms. In the animal study, adult Sprague-Dawley rats(n=15) were assigned into sham surgery(sham), middle cerebral artery occlusion/reperfusion(MCAO/R), and MCAO/R+TMP(intraperitoneal injection of 20 mg·kg~(-1)) groups. The neurological function was evaluated by the Z-Longa method. The cerebral infarction volume was detected by TTC staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the expression of vascular endothelial growth factor(VEGF), angiopoietin(Ang), and platelet-derived growth factor(PDGF). Immunofluorescence staining was employed to detect Ki67 and the expression of vascular endothelial growth factor A(VEGFA) and slient information regulator 1(SIRT1). Western blot was employed to determine the expression levels of VEGFA, SIRT1, angiopoietin-2(Ang-2), and platelet-derived growth factor B(PDGFB). In the cell study, mouse brain-derived endothelial cells(Bend.3) were cultured, and the optimal concentration of TMP was determined. Then, VEGF, Ang, and PDGF were detected by ELISA after the addition of cabozantinib. Western blot was employed to measure the expression of VEGFA, Ang-2, and PDGFB. Immunofluorescence staining was used to detect CD31, CD34, and Ki67, and the proliferation, migration, and tube formation ability of Bend.3 cells were observed in vitro. Western blot and immunofluorescence staining were performed to measure the expression of SIRT1 and VEGFA after addition of the SIRT1-specific inhibitor selisistat(EX-527). The results showed that compared with the sham group, the MCAO/R group had severe neurological function damage, increased infarction volume, up-regulated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, and PDGFB, and down-regulated expression of Ki67 and SIRT1(P<0.01). Compared with the MCAO/R group, the MCAO/R+TMP group presented alleviated neurological function damage, reduced infarction volume, and activated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, Ki67, and SIRT1(P<0.01). The cell experiments showed that compared with the normal group, Bend.3 cells were activated by oxygen glucose deprivation/reoxygenation(OGD/R) treatment(P<0.05, P<0.01). Compared with the OGD/R group, the OGD/R+TMP group upregulated the expression levels of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, SIRT1, Ki67, CD31, and CD34, enhanced the angiogenic ability of Bend.3 cells without being inhibited by BMS or EX-527(P<0.05, P<0.01, P<0.001). The results suggest that TMP can activate the SIRT1/VEGFA signaling pathway to stimulate angiogenesis and alleviate CIS injury.

Effect of different interventions on the treatment of high-risk human papillomavirus infection: a systematic review and network meta-analysis.

Background: Persistent infection with high-risk human papillomavirus (HR-HPV) can lead to cervical intraepithelial neoplasia and cancer. At present, there is no medication that specifically targets HR-HPV infection. Objective: This study aimed to evaluate the effectiveness of different interventions in promoting HR-HPV regression using a MeSH meta-analysis method. Methods: A search for randomized controlled trials (RCTs) reporting different interventions for the treatment of HR-HPV infection included PubMed, Web of Science, Embase and Cochrane Library from the inception of the databases to March 8, 2023. Two researchers independently screened the articles, extracted data, and evaluated the quality. The literature that met the inclusion criteria was selected, the quality and risk of bias of the included studies were assessed according to the Cochrane 5.1 manual, and NMA was performed using Stata 16.0. The area under the cumulative ranking probability graph (SUCRA) represented the probability that each treatment would be the best intervention. Results: Nine studies involving 961 patients and 7 treatment options were included in the analysis. The results of the network meta-analysis indicated the following rank order in terms of promoting HR-HPV conversion: Anti-HPV biological dressing > vaginal gel > imiquimod > REBACIN® > interferon > probiotics > observation/placebo > Polyphenon E. Conclusion: Anti-HPV biological dressing treatment was found to be significantly effective in promoting HR-HPV conversion. However, further validation of the findings is necessary due to the limited number and quality of studies included in the analysis. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023413917.

Biosynthesis of Nicotinamide Mononucleotide: Synthesis Method, Enzyme, and Biocatalytic System.

Nicotinamide mononucleotide (NMN) has garnered substantial interest as a functional food product. Industrial NMN production relies on chemical methods, facing challenges in separation, purification, and regulatory complexities, leading to elevated prices. In contrast, NMN biosynthesis through fermentation or enzyme catalysis offers notable benefits like eco-friendliness, recyclability, and efficiency, positioning it as a primary avenue for future NMN synthesis. Enzymatic NMN synthesis encompasses the nicotinamide-initial route and nicotinamide ribose-initial routes. Key among these is nicotinamide riboside kinase (NRK), pivotal in the latter route. The NRK-mediated biosynthesis is emerging as a prominent trend due to its streamlined route, simplicity, and precise specificity. The essential aspect is to obtain an engineered NRK that exhibits elevated activity and robust stability. This review comprehensively assesses diverse NMN synthesis methods, offering valuable insights into efficient, sustainable, and economical production routes. It spotlights the emerging NRK-mediated biosynthesis pathway and its significance. The establishment of an adenosine triphosphate (ATP) regeneration system plays a pivotal role in enhancing NMN synthesis efficiency through NRK-catalyzed routes. The review aims to be a reference for researchers developing green and sustainable NMN synthesis, as well as those optimizing NMN production.

PRMT1 Integrates Immune Microenvironment and Fatty Acid Metabolism Response in Progression of Hepatocellular Carcinoma.

Background: Protein arginine methyltransferase (PRMT) family members have important roles in cancer processes. However, its functions in the regulation of cancer immunotherapy of hepatocellular carcinoma (HCC) are incompletely understood. This study aimed to investigate the roles of PRMT1 in HCC. Methods: Single-cell RNA sequencing (scRNA-seq) and clinicopathological data were obtained and used to explore the diagnostic and prognostic value, cellular functions and roles in immune microenvironment regulation of PRMT1 in HCC. The functions of PRMT1 were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), as well as gene set enrichment analysis (GSEA). TIMER and CIBERSORT were used to analyze the relationships between PRMT1 expression and immune cell infiltration. The STRING database was used to construct a protein-protein interaction (PPI) network. Results: PRMT1 was aberrantly expressed in HCC, which high expression was associated with tumor progression, worse overall survival (OS) and disease-free survival (DFS) of patients with HCC. PRMT1 was also associated with immune cell infiltration. Moreover, it was specifically expressed in immune cells, including exhausted CD8 T cells, B cells, and mono/macro cells in patients with immunotherapy. The expression of immune checkpoints was significantly increased in the high-PRMT1 expression groups of HCC patients. Regarding biological mechanisms, cell viability, migration and invasion, and the expression of genes related to fatty acid metabolism were suppressed in PRMT1 knockdown HCC cells. Moreover, genes co-expressed with PRMT1 were involved in the fatty acid metabolic process and enriched in fatty and drug-induced liver disease. Conclusion: Taken together, these results indicate that PRMT1 might exert its oncogenic effects via immune microenvironment regulation and fatty acid metabolism in HCC. Our finding will provide a foundation for further studies and indicate a potential clinical therapeutic target for liver cancer.

Koningipyridines A and B, two nitrogen-containing polyketides from the fungus Trichoderma koningiopsis SC-5.

Two novel koninginin derivatives, koningipyridines A and B (1 and 2), along with four known compounds (3-6) were isolated from the EtOAc extract of the endophytic fungus Trichoderma koningiopsis SC-5. Among them, koningipyridine A featured an unprecedented pentacyclic ketal skeleton with the formation of a fascinating 6/6/5/6/5 fused ring system and shared a characteristic pyridine core, which represents the first example of nitrogen-containing koninginin-type natural product. Moreover, koningipyridine B was the first member in the koninginin family sharing a unique 6/6/5 dihydropyridine skeleton, and it was suggested to be the critical biosynthetic precursor of koningipyridine A. The structures of 1 and 2 were elucidated by the interpretation of 1D and 2D NMR spectroscopy, HRESIMS data, as well as theoretical calculations of 13C NMR and electronic circular dichroism (ECD). Moreover, all isolates were screened for antimicrobial activities against Staphylococcus aureus, MRSA, and Escherichia coli as well as the cytotoxic effects against three cancer cell lines (A549, Hela, and HepG2).

Cloning, expression and functional characterization of recombinant tumor necrosis factor α1 (TNFα1) from white crucian carp in gut immune regulation.

TNFα is one of important cytokines belonging to TNF superfamily, which can exhibit a pleiotropic effect in immune modulation, homeostasis as well as pathogenesis. However, its immunoregulatory function on mucosal immunity in fish gut are still unclear. In this study, we aimed to investigated the immunoregulatory role of TNFα1 in midgut of white crucian carp (WCC). WCC-TNFα1 sequence and its deduced structure were firstly identified in WCC. Then, tissue-specific analysis revealed that high-level WCC-TNFα1 expression was detected in gill. After Aeromonas hydrophila and lipopolysaccharide (LPS) stimulated, increased trends of WCC-TNFα1 expressions were detected in immune-related tissues and cultured fish cells, respectively. WCC anal-intubated with WCC-TNFα1 fusion protein showed the increased levels of edema and fuzzy appearance in impaired villi, along with atrophy and reduction of goblet cells (GC). Moreover, the expression levels of tight junction (TJ) genes and mucin genes were consistently lower than those of the control (P < 0.05). WCC-TNFα1 treatment could sharply decrease antioxidant status in midgut, while the expression levels of caspase (CASP) genes, unfolded protein response (UPR) genes and redox response genes increased dramatically. Our results suggested that WCC-TNFα1 could exhibit a detrimental effect on antioxidant and mucosal immune regulation in midgut of WCC.

Anemoside B4, a new pyruvate carboxylase inhibitor, alleviates colitis by reprogramming macrophage function.

OBJECTIVES: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. METHODS: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. RESULTS: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. CONCLUSION: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis.