Correlation between serum tryptophan metabolism and treatment efficacy of dapoxetine in patients with premature ejaculation: A pilot study.

INTRODUCTION: Primary premature ejaculation (PPE) is a common male neurobiological disorder. Currently, there is consensus that the impairment in central serotonin (5-HT) neurotransmission constitutes a key pathogenic factor in PPE. Selective serotonin reuptake inhibitors (SSRIs) serve as the primary pharmacological intervention; however, a comprehensive elucidation of their mechanism of action remains incomplete. Owing to significant individual variability in efficacy, SSRIs exhibit a high discontinuation rate. Hence, there is an urgent need to address the selection of SSRIs for PPE treatment. OBJECTIVE: This study aims to investigate the characteristics of tryptophan (TRP) metabolism in patients with PPE and to assess its influence on the efficacy of SSRIs. METHODS: The exploratory study included a total of 16 patients with PPE and 16 control subjects who were healthy men without any sexual dysfunction. Upon enrollment in the study, all participants underwent a thorough medical history review and physical examination. Subsequently, their serum levels of TRP, its metabolites, large neutral amino acids (LNAAs), and metabolite ratios were assessed using a liquid chromatography-mass spectrometry (LC-MS) assay. After a period of 4 weeks of dapoxetine treatment, all patients with PPE underwent reassessment using the Premature Ejaculation Diagnostic Tool (PEDT) score and intravaginal ejaculatory latency time (IELT) test. RESULTS: The ratio of serum TRP to other LNAAs (TRP/LNAAs) in patients with PPE was found to be significantly lower compared to the control group (P < 0.05). Conversely, the ratio of kynurenine to TRP (KYN/TRP) was observed to be significantly higher in the PPE patients compared to the control group (P < 0.05). Including the serum TRP/LNAAs ratio and KYN/TRP ratio in the prediction model yielded the highest prediction efficiency for PPE. There was a significant negative correlation between the ratio of TRP/LNAAs before the treatment and the IELT after 4 weeks of the treatment. Additionally, there was a significant positive correlation observed between the ratio of TRP/LNAAs before the treatment and the PEDT score after 4 weeks of the treatment. CONCLUSIONS: This study demonstrates that the reduction in the TRP/LNAAs ratio and the elevation of the KYN/TRP ratio are significant characteristics associated with PPE. These findings suggest that diminished tryptophan availability in the brain and the activation of the kynurenine (KYN) pathway may play a role in the pathogenesis of PPE. The TRP/LNAAs ratio has potential as a reliable indicator of central serotonin (5-HT) levels. Considering the TRP/LNAAs ratio when selecting SSRIs for the treatment of PPE may enhance the response rate of this medication.

Inflammation-related signature for prognostic prediction, tumor immune, genomic heterogeneity, and drug choices in prostate cancer: Integrated analysis of bulk and single-cell RNA-sequencing.

Background: Prostate cancer (PCa) ranks as the second most prevalent malignancy among males on a global scale. Accumulating evidence suggests that inflammation has an intricate relationship with tumorigenesis, tumor progression and tumor immune microenvironment. However, the overall impact of inflammation-related genes on the clinical prognosis and tumor immunity in PCa remains unclear. Methods: Machine learning methods were utilized to construct and validate a signature using The Cancer Genome Atlas (TCGA) for training, while the Memorial Sloan Kettering Cancer Center (MSKCC) and GSE70769 cohorts for independent validation. The efficacy of the signature in predicting outcomes and its clinical utility were assessed through a series of investigations encompassing in vitro experiments, survival analysis, and nomogram development. The association between the signature and precision medicine was explored via tumor immunity, genomic heterogeneity, therapeutic response, and molecular docking analyses, using bulk and single-cell RNA-sequencing data. Results: We identified 7 inflammation-related genes with prognostic significance and developed an inflammation-related prognostic signature (IRPS) with 6 genes. Furthermore, we demonstrated that both the IRPS and a nomogram integrating risk score and pathologic T stage exhibited excellent predictive ability for the survival outcomes in PCa patients. Moreover, the IRPS was found to be significantly associated with the tumor immune, genomic heterogeneity, therapeutic response, and drug selection. Conclusion: IRPS can serve as a reliable predictor for PCa patients. The signature may provide clinicians with valuable information on the efficacy of therapy and help personalize treatment for PCa patients.

Effects of perfluorododecanoic acid on testicular function in mice.

Perfluorodecanoic acid (PFDoA) is a widely distributed environmental pollutant that can affect the functions of many organs. However, systematic evaluations of the effects of PFDoA on testicular functions are lacking. The aim of this study was to investigate the effects of PFDoA on mouse testicular functions, including spermatogenesis, testosterone synthesis, and stem Leydig cells (SLCs) in the interstitial tissue of the testis. PFDoA (0, 2, 5, 10 mg/kg/d) was administered via gavage to 2-month-old mice for 4 weeks. Serum hormone levels and sperm quality were assayed. Furthermore, to investigate the mechanisms by which PFDoA affects testosterone synthesis and spermatogenesis in vivo, the expression of StAR and P450scc in testicular tissue was measured by immunofluorescence staining and quantitative real-time PCR. In addition, the levels of SLC markers, including nestin and CD51, were studied. PFDoA decreased the luteinizing hormone concentration and sperm quality. Although the difference was not statistically significant, mean testosterone levels showed a downward trend. The expression of StAR, P450scc, CD51, and nestin was also suppressed in the PFDoA-treated groups compared with the control group. Our study suggested that PFDoA exposure can decrease testosterone biosynthesis, and even reduce the number of SLCs. These results indicated that PFDoA suppressed the main functions of testis, and further researches are required to identify strategies for preventing or reducing the effect of PFDoA on testicular function.

Multi-omics analysis reveals a macrophage-related marker gene signature for prognostic prediction, immune landscape, genomic heterogeneity, and drug choices in prostate cancer.

Introduction: Macrophages are components of the innate immune system and can play an anti-tumor or pro-tumor role in the tumor microenvironment owing to their high heterogeneity and plasticity. Meanwhile, prostate cancer (PCa) is an immune-sensitive tumor, making it essential to investigate the value of macrophage-associated networks in its prognosis and treatment. Methods: Macrophage-related marker genes (MRMGs) were identified through the comprehensive analysis of single-cell sequencing data from GSE141445 and the impact of macrophages on PCa was evaluated using consensus clustering of MRMGs in the TCGA database. Subsequently, a macrophage-related marker gene prognostic signature (MRMGPS) was constructed by LASSO-Cox regression analysis and grouped based on the median risk score. The predictive ability of MRMGPS was verified by experiments, survival analysis, and nomogram in the TCGA cohort and GEO-Merged cohort. Additionally, immune landscape, genomic heterogeneity, tumor stemness, drug sensitivity, and molecular docking were conducted to explore the relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection. Results: We identified 307 MRMGs and verified that macrophages had a strong influence on the development and progression of PCa. Furthermore, we showed that the MRMGPS constructed with 9 genes and the predictive nomogram had excellent predictive ability in both the TCGA and GEO-Merged cohorts. More importantly, we also found the close relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection by multi-omics analysis. Discussion: Our study reveals the application value of MRMGPS in predicting the prognosis of PCa patients. It also provides a novel perspective and theoretical basis for immune research and drug choices for PCa.

SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation.

Our previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.

Folding Sheets with Ion Beams.

Focused ion beams (FIBs) are versatile tools with cross-disciplinary applications from the physical and life sciences to archeology. Nevertheless, the nanoscale patterning precision of FIBs is often accompanied by defect formation and sample deformation. In this study, the fundamental mechanisms governing the large-scale plastic deformation of nanostructures undergoing FIB processes are revealed by a series of molecular dynamic simulations. A surprisingly simple linear correlation between atomic volume removed from the film bulk and film deflection angle, regardless of incident ion energy and current, is revealed, demonstrating that the mass transport to the surface of material caused by energetic ion bombardment is the primary cause leading to nanostructure deformation. Hence, by controlling mass transport by manipulation of the incident ion energy and flux, it is possible to control the plastic deformation of nanostructures, thereby fabricating nanostructures with complex three-dimensional geometries.

Immunomodulatory activities and antioxidant properties of polysaccharides from Monascus-fermented products in vitro.

BACKGROUND: Monascus-fermented products have featured in Chinese cuisine for thousands of years and are widely used as food colourants and dietary materials in many Asian countries. Rice and dioscorea fermented with Monascus purpureus NTU 568 have health-promoting attributes in vitro and in vivo. The aim of this study was to investigate the immunomodulatory and antioxidant effects of polysaccharides from red mould rice (RMRP) and red mould dioscorea (RMDP) in Raw 264.7 cells. RESULTS: The results showed the antioxidant capabilities (including scavenging, chelating, inhibition of lipid peroxidation, and reducing power) of RMRP and RMDP at a concentration of 10 mg mL(-1). RMRP and RMDP also stimulated cell proliferation, nitric oxide production, phagocytosis and cytokine production (including IL1-ß, IL-6 and TNF-α) in Raw 264.7 cells. CONCLUSION: These findings demonstrate that RMRP and RMDP have antioxidant and immunomodulation potential to be developed as novel dietary supplements.

Synchronous high-performance liquid chromatography with a photodiode array detector and mass spectrometry for the determination of citrinin, monascin, ankaflavin, and the lactone and acid forms of monacolin K in red mold rice.

The Monascus fermentation product red mold rice (RMR) has been found to contain the cholesterol-lowering agent monacolin K (MK) in both its lactone (MKL) and acid (MKA) forms and the mycotoxin citrinin (CT). The yellow pigments in RMR, namely, monascin (MS) and ankaflavin (AK), have been reported to exhibit antimetastatic and antiangiogenic activities. Currently, MK and these yellow pigments are usually detected in RMR by different analytical methods that are inconvenient, expensive, and time-consuming. The goal of this study was to establish a rapid, synchronous analytical method for determination of the MKA, MKL, MS, AK, and CT levels in RMR. MKA, MKL, MS, AK, and CT were extracted by the same extraction method, then separated by RP-HPLC with a C18 column. The effluent from the column was passed through a photodiode array detector and then introduced directly into a fluorescence detector. The results showed that high recovery rates of MKA, MKL, MS, AK, and CT are possible if RMR powder is extracted with 75% ethanol (10 mL) at 80 degrees C for 30 min. With regard to the optimal conditions of the HPLC, the peaks of MKA, MKL, MS, AK, and CT can be clearly separated from any noise peaks by isocratic elution with a mobile phase comprising 0.05% trifluoroacetic acid in acetonitrile-water (62.5 + 37.5, v/v).

Monascin and ankaflavin act as novel hypolipidemic and high-density lipoprotein cholesterol-raising agents in red mold dioscorea.

Monascus-fermented red mold dioscorea (RMD) has been proven to possess greater hypolipidemic effect than red mold rice (RMR) even though they include equal levels of cholesterol-lowering agent monacolin K. However, higher concentrations of yellow pigments (monascin and ankaflavin) were found in RMD than in RMR. In this study, purified monascin and ankaflavin were administered to hyperlipidemic hamsters for 8 weeks, respectively, to test whether these two compounds were novel hypolipidemic ingredients. In the statistical results, monascin and ankaflavin showed significant effect on lowering cholesterol, triglyceride, and low-density lipoprotein cholesterol levels in serum, as well as aorta lipid plaque (p < 0.05). Importantly, monascin and ankaflavin, unlike monacolin K, were able to perform up-regulation rather than down-regulation on high-density lipoprotein cholesterol (HDL-C) levels in serum. This finding not only explained why RMD showed greater hypolipidemic and HDL-C-raising effect than RMR but also proved that monascin and ankaflavin would act as novel and potent hypolipidemic ingredients.

Red mold rice promotes neuroprotective sAPPalpha secretion instead of Alzheimer's risk factors and amyloid beta expression in hyperlipidemic Abeta40-infused rats.

Amyloid beta (Abeta) peptide is closely related to the onset of Alzheimer's disease (AD). A high-cholesterol or high-energy diet was demonstrated to stimulate Abeta formation and deposition in the amyloid precursor protein (APP) pathway and, oppositely, downregulate the secretion of the neuroprotective soluble APP alpha-fragment (sAPPalpha). Monascus-fermented red mold rice (RMR) including multiple cholesterol-lowering agents, antioxidants, and anti-inflammatory agents has been proven to ameliorate Abeta40 infusion-induced memory deficit in our previous study. In this study, the ethanol extract of RMR (RE) and natural RMR were respectively tested for their effect on the mediation of the proteolytic process of APP in cholesterol-treated human neuroblastoma IMR32 cell, as well as their effect on memory and learning ability and the expression of AD risk factors in intracerebroventricular Abeta40-infused hyperlipidemic rats. In the results, RE suppressed cholesterol-raised beta-secretase activity and further resulted in the increase of sAPPalpha secretion in the IMR32 cell. In the animal test, RMR potently reversed the memory deficit in the water maze and passive avoidance tasks. RMR administration could prevent against Abeta40 infusion plus the great damage caused by a high energy diet in hippocampus and cortex involved in the raise of thiobarbituric acid reactive substances and reactive oxygen species. The neuroprotection provided by RMR downregulates Abeta40 formation and deposition by suppressing the cholesterol-raised beta-secretase activity and apolipoprotein E expression, as well as mediates the proteolytic process of APP toward neuroprotective sAPPalpha secretion in hippocampus.

Red mold dioscorea has a greater antihypertensive effect than traditional red mold rice in spontaneously hypertensive rats.

The aim of this study is to investigate the antihypertensive effects of red mold rice (RMR) and red mold dioscorea (RMD) by low-dose oral administration to spontaneously hypertensive rats (SHRs). A single oral dose of 1-fold RMD (150 mg/kg) significantly (p < 0.05) decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) after 8 h of administration, but RMR showed no significant effect. During the chronic oral administration of 1-fold RMR (150 mg/kg), 0.5-fold RMD, 1-fold RMD, and 5-fold RMD to SHRs for 8 weeks, the increase of blood pressure was slowed significantly. The results indicated that only a 0.5-fold dose of RMD was able to significantly decrease both SBP and DBP. A 1-fold RMD showed a greater antihypertensive effect than 1-fold RMR, and both RMR and RMD can improve the vascular elastin structure remodeling. In comparison to RMR, RMD contained a higher amount of gamma-aminobutyric acid (GABA) and anti-inflammatory yellow pigments (monascin and ankaflavin). Moreover, RMD also exhibited higher angiotensin-I-converting enzyme (ACE) inhibitory activity than RMR. These results suggest that RMD has greater antihypertensive bioavailability.