Comparative profiling of serum, urine, and feces bile acids in humans, rats, and mice.

Bile acids (BAs) play important pathophysiological roles in both humans and mammalian animals. Laboratory rats and mice are widely used animal models for assessing pharmacological effects and their underlying molecular mechanisms. However, substantial physiological differences exist in BA composition between humans and murine rodents. Here, we comprehensively compare BA profiles, including primary and secondary BAs, along with their amino acid conjugates, and sulfated metabolites in serum, urine, and feces between humans and two murine rodents. We further analyze the capabilities in gut microbial transform BAs among three species and compare sex-dependent variations within each species. As a result, BAs undergo amidation predominately with glycine in humans and taurine in mice but are primarily unamidated in rats. BA sulfation is a unique characteristic in humans, whereas rats and mice primarily perform multiple hydroxylations during BA synthesis and metabolism. For gut microbial transformed BA capabilities, humans are comparable to those of rats, stronger than those of mice in deconjugation and 7α-dehydroxylation, while humans are weak than those of rats or mice in oxidation and epimerization. Such differences enhance our understanding of the divergent experimental outcomes observed in humans and murine rodents, necessitating caution when translating findings from these rodent species to humans.

Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity.

The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.

Tofacitinib for managing granuloma formation after dermal filler injection: three case reports and literature review.

BACKGROUND: Granuloma formation is an uncommon and persistent skin inflammatory condition caused by the injection of dermal fillers. The exact cause of this reaction is not well understood, but it may be associated with irritating components or abnormal immune function. Treating granulomas can be difficult. However, recent research has shown that Janus kinase (JAK) inhibitors hold promise as a potential therapy for refractory granulomatous diseases. OBJECTIVES: The aim was to evaluate the efficacy and safety of tofacitinib as a treatment for granulomas secondary to filler injection and the possible mechanisms were discussed and summarized. METHODS: This study focuses on three cases of patients who experienced granuloma formation after receiving filler injections and were subsequently treated with tofacitinib. The efficacy and safety of the treatment were evaluated using parameters such as photographs and monitoring for any adverse reactions. In addition, a literature review was conducted to explore the underlying mechanisms and potential effects of tofacitinib. RESULTS: All three cases recovered from swelling and nodules without side effects through the off-label use of oral tofacitinib. Existing data review reveals some approaches for cutaneous granulomatous disorders like inhibiting macrophage activation and downregulation of the JAK-STAT pathway. CONCLUSION: This report emphasizes the effectiveness of JAK inhibitors in treating granulomas caused by filler injections. Recent advancements in understanding the underlying mechanisms of granulomatous reactions have paved the way for JAK inhibitors to be regarded as a promising treatment choice. However, further research is necessary to fully assess the safety and long-term effectiveness of using tofacitinib for granuloma treatment.

Longitudinal mediation effect of hassles between neuroticism and dimensions of the tripartite model in college students.

This study addresses a gap in the literature by exploring the longitudinal effects of hassles in mediating the relationship between neuroticism and the tripartite model of depression and anxiety. The research investigates these associations in a large sample of university students, utilising baseline and 6-month follow-up data. Initial assessments involved participants completing measures for neuroticism, depression and anxiety symptoms, and the occurrence of stress, followed by monthly assessments of stress, anxiety symptom and mood symptoms over a 6-month period. Our results illuminate the mediating role of daily hassles in the relationship between neuroticism and various dimensions of anxiety and depression, including general distress, specific depression, and anxiety symptoms. These findings underscore the significant impact of neuroticism and hassles on a broad spectrum of mood symptoms, offering valuable insights for both research and clinical practice. Discussions around the implications of these findings are provided in the our paper, where we also outline potential directions for future research and clinical applications.

A longitudinal investigation of the cross-dimensional mediating role of negative life events between neuroticism and depressive symptoms in adolescents.

BACKGROUND: Neuroticism has been identified as a significant predictor for depression within the adolescent population However, few longitudinal studies have investigated this association and explored the mediation effect of the negative life events. This study aimed to examine the longitudinal association between neuroticism, negative life events, and depression in a large sample of Chinese adolescents. METHODS: Data on Five Factor Inventory-Neuroticism Subscale (FFI-N) was collected from 1150 participants aged 14-19 years old at baseline, and data on Adolescent Life Event Questionnaire (ALEQ) and Center of Epidemiological Study-Depression (CES-D) were collected both at baseline and 6-month follow-up. Multilevel modelings were used to analyze the longitudinal associations among neuroticism, negative life events and depression. RESULTS: Through a longitudinal study design, results from multilevel regression analyses indicated a direct correlation between increased levels of neuroticism and the aggregation of negative life events with the prediction of more severe depressive symptoms. Further, results of multilevel mediations suggested that the negative life events served to partially mediate the relationship between neuroticism and each dimension of depression. LIMITATIONS: The results cannot be used to make a clinical diagnosis. CONCLUSION: The current findings suggest the negative life events as a cross-dimensional mediator in the relationship between neuroticism and each dimension of depression. Regulating neuroticism levels and implementing strategies to coping stress derived from daily life events could be integral approaches to reducing the prevalence of depression within the adolescent population.

Clinical efficacy of intense pulsed light combined with low-dose intralesional corticosteroids in treating noninfectious granulomas after mesotherapy: A case series analysis.

BACKGROUND: Mesotherapy is a popular cosmetic procedure for localized delivery of substances. However, due to the lack of standardized processes, there are potential risks of adverse reactions. Granulomas formation is one of the chronic reactions which impose significant physical and mental burdens on patients. OBJECTIVES: The aim of this analysis is to evaluate the safety and feasibility of combining intense pulsed light (IPL) with intralesional corticosteroids for treating noninfectious granulomas after mesotherapy. METHODS: This retrospective observational case series included patients who suffer from noninfectious granulomas after mesotherapy and received combination of IPL and intralesional corticosteroids treatment between October 2021 and December 2022 at Peking University Shenzhen Hospital, Shenzhen, China. The process and effect were analyzed and summarized. RESULTS: Among the seven patients, five expressed extreme satisfaction with the efficacy, while two was slightly satisfied. The physicians believed that all patients had shown significant improvement. No adverse reactions or recurrences were observed during follow-up. CONCLUSION: Based on this analysis, the application of the combined treatment in patients suffering from noninfectious granuloma due to mesotherapy demonstrates good clinical efficacy and safety, making it worth considering as a treatment option.

Effect of interaction between dissolved organic matter and iron/manganese (hydrogen) oxides on the degradation of organic pollutants by in-situ advanced oxidation techniques.

Iron and manganese (hydrogen) oxides (IMHOs) exhibit excellent redox capabilities for environmental pollutants and are commonly used in situ chemical oxidation (ISCO) technologies for the degradation of organic pollutants. However, the coexisting dissolved organic matter (DOMs) in surface environments would influence the degradation behavior and fate of organic pollutants in IMHOs-based ISCO. This review has summarized the interactions and mechanisms between DOMs and IMHOs, as well as the properties of DOM-IMHOs complexes. Importantly, the promotion or inhibition impact of DOM was discussed from three perspectives. First, the presence of DOMs may hinder the accessibility of active sites on IMHOs, thus reducing their efficiency in degrading organic pollutants. The formation of compounds between DOMs and IMHOs alters their stability and activity in the degradation process. Second, the presence of DOMs may also affect the generation and transport of active species, thereby influencing the oxidative degradation process of organic pollutants. Third, specific components within DOMs also participate and affect the degradation pathways and rates. A comprehensive understanding of the interaction between DOMs and IMHOs helps to better understand and predict the degradation process of organic pollutants mediated by IMHOs in real environmental conditions and contributes to the further development and application of IMHO-mediated ISCO technology.

Serum Bile Acids Improve Prediction of Alzheimer's Progression in a Sex-Dependent Manner.

Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.

PRRG4 regulates mitochondrial function and promotes migratory behaviors of breast cancer cells through the Src-STAT3-POLG axis.

BACKGROUND: Breast cancer is the leading cause of cancer death for women worldwide. Most of the breast cancer death are due to disease recurrence and metastasis. Increasingly accumulating evidence indicates that mitochondria play key roles in cancer progression and metastasis. Our recent study revealed that transmembrane protein PRRG4 promotes the metastasis of breast cancer. However, it is not clear whether PRRG4 can affect the migration and invasion of breast cancer cells through regulating mitochondria function. METHODS: RNA-seq analyses were performed on breast cancer cells expressing control and PRRG4 shRNAs. Quantitative PCR analysis and measurements of mitochondrial ATP content and oxygen consumption were carried out to explore the roles of PRRG4 in regulating mitochondrial function. Luciferase reporter plasmids containing different lengths of promoter fragments were constructed. Luciferase activities in breast cancer cells transiently transfected with these reporter plasmids were analyzed to examine the effects of PRRG4 overexpression on promoter activity. Transwell assays were performed to determine the effects of PRRG4-regulated pathway on migratory behaviors of breast cancer cells. RESULTS: Analysis of the RNA-seq data revealed that PRRG4 knockdown decreased the transcript levels of all the mitochondrial protein-encoding genes. Subsequently, studies with PRRG4 knockdown and overexpression showed that PRRG4 expression increased mitochondrial DNA (mtDNA) content. Mechanistically, PRRG4 via Src activated STAT3 in breast cancer cells. Activated STAT3 in turn promoted the transcription of mtDNA polymerase POLG through a STAT3 DNA binding site present in the POLG promoter region, and increased mtDNA content as well as mitochondrial ATP production and oxygen consumption. In addition, PRRG4-mediated activation of STAT3 also enhanced filopodia formation, migration, and invasion of breast cancer cells. Moreover, PRRG4 elevated migratory behaviors and mitochondrial function of breast cancer cells through POLG. CONCLUSION: Our results indicate that PRRG4 via the Src-STAT3-POLG axis enhances mitochondrial function and promotes migratory behaviors of breast cancer cells.

Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis.

Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.

Clinical features and treatment outcomes of Vibrio vulnificus infection in the coastal city of Ningbo, China.

Background: Vibrio vulnificus is a gram-negative, opportunistic pathogen common to warm waters worldwide. Human V. vulnificus infection is rare and typically affects those residing in coastal areas during the summer months, but it causes rapid deterioration and is fatal. Methods: The medical records of six patients with sepsis caused by V. vulnificus infection who were treated at the First Affiliated Hospital of Ningbo University from 2020 to 2022 were retrospectively reviewed. The patient demographics, clinical symptoms, laboratory test results, treatments, and outcomes are summarized. Results: Vibrio vulnificus infection was confirmed by blood or pus culture, 16S ribosomal DNA sequencing, and metagenomic next-generation sequencing. All six patients were male with pre-existing liver diseases and two reported consuming seafood before the onset of symptoms. Of the six patients, four succumbed to the disease, two recovered, and one underwent leg amputation. Conclusion: Vibrio vulnificus infection progresses rapidly and is highly fatal, thus prompt and aggressive treatment is necessary. Vibrio vulnificus infection should be considered in older (>40 years) patients with a history of liver disease and recent consumption of seafood or exposure to seawater, especially those residing in coastal areas during the summer months.

Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment.

BACKGROUND AIMS: Regulatory T cells (Tregs) are an obstacle to PD-1 blockade-mediated antitumor efficacy. However, the behaviors of Tregs response to anti-PD-1 in HCC and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues to the tumor are still unclear. APPROACH RESULTS: Here, we determine that PD-1 monotherapy potentially augments the accumulation of tumor CD4 + Tregs. Mechanistically, anti-PD-1 mediates Tregs proliferation in lymphoid tissues rather than in the tumor. Increased peripheral Tregs burden replenishes intratumoral Tregs, raising the ratio of intratumoral CD4 + Tregs to CD8 + T cells. Subsequently, single-cell transcriptomics revealed that neuropilin-1 (Nrp-1) supports Tregs migration behavior, and the genes of Crem and Tnfrsf9 regulate the behaviors of the terminal suppressive Tregs. Nrp-1 + 4-1BB - Tregs stepwise develop to the Nrp-1 - 4-1BB + Tregs from lymphoid tissues into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with the 4-1BB agonist to enhance the antitumor response. Finally, a combination of the Nrp-1 inhibitor and the 4-1BB agonist in humanized HCC models showed a favorable and safe outcome and evoked the antitumor effect of the PD-1 blockade. CONCLUSION: Our findings elucidate the potential mechanism of anti-PD-1-mediated intratumoral Tregs accumulation in HCC and uncover the tissue adaptation characteristics of Tregs and identify the therapeutic potential of targeting Nrp-1 and 4-1BB for reprogramming the HCC microenvironment.

A method for quantifying hepatic and intestinal ceramides on mice by UPLC-MS/MS.

BACKGROUND: Ceramide is one type of sphingolipids, is associated with the occurrence of metabolic diseases, including obesity, diabetes, cardiovascular disease, cancer, and nonalcoholic fatty liver disease. Dihydroceramide, the direct precursors of ceramide, which is converted to ceramide with the dihydroceramide desaturase, is recently regarded as involving in various biological processes and metabolic diseases. The liver and gut ceramide levels are interactional in pathophysiological condition, quantifying hepatic and intestinal ceramide levels become indispensable. The aim of this study is to establish a rapid method for the determination of ceramides including dihydroceramides in liver and small intestinal tissues for researching the mechanisms of ceramide related diseases. METHODS: The levels of Cer d18:1/2:0, Cer d18:1/6:0, Cer d18:1/12:0, Cer d18:1/14:0, Cer d18:1/16:0, Cer d18:1/17:0, Cer d18:1/18:0, Cer d18:1/20:0, Cer d18:1/22:0, Cer d18:1/24:1, Cer d18:1/24:0, dHCer d18:0/12:0, dHCer d18:0/14:0, dHCer d18:0/16:0, dHCer d18:0/18:0, dHCer d18:0/24:1 and dHCer d18:0/24:0 in mice liver and small intestine were directly quantified by ultra-high performance liquid chromatography-tandem mass spectrometry after methanol extraction. In detail, liver or small intestine tissues were thoroughly homogenized with methanol. The resultant ceramides were separated on a Waters BEH C18 column using gradient elution within 10 min. Positive electrospray ionization with multiple reaction monitoring was applied to detect. In the end, the levels of ceramides in mice liver and small intestine tissues were quantified by this developed method. RESULTS: The limits of detection and quantification of 11 ceramides and 6 dihydroceramides were 0.01-0.5 ng/mL and 0.02-1 ng/mL, respectively, and all detected ceramides had good linearities (R2 > 0.997). The extraction recoveries of ceramides at three levels were within 82.32%-115.24% in the liver and within 83.21%-118.70% in the small intestine. The relative standard deviations of intra- and inter-day precision were all within 15%. The extracting solutions of the liver and small intestine could be stably stored in the autosampler 24 h at 10 °C, the lyophilized liver and small intestine for ceramides quantification could be stably stored at least 1 week at -80 °C. The ceramides and dihydroceramides in normal mice liver and small intestinal tissues analyzed by the developed method indicated that the detected 9 ceramide and 5 dihydroceramides levels were significantly different, in which Cer d18:1/16:0, Cer d18:1/22:0, Cer d18:1/24:1, Cer d18:1/24:0 and dHCer d18:0/24:1 are the main components in the liver, whereas Cer d18:1/16:0 and dHCer d18:0/16:0 accounts for the majority of proportion in the intestinal tissues. CONCLUSION: A simple and rapid method for the quantification of 11 ceramides and 6 dihydroceramides in the animal tissues was developed and applied. The compositions of ceramides in two tissues suggested that the compositional features should to be considered when exploring the biomarkers or molecular mechanisms.