Taurocholate Research Articles

Effects of dietary primary bile acids on the growth, intestinal morphology, gene expression, serum metabolites and intestinal microbiota in pearl gentian grouper fed a high lipid diet

The grouper aquaculture industry flavors high lipid diets for economic reasons, yet this inevitably produces negative effects on the growth performance and intestinal function. Bile acids have been extensively reported to mitigate the negative effects on fish fed a high lipid diet, but it remains unclear whether this mechanism is bile acid type dependent. Therefore, an eight-week feeding trial was conducted to investigate the response of growth and intestinal health parameters in pearl gentian grouper Epinephelus fuscoguttatus♂ × E. lanceolatus♀ fed with high lipid diets to different types of bile acids. A high lipid diet (diet HL) containing 167 g/kg crude lipid served as the control diet, and three of primary bile acids glycocholic acid, taurocholic acid, and cholic acid were added at a dose of 900 mg/kg to generate the bile acid diets HBG, HBT, and HBC, respectively. Results revealed that dietary supplementation with glycocholic acid, taurocholic acid, or cholic acid does not affect the feed intake and growth of pearl gentian grouper fed a high lipid diet, while increasing the relative abundance of intestinal opportunistic pathogens such as Staphylococcus and Pseudomonas in this species. Dietary supplementation with glycocholic acid or cholic acid decreases muscle layer thickness and villus height, while increases intestinal injury score. Grouper fed with taurocholic acid showed higher villus width and serum antioxidant enzyme activity, along with lower intestinal injury score and serum lipid peroxidation level. For the protein and gene involved in the PI3K/AKT/mTOR pathways, S6K1 signaling, and bile acids metabolism, grouper fed with taurocholic acid exhibited an increase in the protein expression of PP70 and the mRNA expression of nrf2, pi3k, pdk1, tsc2, akt, mtorc1, fxr and tgr5. Moreover, the serum metabolites can be significantly influenced by the intestinal bacteria. Overall, dietary supplementation of 900 mg/kg taurocholic acid is recommended when feeding high lipid diets to grouper.

Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice

As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.

The Pharmacokinetics and Liver-Targeting Evaluation of Silybin Liposomes Mediated by the NTCP/OCTN2 Dual Receptors.

The disadvantage of a traditional dosage regimen is the inability to deliver a sufficient drug concentration to the lesion site, which can result in adverse side effects due to nonspecific drug delivery. Actively targeting hepatic cells is a promising therapeutic strategy for liver disease. In this study, l-carnitine and a targeting peptide derived from the hepatitis B virus large envelope protein were used to modify liposomes for drug delivery to the liver through the sodium taurocholate cotransporting polypeptide (NTCP) and the organic cation/carnitine transporter 2 (OCTN2) receptors. Silybin was selected as the model drug. The solubility of silybin can reach 0.3 mg/mL after encapsulation in liposomes. The NTCP-specific and OCTN2-accelerated Myrcludex B and l-carnitine dual-modified liposomes were validated in vitro. The uptake of coumarin-6 in dual ligand-modified liposomes by hepatocytes was up to 2.36 μg/mg compared with unmodified liposomes (1.05 μg/mg). The pharmacokinetics and targeting abilities of various liposome formulations were evaluated in Kunming mice. Targeted liposomes increased the concentration of silybin and prolonged the drug's retention time in the liver. The area under the liver's pharmacokinetic curve of targeted liposomes was twice that of silybin injection, suggesting the promising application potential of silybin-loaded hepatotropic nanovesicles.

Gut microbiota and metabolomic profile changes play critical roles in tacrolimus-induced diabetes in rats.

Hyperglycemia is one of the adverse effects of tacrolimus (TAC), but the underlying mechanism is not fully identified. We used multi-omics analysis to evaluate the changes in the gut microbiota and metabolic profile of rats with TAC-induced diabetes. To establish a diabetic animal model, Sprague Dawley rats were divided randomly into two groups. Those in the TAC group received intraperitoneal injections of TAC (3 mg/kg) for 8 weeks, and those in the CON group served as the control. 16S rRNA sequencing was used to analyze fecal microbiota. The metabolites of the two groups were detected and analyzed by nontargeted and targeted metabolomics, including amino acids (AAs), bile acids (BAs), and short-chain fatty acids (SCFAs). The rats treated with TAC exhibited hyperglycemia as well as changes in the gut microbiota and metabolites. Specifically, their gut microbiota had significantly higher abundances of Escherichia-Shigella, Enterococcus, and Allobaculum, and significantly lower abundances of Ruminococcus, Akkermansia, and Roseburia. In addition, they had significantly reduced serum levels of AAs including asparagine, aspartic acid, glutamic acid, and methionine. With respect to BAs, they had significantly higher serum levels of taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), but significantly lower levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). There were no differences in the levels of SCFAs between the two groups. Correlations existed among glucose metabolism indexes (fasting blood glucose and fasting insulin), gut microbiota (Ruminococcus and Akkermansia), and metabolites (glutamic acid, hydroxyproline, GCDCA, TDCA, and TUDCA). Both AAs and BAs may play crucial roles as signaling molecules in the regulation of TAC-induced diabetes.

Tauroursodeoxycholic Acid Improves Nonalcoholic Fatty Liver Disease by Regulating Gut Microbiota and Bile Acid Metabolism.

Tauroursodeoxycholic acid (TUDCA) is a synthetic bile salt that has demonstrated efficacy in the management of hepatobiliary disorders. However, its specific mechanism of action in preventing and treating nonalcoholic fatty liver disease (NAFLD) remains incompletely understood. This research revealed that TUDCA treatment can reduce obesity and hepatic lipid buildup, enhance intestinal barrier function and microbial balance, and increase the presence of Allobaculum and Bifidobacterium in NAFLD mouse models. TUDCA can influence the activity of farnesoid X receptor (FXR) and cholesterol 7α-hydroxylase (CYP7A1), resulting in higher hepatic bile acid levels and increased expression of sodium taurocholate cotransporting polypeptide (NTCP), leading to elevated concentrations of liver-bound bile acids in mice. Furthermore, TUDCA can inhibit the expression of FXR and fatty acid transport protein 5 (FATP5), thereby reducing fatty acid absorption and hepatic lipid accumulation. This investigation provides new insights into the potential of TUDCA for preventing and treating NAFLD.

The Impact of YabG Mutations on Clostridioides difficile Spore Germination and Processing of Spore Substrates.

YabG is a sporulation-specific protease that is conserved among sporulating bacteria. Clostridioides difficile YabG processes the cortex destined proteins preproSleC into proSleC and CspBA to CspB and CspA. YabG also affects synthesis of spore coat/exosporium proteins CotA and CdeM. In prior work that identified CspA as the co-germinant receptor, mutations in yabG were found which altered the co-germinants required to initiate spore germination. To understand how these mutations in the yabG locus contribute to C. difficile spore germination, we introduced these mutations into an isogenic background. Spores derived from C. difficile yabGC207A (a catalytically inactive allele), C. difficile yabGA46D, C. difficile yabGG37E, and C. difficile yabGP153L strains germinated in response to taurocholic acid alone. Recombinantly expressed and purified preproSleC incubated with E. coli lysate expressing wild type YabG resulted in the removal of the presequence from preproSleC. Interestingly, only YabGA46D showed any activity toward purified preproSleC. Mutation of the YabG processing site in preproSleC (R119A) led to YabG shifting its processing to R115 or R112. Finally, changes in yabG expression under the mutant promoters were analyzed using a SNAP-tag and revealed expression differences at early and late stages of sporulation. Overall, our results support and expand upon the hypothesis that YabG is important for germination and spore assembly and, upon mutation of the processing site, can shift where it cleaves substrates.

Adsorption of bile salts onto crystalline ritonavir particles under simulated gastrointestinal conditions

The formation of a biomolecular corona on nanoparticles in blood is a well-known phenomenon influencing in vivo performance. Analogous phenomena in other biological fluids, such as the formation of a gastrointestinal (GI) corona, remain under-investigated. The ingestion of medicines leads to the generation of drug particles in the GI fluids. Consequently, an understanding of the behavior of drug particles in the gut requires determination of the adsorption of bile components onto these drug particles. This work aims to elucidate the factors affecting adsorption of bile salts onto ritonavir (RTV) particles. Crystalline RTV particles were incubated with non-micellar or micellar bile salts and bile salt depletion from solution was measured using HPLC and small angle X-ray scattering (SAXS). HPLC results show that bile salts adsorb onto RTV particles, with greater adsorption observed for more hydrophobic bile salts, following the order sodium glycodeoxycholate (SGDC)>sodium taurodeoxycholate (STDC)>sodium glycochenodeoxycholate SGCDC>sodium glycocholate (SGC)>sodium taurocholate (STC). Increasing the ionic strength of the solution led to increased adsorption of STDC, where buffer containing 300 mM NaCl resulted in greater adsorption than 150 mM NaCl. Additionally, micellar bile salts showed greater affinity for RTV particles than unimeric bile salts. In contrast, the extent of bile salt depletion was unaltered by addition of phospholipid to form mixed micelles. SAXS analysis of mixed micelles after incubation with RTV particles confirms depletion of bile salt from the supernatant, evidenced by reduced intensity of the micellar scattering feature. In conclusion, this study investigated factors influencing bile salt adsorption onto drug particles, highlighting the need to consider adsorption of bile components in forming the GI-corona.

Metabolomic profiles differentiate between porto-sinusoidal vascular disorder, cirrhosis, and health

Background & AimsPorto-sinusoidal vascular disorder (PSVD) is a rare and diagnostically challenging vascular liver disease. This study aimed to identify distinct metabolomic signatures in patients with PSVD, cirrhosis, and healthy volunteers (HV) to facilitate non-invasive diagnosis and elucidate perturbed metabolic pathways. MethodsSerum samples from 20 HV and patients with histologically confirmed PSVD or cirrhosis were analyzed. Metabolites were measured using liquid chromatography-mass spectrometry (LC-MS). Differential abundance was evaluated with Limma’s moderated t-statistics. Artificial neural network (ANN) and support vector machine (SVM) models were developed to classify PSVD against cirrhosis or HV metabolomic profiles. An independent cohort was used for validation. ResultsA total of 283 metabolites were included for downstream analysis. Clustering effectively separated PSVD metabolomes from HV, although a subset of PSVD patients (n=5, 25%) overlapped with cirrhosis. Differential testing revealed significant PSVD-linked metabolic perturbations, including taurocholic and adipic acids, distinguishing PSVD from both HV and cirrhosis. Alterations in pyrimidine, glycine, serine, and threonine pathways were exclusively associated with PSVD. Machine learning models utilizing selected metabolic signatures reliably differentiated PSVD from HV or cirrhosis using only 4 to 6 metabolites. Validation in an independent cohort demonstrated the high discriminative ability of taurocholic acid (AUROC 0.899) for PSVD vs HV and the taurocholic acid/aspartic acid ratio (AUROC 0.720) for PSVD vs cirrhosis. ConclusionsHigh-throughput metabolomics enabled the identification of distinct metabolic profiles for differentiating PSVD, cirrhosis, and healthy individuals. Unique alterations in the glycine, serine, and threonine pathways suggest their potential involvement in PSVD pathogenesis. Impact And ImplicationsPorto-sinusoidal vascular disorder (PSVD) is a vascular liver disease that can lead to pre-sinusoidal portal hypertension in the absence of cirrhosis, with poorly understood pathophysiology and no established treatment. Our study demonstrates that analyzing the serum metabolome could reveal distinct metabolic signatures in PSVD patients, including alterations in the pyrimidine, glycine, serine and threonine pathways and potentially shedding light on the disease's underlying pathways. These findings hold potential for earlier and non-invasive diagnosis of PSVD, potentially reducing reliance on invasive procedures like liver biopsy and guiding diagnostic pathways.

Food and bile micelle binding of zwitterionic antihistamine drugs.

The food effects on oral drug absorption are challenging to predict from in vitro data. Food intake has been reported to reduce the oral absorption of several zwitterionic antihistamine drugs. However, the mechanism for this negative food effect has not been clear. The purpose of the present study was to evaluate the bile micelle and food binding of zwitterionic antihistamine drugs as a possible mechanism for the negative food effects on their oral drug absorption. Bilastine (BIL), cetirizine (CET), fexofenadine (FEX), and olopatadine (OLO) were employed as model drugs. The fed/fasted AUC ratios of BIL, CET, FEX, and OLO after oral administration are reported to be 0.60 to 0.7, 0.92, 0.76 to 0.85, and 0.84, respectively. The unbound fraction (f u) of these drugs in the fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) was measured by dynamic dialysis. The FeSSIF/ FaSSIF fu ratios were 0.90 (BIL), 0.46 (CET), 0.76 (FEX), and 0.78 (OLO). In the presence of BFH, the fu ratios were reduced to 0.52 (BIL), 0.22 (CET), 0.39 (FEX), and 0.44 (OLO). Despite being zwitterion at pH 6.5, the antihistamine drugs were bound to bile micelles. Bile micelle and food binding were suggested to cause a negative food effect on the oral absorption of these drugs. However, the AUC ratio was not quantitatively predicted by using FeSSIF + BFH.

Effects of low temperature air exposure and immersion on antioxidant, immune, intestinal flora and metabolome of Chinese mitten crab (Eriocheir sinensis)

The aim of this study was to investigate the effects of immersion on immune enzyme activity, haemolymph index, intestinal microbiome and metabolome of E. sinensis after low temperature air exposure. The results showed that low temperature air exposure induced stress response, which led to hepatopancreas injury and increased membrane permeability, but this situation was reversible and alleviated after immersion. In addition, after exposure to low temperature air, haemolymph metabolism-related substances such as glucose and total cholesterol were significantly different from the initial value (P < 0.05), and gradually returned to the initial level after immersion. The changes of intestinal flora and hepatopancreas metabolism caused by low temperature air exposure did not fully recover after immersion, and its negative effects did not completely disappear. The sequencing results showed that the species composition and diversity of intestinal microorganisms of Chinese mitten crabs were changed after low temperature air exposure and immersion treatment. The relative abundance of Bacteroidetes and Proteobacteria were increased, while the relative abundance of Firmicutes was decreased (P < 0.05). Metabolomics analysis showed that lysine levels increased significantly, taurocholic acid levels decreased significantly, and amino acid metabolism and lipid metabolism balance were disturbed in hepatopancreas of E. sinensis after exposure to low temperature air and immersion (P < 0.05). This study will provide new insights into the recovery mechanism of water immersion on Chinese mitten crabs after exposure to air.

Neuroprotective effects of mesenchymal stromal cells in mouse models of Alzheimer’s Disease: The Mediating role of gut microbes and their metabolites via the Microbiome-Gut-Brain axis

The intricacy and multifaceted nature of Alzheimer’s disease (AD) necessitate therapies that target multiple aspects of the disease. Mesenchymal stromal cells (MSCs) emerge as potential agents to mitigate AD symptoms; however, whether their therapeutic efficacy involves modulation of gut microbiota and the microbiome-gut-brain axis (MGBA) remains unexplored. In this study, we evaluated the effects of three distinct MSCs types—derived from the umbilical cord (UCMSC), dental pulp (SHED), and adipose tissue (ADSC)—in an APP/PS1 mouse model of AD. In comparison to saline control, MSCs administration resulted in a significant reduction of behavioral disturbances, amyloid plaques, and phosphorylated tau in the hippocampus and frontal cortex, accompanied by an increase in neuronal count and Nissl body density across AD-afflicted brain regions. Through 16S rRNA gene sequencing, we identified partial restoration of gut microbial balance in AD mice post-MSCs treatment, evidenced by the elevation of neuroprotective Akkermansia and reduction of the AD-associated Sphingomonas. To examine whether gut microbiota involved in MSCs efficacy in treating AD, SHED with better anti-inflammatory and gut microbiota recovery effects among three MSCs, and another AD model 5 × FAD mice with earlier and more pathological proteins in brain than APP/PS1, were selected for further studies. Antibiotic-mediated gut microbial inactivation attenuated MSCs efficacy in 5 × FAD mice, implicating the involvement of gut microbiota in the therapeutic mechanism. Functional analysis of altered gut microbiota and targeted bile acid metabolism profiling revealed a significant enhancement in bile acid variety following MSCs therapy. A chief bile acid constituent, taurocholic acid (TCA), was orally administered to AD mice and similarly abated AD symptoms. Nonetheless, the disruption of intestinal neuronal integrity with enterotoxin abrogated the ameliorative impact of both MSCs and TCA treatments. Collectively, our findings substantiate that MSCs confer therapeutic benefits in AD within a paradigm that primarily involves regulation of gut microbiota and their metabolites through the MGBA.

Cubosomes and hexosomes stabilized by sorbitan monooleate as biocompatible nanoplatforms against skin metastatic human melanoma

Nanoparticles have become versatile assets in the medical field, providing notable benefits across diverse medical arenas including controlled drug delivery, imaging, and immunological assays. Among these, non-lamellar lipid nanoparticles, notably cubosomes and hexosomes, showcase remarkable biocompatibility and stability, rendering them as optimal choices for theranostic applications. Particularly, incorporating edge activators like sodium taurocholate enhances the potential of these nanoparticles for dermal and transdermal drug delivery, overcoming the stratum corneum, a first line of defense in our skin. This study reports on the formulation of monoolein-based cubosomes and hexosomes incorporating taurocholate and stabilized by Span 80 and co-encapsulating Chlorin e6 and coenzyme QH for photodynamic therapy in skin metastatic melanoma. The formulations were optimized using small-angle X-ray scattering, and cryo-transmission electron microscopy confirmed the presence of cubosomes or hexosomes, depending on the ratio between taurocholate and Span 80. Furthermore, the co-loaded nanoparticles exhibited high encapsulation efficiencies for both Ce6 and the coenzyme QH. In vitro studies on human melanoma cells (Me45) demonstrated the biocompatibility and photodynamic activity of the loaded formulations. These findings show the possibility of formulating more biocompatible cubosomes and hexosomes for photodynamic therapy in skin cancer treatment.

High-Throughput Assessment of Bile Salt Export Pump Inhibition Using RapidFire-MS and DESI-MS.

The bile salt export pump (BSEP) assay is widely used to evaluate the potential for drug-induced liver injury (DILI) early in the drug discovery process. While traditional liquid chromatography-mass spectrometry (LC-MS)-based approaches have been utilized for BSEP activity testing, they have intrinsic limitations in either throughput or the requirement for sample preparation and are difficult to scale up in order to screen drug candidates. Here we demonstrate the use of two different high-throughput MS methods based on solid-phase extraction (SPE) and desorption electrospray ionization (DESI) for high-throughput BSEP activity assessment in a label-free manner, with minimal needs for sample workup, at sampling rates of ∼11 and ∼5.5 s/sample, respectively. Both approaches were validated, compared, and successfully applied to the evaluation of 96 drug candidates for the inhibition of taurocholic acid (TCA) transport using BSEP vesicles.

Protective effects of forsythoside A against severe acute pancreatitis- induced brain injury in mice

ObjectivesThis study aimed to evaluate the therapeutic effects of forsythoside A (FA) on brain injury induced by severe acute pancreatitis (SAP) using a murine model. MethodsMice were induced with 3.5 % sodium taurocholate to model SAP-induced brain injury (SAP-IBI) and were randomly assigned to four distinct treatment regimens: the SAP-IBI model group (SAP-IBI), low-dose FA treatment group (FA L+SI), middle-dose FA treatment group (FA M+SI), and high-dose FA treatment group (FA H+SI). A sham-operation group (SO) served as a negative control. Serum levels of interleukin-1β (IL-1β) and IL-18 were quantified via ELISA, and serum amylase levels were assessed using optical turbidimetry. mRNA expression levels of AIM2, ASC, Caspase-1, and GAPDH in hippocampal brain tissue were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Protein levels of NLRP3, GSDMD, IL-1β, and IL-18 in hippocampal brain tissue were evaluated using Western blotting. Neurological function in surviving mice was assessed through modified neurological severity scores (mNSS). Transmission electron microscopy (TEM) provided ultrastructural analysis of the hippocampus. Additionally, water content and pathological changes in hippocampal brain tissue were examined 24 hours post-operation, along with other relevant indicators. ResultsAt 24 hours post-operation, the FA H+SI group exhibited significantly reduced levels of serum amylase, IL-1β, and IL-18, along with decreased expression of AIM2, ASC, and Caspase-1 mRNA. Furthermore, NLRP3 protein levels, water content, pancreas and hippocampal brain pathological scores, and mNSS were significantly lower compared to the SAP-IBI group (P<0.01). ConclusionsFA demonstrates protective effects against SAP-IBI in mice, suggesting potential therapeutic benefits.

Characterisation of the lipolytic enzymatic activities of fungal rizoenzymes from Rhizopus oryzae in comparison to pancreatin from pigs

Abstract Aim In case of exocrine pancreatic insufficiency (EPI), the replacement of digestive enzymes with, for example porcine pancreatin or fungal rizoenzymes, is unavoidable under certain conditions. Current guidelines indicate that preparations from porcine pancreas have more advantageous physicochemical properties compared to those from fungi, especially at high bile salt concentrations, and that the latter can, therefore, only be used clinically to a limited extent. Since rizoenzymes are increasingly used in clinical practice, the present in vitro study investigated efficiency of enzymatic activity of rizoenzymes in comparison to pancreatin under various physiological and partly extreme environmental conditions. Materials and Methods The lipolytic properties of two typical preparations containing digestive enzymes from porcine pancreatin and rizoenzymes were compared (same dosage of activity units) at different pH values (pH 3–9), with the addition of different bile salt concentrations (0–15 mmol/L sodium taurocholate). Lipolytic activity was measured by quantifying the fatty acids released from olive oil substrate by liquid chromatography–tandem mass spectrometry after enzymatic digestion. Results For both enzyme preparations, the lipolytic activity maximum was reached at pH 7 with comparable fatty acid conversion rates (57% pancreatin, 58% rizoenzymes). However, in contrast to pancreatin, rizoenzymes were already active for certain fatty acids from pH 3 to 4. At a bile salt concentration up to 10 mmol/L taurocholate, there was an increase in activity of both enzyme preparations (rizoenzymes 69% vs. pancreatin 58% enzymatic conversion). Only at rather unphysiological concentration of 15 mmol/L during EPI, there was a slight decrease in activity (to 56%) for the rizoenzymes. Conclusions Rizoenzymes are an alternative therapeutic option for EPI. Relevant differences between rizoenzymes and pancreatin with regard to lipolytic activity under different physicochemical conditions could not be demonstrated in this study, whereas a potential advantage in favor of rizoenzymes activity at already low pH values was observed.

Voice-based depression assessment in patients with gynecological cancer.

161 Background: Although depression in patients with cancer can lead to a deterioration of treatment adherence and quality of life (QOL), diagnosis of depression in patients with cancer is difficult due to symptoms overlapping with side effects of cancer treatment such as fatigue. Traditional screening tools like the PHQ-9 questionnaire are underutilized in clinical practice. Recently, interest has grown in utilizing patients' voices to assess their mental well-being. This study aims to evaluate depression in patients with gynecological cancer and explore the usefulness of voice analysis as a depression detection tool. Methods: PHQ-9 scores were collected from 197 patients with gynecological cancer, with 28 cases undergoing longitudinal assessments at diagnosis, postoperatively, and during chemotherapy. Voice recordings were obtained from 70 patients at diagnosis, alongside serum samples from 22 patients. The PHQ-9 scores were compared across different treatment periods, with a specific focus on patients exhibiting a PHQ score of ≧10, who can be diagnosed with Major Depressive Disorder (MDD). The provision of supportive care for MDD patients was also verified. A random forest model was developed from voice features obtained from 70 patients, with hyperparameter tuning and cross-validation to predict mild depression. Serum metabolites were comprehensively analyzed between depression prediction group and normal prediction group by the depression prediction model. Results: Mean PHQ-9 scores decreased over time since diagnosis; initially 6.50 ± 4.99 (mean ±SD), post-operatively 6.18 ± 4.25, and during chemotherapy 4.88 ± 4.29. The frequencies of MDD also decreased over the clinical course; at diagnosis 24.3%, post-operatively 15.5%, and during chemotherapy 15.4%. Out of 17 cases of MDD during chemotherapy, only one (6.25%) received psychiatric intervention. All MDD cases during chemotherapy had PHQ-9 scores of 5 or higher, representing mild depression at diagnosis. Mild depression at diagnosis could be predicted with an AUC of 0.89 using voice features. Metabolites identified by the voice-based depression prediction model were associated with depression, such as xanthine, methionine, and taurocholic acid. Conclusions: Depression during chemotherapy is often not intervened. Patients with mild depression at diagnosis tend to develop MDD during chemotherapy. Voice-based mental health assessment at diagnosis is possibly a promising screening tool for depression during subsequent cancer treatment. Clinical trial information: UMIN000044266 .

Understanding the side effects of chronic silodosin administration via untargeted metabolomics approach

Precision medicine, which looks for high efficacy and low toxicity in therapies, has increased in popularity with omics technology. This work aims to discover novel and low-toxicity therapy options by examining the complex relationship between silodosin-induced side effects and the metabolomic profiles associated with its administration. The plasma samples of the control group and silodosin-treated rats were analyzed by LC-Q-TOF-MS/MS. Employing XCMS and MetaboAnalyst software, MS/MS data processed to detect compounds and investigate metabolic pathways. MATLAB 2019b was used for data categorization and multivariate analysis. A thorough comparison of METLIN and HMDB databases revealed 41m/z values with significant differences between the drug-treated and control groups (p <0.01 and fold analysis≥1.5). According to multivariate data analysis, 17-β-estradiol, taurocholic acid, L-kynurenine, N-formylkynurenine, D-glutamine, L-arginine, prostaglandin H2, prostaglandine G2, 15-keto-prostaglandin E2, calcidiol, thromboxane A2, 5'-methylthioadenosine, L-methionine and S-adenosylmethionine levels changed significantly compared to the control group. Differences in the metabolisms of glycerophospholipid, tyrosine, phenylalanine, arachidonic acid, cysteine and methionine, and biosynthesis of phenylalanine, tyrosine, and tryptophan, and aminoacyl-tRNA have been successfully demonstrated by metabolic pathway analysis. According to this study, vitamin D, D-glutamine, and L-arginine supplements can be recommended to prevent side effects such as fatigue, intraoperative floppy iris syndrome, blurred vision, and dizziness in the treatment of silodosin. Silodosin treatment negatively affected the immune system by affecting the kynurenine and tryptophan metabolism pathways. The study is a guide for silodosin treatments that offer low side effects and high therapeutic effect within the scope of precision medicine.

Autophagy-mediated ferroptosis is involved in development of severe acute pancreatitis

BackgroundFerroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated.MethodsWe established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy.ResultsOur study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP.ConclusionsOur results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.

MTORC2 knockdown mediates lipid metabolism to alleviate hyperlipidemic pancreatitis through PPARα.

Hyperlipidemic pancreatitis (HP) is an inflammatory injury of the pancreas triggered by elevated serum triglyceride (TG) levels. The mechanistic target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating lipid homeostasis and inflammation. This study aimed to investigate whether the activity of mTOR complex 2 (mTORC2) affects the progression of HP and its underlying mechanisms. In vivo, a high-fat diet and retrograde administration of sodium taurocholate were employed to establish theHP models in rats, with pancreatic tissue pathology evaluated. The expression of Rictor and peroxisome proliferator-activator receptor (PPAR) was examined. The serum levels of TG, fatty acid metabolites, inflammatory and lipid metabolism-related factors were determined. In vitro, pancreatic acinar cells (PACs) were exposed to palmitic acid and cholecystokinin-8. PAC apoptosis, pyroptosis, and ferroptosis were assessed. In the HP models, rats and PACs exhibited upregulated Rictor and downregulated PPARα, and Rictor knockdown promoted PPARα expression. In vivo, Rictor knockdown decreased the serum levels of TG, α-amylase, total cholesterol, low-density lipoprotein cholesterol, lactate dehydrogenase, and inflammatory factors, while increasing high-density lipoprotein cholesterol levels. Rictor knockdown increased ACOX1 and CPT1α and decreased SREBP-1, CD36, SCD1, ACLY, and ACACA. Rictor knockdown reduced damage to pancreatic tissue structure. In vitro, Rictor knockdown inhibited PAC apoptosis, pyroptosis, and ferroptosis. Treatment with the PPARα antagonist GW6471 abolished the beneficial effects of Rictor knockdown. Rictor/mTORC2 deficiency reduces serum TG levels, maintains lipid homeostasis, and suppresses inflammation by inhibiting PPARα expression. Weakening mTORC2 activity holds promise as a novel therapeutic strategy for HP.

Breaking the chain in organ failure: Role of umbilical cord and bone marrow derived mesenchymal stem cells in treatment of severe acute pancreatitis

BackgroundPrevious studies showed that MSCs could mitigate damage in the pancreas during acute pancreatitis (AP). However, acute mortality associated with AP was more often a result of persistent failure of remote organs, rather than local damage, especially in severe acute pancreatitis (SAP), and the effect of MSCs may vary depending on their origin. MethodsAn SAP model was induced in 8-week C57BL/6 J male mice by retrograde injection of 5 % sodium taurocholate solution through the bile duct. SAP mice were divided into the SAP group, UC-MSCs group, and BMSCs group, which were treated with saline, 1 × 106 UC-MSCs, and 1 × 106 BMSCs respectively, through the tail vein. After treatment, serum markers, inflammation, and morphology were assessed in the pancreas, kidneys, lungs, and hearts. ResultsMSCs infusion ameliorated the systemic inflammatory response in SAP mice. In the MSCs-treated SAP mice, local tissue injury and inflammation response in the pancreas were alleviated. But more importantly, the renal and lung injury were all significantly and drastically mitigated, and the levels of pro-inflammatory factors such as IL-6, MCP-1, IL-1β, and TNF-α in the kidney, lung and heart were sharply decreased. In terms of origin, UC-MSCs exhibited superior efficacy compared with BMSCs. Furthermore, compared to the normal control mice, UC-MSCs showed an earlier appearance, higher distribution densities, and longer duration of presence in the injured tissue. ConclusionsThis study provides compelling evidence supporting the therapeutic potential of MSCs in SAP treatment and particularly their ability to mitigate multi-organ failure. Our results also suggested that UC-MSCs may offer greater advantages over BMSCs in SAP therapy.