Inhibition of the endoplasmic reticulum stress-associated IRE-1 pathway alleviates preterm birth.

BACKGROUND: Premature birth (PTB) remains a major global health concern due to its association with neonatal morbidity and mortality. The unfolded protein response (UPR) within the endoplasmic reticulum (ER) is tightly regulated by Inositol-requiring enzyme type 1 (IRE-1), a pivotal cellular modulator. This study seeks to elucidate the role of the ER stress (ERS)-related IRE-1 pathway in PTB. METHODS: Human placental trophoblast cells HTR8/Svneo were exposed to the ER-stress inducer tunicamycin (TM). The expression of IRE-1 and ERS-associated proteins ATF6, GRP78, and XBP-1 was assessed in placental tissues and TM-treated cells. Cellular viability, migration, invasion, and apoptosis were evaluated through a series of experimental assays. Additionally, various methods were employed to assess and verify the activation of autophagy, using the autophagy marker, microtubule-associated protein 1A/1B-light chain 3 (LC3). Additionally, TUDCA (an ERS inhibitor) was used to assess its potential to counteract the TM-induced cell effects. RESULTS: Elevated levels of ATF6, GRP78, and XBP-1 were observed in PTB tissues and cells. TM treatment substantially reduced cell viability, migration, and invasion while promoting apoptosis. Treatment with TUDCA (an ERS inhibitor) counteracted the effects of TM on the cells. Furthermore, we identified an overexpression of IRE-1 in PTB tissues and cells and its knockdown enhanced cell viability, migration, and invasion while suppressed apoptosis and autophagy under TM stimulation. Notably, IRE-1 was found to modulate the activity of the IRE-1/XBP1/CHOP signaling pathway in TM-treated cells. CONCLUSION: The upregulation of IRE-1 in PTB placental tissues is implicated in the pathogenesis of PTB. Importantly, inhibiting the ERS-associated IRE-1/XBP1/CHOP pathway may be a good strategy in mitigating PTB.

Alteration of serum bile acid profiles of HBV-related hepatocellular carcinoma identified by LC-MS/MS.

BACKGROUND: Hepatocellular carcinoma closely related to metabolic disorders is a common and aggressive liver malignancy. The dysregulation of bile acid homeostasis has emerged as a key factor for the development and progression of HCC. We aimed to investigate the relationship between bile acids and HCC diagnosis and progression. METHODS: A total of 744 HBV-related patients (including 396 HCC patients and 348 patients with chronic liver diseases) were enrolled in the current study. The baseline characteristics of patients were collected from electronic medical records, and the levels of bile acid profiles were determined by LC-MS/MS. Propensity score matching analysis was conducted to reduce the effect of selection bias, and receiver operating characteristic analysis was performed to evaluate the clinical application values of bile acid. RESULTS: Significant differences were observed for most characteristics between the HCC group and the CLD group before PSM analysis. Patients with HCC were older and fatter (p < 0.05). After adjusting with a 1:1 ratio for age, gender and BMI, 42 HCC patients and 42 non-HCC patients were matched in 2 groups, respectively. The total bile acid level in HCC patients was lower than that in patients with chronic liver diseases before and after PSM analysis (p < 0.05). However, patients with HCC had significantly higher levels of DCA, LCA, and GLCA and lower levels of TCDCA, GUDCA, and TUDCA (p < 0.05, respectively). Besides, the TCDCA, TUDCA, GLCA, and GUDCA were significantly correlated with tumor procession. Moreover, the BAs profiles had a superior predictive ability for predicting the development of HCC even in patients with low serum AFP levels. CONCLUSION: Patients with HCC had significantly lower levels of total bile acid, but higher levels of secondary bile acids (DCA, LCA, and GLCA). The levels of primary bile acid (TCDCA) were closely related to tumor size and stage, which indicated that the bile acids were involved in the HCC procession and had important clinical application values.

Exploring the impact of high-altitude de-acclimatization on renal function: The roles of oxidative and endoplasmic reticulum stress in rat models.

BACKGROUND: High-altitude de-acclimatization (HADA) significantly impacts physiological functions when individuals acclimatize to high altitudes return to lower altitudes. This study investigates HADA's effects on renal function and structure in rats, focusing on oxidative and endoplasmic reticulum stress as potential mechanisms of renal injury. OBJECTIVE: To elucidate the pathophysiological mechanisms of renal damage in HADA and evaluate the efficacy of antioxidants Vitamin C (Vit C) and tauroursodeoxycholic acid (TUDCA) in mitigating these effects. METHODS: 88 male Sprague-Dawley rats were randomly divided into a control group, a high-altitude (HA) group, a high-altitude de-acclimatization (HADA) group, and a treatment group. The control group was housed in a sea level environment (500 m), while the HA, HADA, and treatment groups were placed in a simulated high-altitude chamber (5000 m) for 90 days. After this period, the HA group completed the modeling phase; the HADA group was further subdivided into four subgroups, each continuing to be housed in a sea level environment for 3, 7, 14, and 30 days, respectively. The treatment group was split into the Vit C group, the TUDCA group, and two placebo groups, receiving medication for 3 consecutive days, once daily upon return to the sea level. The Vit C group received 100 mg/kg Vit C solution via intravenous injection, the TUDCA group received 250 mg/kg TUDCA solution via intraperitoneal injection, and the placebo groups received an equivalent volume of saline similarly. Serum, urine, and kidney tissues were collected immediately after the modeling phase. Renal function and oxidative stress levels were assessed using biochemical and ELISA methods. Renal histopathology was observed with H&E, Masson's trichrome, PAS, and PASM staining. Transmission electron microscopy was used to examine the ultrastructure of glomeruli and filtration barrier. TUNEL staining assessed cortical apoptosis in the kidneys. Metabolomics was employed for differential metabolite screening and pathway enrichment analysis. RESULTS: Compared to the control and HA groups, the HADA 3-day group (HADA-3D) exhibited elevated renal function indicators, significant pathological damage, observable ultrastructural alterations including endoplasmic reticulum expansion and apoptosis. TUNEL-positive cells significantly increased, indicating heightened oxidative stress levels. Various differential metabolites were enriched in pathways related to oxidative and endoplasmic reticulum stress. Early intervention with Vit C and TUDCA markedly alleviated renal injury in HADA rats, significantly reducing the number of apoptotic cells, mitigating endoplasmic reticulum stress, and substantially lowering oxidative stress levels. CONCLUSION: This study elucidates the pivotal roles of oxidative and endoplasmic reticulum stress in the early-stage renal injury in rats undergoing HADA. Early intervention with the Vit C and TUDCA significantly mitigates renal damage caused by HADA. These findings provide insights into the pathophysiological mechanisms of HADA and suggest potential therapeutic strategies for its future management.

Investigating the effects of tauroursodeoxycholic acid (TUDCA) in mitigating endoplasmic reticulum stress and cellular responses in Pak choi.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) within plant cells due to unfavourable conditions leads to ER stress. This activates interconnected pathways involving reactive oxygen species (ROS) and unfolded protein response (UPR), which play vital roles in regulating ER stress. The aim of this study is to investigate the underlying mechanisms of tunicamycin (TM) induced ER stress and explore the potential therapeutic applications of tauroursodeoxycholic acid (TUDCA) in mitigating cellular responses to ER stress in Pak choi (Brassica campestris subsp. chinensis). The study revealed that ER stress in Pak choi leads to detrimental effects on plant morphology, ROS levels, cellular membrane integrity, and the antioxidant defence system. However, treatment with TUDCA in TM-induced ER stressed Pak choi improved morphological indices, pigment contents, ROS accumulation, cellular membrane integrity, and antioxidant defence system restoration. Additionally, TUDCA also modulates the transcription levels of ER stress sensors genes, ER chaperone genes, and ER-associated degradation (ERAD) genes during ER stress in Pak choi. Furthermore, TUDCA has demonstrated its ability to alleviate ER stress, stabilize the UPR, reduce oxidative stress, prevent apoptosis, and positively influence plant growth and development. These results collectively comprehend TUDCA as a promising agent for mitigating ER stress-induced damage in Pak choi plants and provide valuable insights for further research and potential applications in crop protection and stress management.

Chemical chaperone TUDCA selectively inhibits production of allergen-specific IgE in a low-dose model of allergy.

The cellular response to endoplasmic reticulum (ER) stress accompanies plasma cell maturation and is one of triggers and cofactors of the local inflammatory response. Chemical chaperones, low-molecular substances that eliminate pathological ER stress, are proposed as means of treating pathologies associated with ER stress. The aim of this study was to evaluate the effect and mechanisms of influence of chemical chaperones on the humoral response in a low-dose model of allergy. The allergic immune response was induced in BALB/c mice by repeated administration of ovalbumin at a dose of 100 ng for 6 weeks. Some animals were injected with both the antigen and the chemical chaperones, TUDCA (tauroursodeoxycholic acid) or 4-PBA (4-phenylbutyrate). Administration of TUDCA, but not 4-PBA, suppressed production of allergen-specific IgE (a 2.5-fold decrease in titer). None of the chemical chaperones affected the production of specific IgG1. The effect of TUDCA was associated with suppression of the switch to IgE synthesis in regional lymph nodes. This phenomenon was associated with suppressed expression of genes encoding cytokines involved in type 2 immune response, especially Il4 and Il9, which in turn could be caused by suppression of IL-33 release. In addition, TUDCA significantly suppressed expression of the cytokine APRIL, and to a lesser extent, BAFF. Thus, TUDCA inhibition of the allergy-specific IgE production is due to suppression of the release of IL-33 and a decrease in the production of type 2 immune response cytokines, as well as suppression of the expression of the cytokines APRIL and BAFF.

SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA.

Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness. The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss. Importantly, muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression, and TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics. These findings point to ERO1A as a biomarker and a viable target for intervention and to TUDCA as a pharmacological treatment for SEPN1-RM.

Tauroursodeoxycholic acid liposome alleviates DSS-induced ulcerative colitis through restoring intestinal barrier and gut microbiota.

Ulcerative colitis (UC) is a chronic and progressive inflammatory disease that damages the colonic mucosa and disrupts the intestinal epithelial barrier. The current clinical treatment for UC is mainly chemotherapy, which has the limited effectiveness and severe side effects. It mainly focuses on the treatment of inflammation while neglecting the repair of the intestinal mucosa and the restoration of the microbiota balance. Here, we aimed to address these challenges by using an amphipathic bile acid -tauroursodeoxycholic acid (TUDCA) to replace cholesterol (CHL) in conventional liposomes. We prepared TUDCA/Emodin liposomes by incorporating the hydrophobic drug emodin. The experimental results indicated that TUDCA/Emodin Lip had uniform particle size distribution, good stability, low cytotoxicity, and exhibited good mucus permeability and anti-inflammatory activity in in vitro experiments, and was able to protect cells from oxidative stress. After oral administration, TUDCA/Emodin Lip significantly alleviated the severity of UC. This was evidenced by increased colon length, decreased inflammation and reduced colonic endoplasmic reticulum stress (ERS). Furthermore, TUDCA/Emodin Lip maintained the normal levels of the tight junction proteins Claudin-1 and ZO-1, thereby restoring the integrity of the intestinal barrier. Importantly, TUDCA/Emodin Lip also promoted the ecological restoration of the gut microbiota, increased overall abundance and diversity. Taken together, TUDCA/Emodin Lip can fundamentally restore intestinal homeostasis, this work provides a new, efficient and easily transformable treatment for UC.

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Akkermansia muciniphila might improve anti-PD-1 therapy against HCC by changing host bile acid metabolism.

PD-1 monoclonal antibodies (mAb) have demonstrated remarkable efficacy in a variety of cancers, including Hepatocellular carcinoma (HCC). However, the patient response rates remain suboptimal, and a significant proportion of initial responders may develop resistance to this therapeutic approach. Akkermansia muciniphila (AKK), a microorganism implicated in multiple human diseases, has been reported to be more abundant in patients who exhibit favorable responses to PD-1mAb. However, the underlying mechanism has yet to be elucidated. In our study, we found that AKK could enhance the efficacy of PD-1mAb against HCC in a tumor-bearing mouse model. It promotes HCC tumor cells apoptosis and raise the CD8+ T proportion in the tumor microenvironment. Additionally, AKK downregulates PD-L1 expression in tumor cells. Furthermore, the analysis of metabonomics demonstrates that AKK induces alterations in the host's bile acid metabolism, leading to a significant increase in serum TUDCA levels. Considering the immunosuppresive roles of TUDCA in HCC development, it is plausible to speculate that AKK may reinforce the immunotherapy of PD-1mAb against HCC through its impact on bile acid metabolism.

Bile acids regulate SF-1 to alter cholesterol balance in adrenocortical cells via S1PR2.

Glucocorticoid synthesis typically occurs in adrenal cortex and is influenced by cholesterol balance, since cholesterol is the sole precursor of steroids. Bile acids as the signaling molecules, have been shown to promote steroidogenesis in steroidogenic cells. However, whether bile acids directly regulate cholesterol balance remains elusive. In this study, we prepared cholestatic mouse models and cultured human adrenocortical cells (H295R) treated with taurochenodeoxycholic acid (TCDCA) to determine transcription levels of cholesterol metabolism associated genes and cholesterol concentrations in adrenocortical cells. Results showed that common bile duct ligation (CBDL) and chenodeoxycholic acid (CDCA) feeding elevated the mRNA levels of Abca1, Cyp51, Hmgcr, Srb1, and Mc2r in adrenals of mice. Meanwhile, the concentrations of total cholesterol and cholesteryl ester in adrenals of CBDL and CDCA-fed mice were dramatically lowered. The total and phosphorylation levels of HSL in adrenal glands of CBDL mice were also enhanced. Similarly, TCDCA treatment in H295R cells decreased intracellular concentrations of total cholesterol and cholesteryl ester and increased transcription levels of SRB1, MC2R, and HSL as well. Inhibition of bile acids' receptor sphingosine 1-phosphate receptor 2 (S1PR2), extracellular signal-regulated kinase (ERK) phosphorylation, and steroidogenic factor 1 (SF-1) respectively successfully abolished effect of TCDCA on H295R cells. SF-1s was found to be phosphorylated at Thr75 in TCDCA-treated H295R cells. While a mild increase of intracellular cAMP concentration was detected upon TCDCA treatment, inhibition of PKA activity with Rp-Isomer in H295R cells failed to decrease the expression of SF-1 and its target genes. Our findings suggest that conjugated bile acids affect cholesterol balance through regulation of SF-1 in adrenocortical cells so as to provide an adequate cholesterol supply for glucocorticoid synthesis, which improves and enriches our understanding of the mechanism whereby bile acids regulate cholesterol balance to affect adrenal function.

Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia.

Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress sequentially occur in bronchopulmonary dysplasia (BPD), and all result in DNA damage. When DNA damage becomes irreparable, tumor suppressors increase, followed by apoptosis or senescence. Although cellular senescence contributes to wound healing, its persistence inhibits growth. Therefore, we hypothesized that cellular senescence contributes to BPD progression. Human autopsy lungs were obtained. Sprague-Dawley rat pups exposed to 95% oxygen between Postnatal Day 1 (P1) and P10 were used as the BPD phenotype. N-acetyl-lysyltyrosylcysteine-amide (KYC), tauroursodeoxycholic acid (TUDCA), and Foxo4 dri were administered intraperitoneally to mitigate myeloperoxidase oxidant generation, ER stress, and cellular senescence, respectively. Lungs were examined by histology, transcriptomics, and immunoblotting. Cellular senescence increased in rat and human BPD lungs, as evidenced by increased oxidative DNA damage, tumor suppressors, GL-13 stain, and inflammatory cytokines with decreased cell proliferation and lamin B expression. Cellular senescence-related transcripts in BPD rat lungs were enriched at P10 and P21. Single-cell RNA sequencing showed increased cellular senescence in several cell types, including type 2 alveolar cells. In addition, Foxo4-p53 binding increased in BPD rat lungs. Daily TUDCA or KYC, administered intraperitoneally, effectively decreased cellular senescence, improved alveolar complexity, and partially maintained the numbers of type 2 alveolar cells. Foxo4 dri administered at P4, P6, P8, and P10 led to outcomes similar to TUDCA and KYC. Our data suggest that cellular senescence plays an essential role in BPD after initial inducement by hyperoxia. Reducing myeloperoxidase toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression.

Tauroursodeoxycholic acid protects Schwann cells from high glucose-induced cytotoxicity by targeting NLRP3 to regulate cell migration and pyroptosis.

Diabetic peripheral neuropathy (DPN) is the most prevalent complication of type 2 diabetes mellitus (T2DM), and it seriously affects the quality of life of patients. Tauroursodeoxycholic acid (TUDCA) is a bile acid that plays a protective role against various diseases. However, the function of TUDCA in DPN progression needs to be elucidated. Hence, this study clarified the action of TUDCA on DPN development and explored its mechanism of action. Fecal samples were collected from 50 patients with T2DM or DPN. Schwann cells induced by high levels were constructed to simulate an uncontrolled diabetic state. Cell viability and migration were measured using the CCK-8 and wound-healing assays, respectively. Reactive oxygen species and pyroptosis were detected using flow cytometry. Parabacteroides goldsteinii and Parabacteroides distasonis levels were decreased in the feces of patients with DPN. TUDCA enhanced the viability and migration ability of high glucose-stimulated Schwann cells. In addition, Schwann cell pyroptosis stimulated by high glucose levels was inhibited by TUDCA. Furthermore, the protective roles of TUDCA in cell viability, migration ability, and pyroptosis of Schwann cells stimulated by high glucose were suppressed by the overexpression of NLRP3. TUDCA enhanced cell viability and migration and suppressed pyroptosis in Schwann cells stimulated by high glucose levels by modulating NLRP3 expression. Thus, TUDCA may be a promising drug for DPN therapy.

Endoplasmic reticulum stress is upregulated in inflammatory bowel disease and contributed TLR2 pathway-mediated inflammatory response.

OBJECTIVE: Endoplasmic reticulum stress (ERS) and Toll-like receptor 2 (TLR2) signaling play an important role in inflammatory bowel disease (IBD); however, the link between TLR2 and ERS in IBD is unclear. This study investigated whether Thapsigargin (TG) -induced ER protein expression levels contributed to TLR2-mediated inflammatory response. METHODS: The THP-1 cells were treated with TLR2 agonist (Pam3CSK4), ERS inducer Thapsigargin (TG) or inhibitor (TUDCA). The mRNA expressions of TLR1-TLR10 were detected by qPCR. The production and secretion of inflammatory factors were detected by PCR and ELISA. Immunohistochemistry was used to detect the expressions of GRP78 and TLR2 in the intestinal mucosa of patients with Crohn's disease (CD). The IBD mouse model was established by TNBS in the modeling group. ERS inhibitor (TUDCA) was used in the treatment group. RESULTS: The expression of TLRs was detected via polymerase chain reaction (PCR) in THP-1 cells treated by ERS agonist Thapsigargin (TG). According to the findings, TG could promote TLR2 and TLR5 expression. Subsequently, in TLR2 agonist Pam3CSK4 induced THP-1 cells, TG could lead to increased expression of the inflammatory factors such as TNF-α, IL-1ß and IL-8, and ERS inhibitor (TUDCA) could block this effect. However, Pam3CSK4 did not significantly impact the GRP78 and CHOP expression. Based upon the immunohistochemical results, TLR2 and GRP78 expression were significantly increased in the intestinal mucosa of patients with Crohn's disease (CD). For in vivo experiments, TUDCA displayed the ability to inhibit intestinal mucosal inflammation and reduce GRP78 and TLR2 proteins. CONCLUSIONS: ERS and TLR2 is upregulated in inflammatory bowel disease, ERS may promote TLR2 pathway-mediated inflammatory response. Moreover, ERS and TLR2 signaling could be novel therapeutic targets for IBD.

Tauro-Urso-Deoxycholic Acid Trials in Amyotrophic Lateral Sclerosis: What is Achieved and What to Expect.

Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable and devastating disease. We review the available evidence on the efficacy and safety of TUDCA, administered alone or in combination, by analyzing and comparing published and ongoing studies on amyotrophic lateral sclerosis. Two independent phase II studies (using TUDCA solo or combined with sodium phenylbutyrate) showed similar efficacy in slowing disease progression measured by functional scales. One open-label follow-up TUDCA+sodium phenylbutyrate study suggested a benefit on survival. Two subsequent phase III studies with TUDCA (solo or combined with sodium phenylbutyrate) have been initiated and are currently ongoing. Their completion is expected by the end of 2023 and beginning of 2024. Evidence collected by phase II studies indicates that there are no safety concerns in patients with amyotrophic lateral sclerosis. The efficacy shown in phase II studies was considered sufficient to grant approval in some countries but not in others, owing to discrepant views on the strength of evidence. It will be necessary to wait for the results of ongoing phase III studies to attain a full appreciation of these data.

Tauroursodeoxycholic Acid Supplementation in In Vitro Culture of Indicine Bovine Embryos: Molecular and Cellular Effects on the In Vitro Cryotolerance.

During embryo development, the endoplasmic reticulum (ER) acts as an important site for protein biosynthesis; however, in vitro culture (IVC) can negatively affect ER homeostasis. Therefore, the aim of our study was to evaluate the effects of the supplementation of tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, in the IVC of bovine embryos. Two experiments were carried out: Exp. 1: an evaluation of blastocyst rate, hatching kinetics, and gene expression of hatched embryos after being treated with different concentrations of TUDCA (50, 200, or 1000 µM) in the IVC; Exp. 2: an evaluation of the re-expansion, hatching, and gene expression of hatched embryos previously treated with 200 µM of TUDCA at IVC and submitted to vitrification. There was no increase in the blastocyst and hatched blastocyst rates treated with TUDCA in the IVC. However, embryos submitted to vitrification after treatment with 200 µM of TUDCA underwent an increased hatching rate post-warming together with a down-regulation in the expression of ER stress-related genes and the accumulation of lipids. In conclusion, this work showed that the addition of TUDCA during in vitro culture can improve the cryotolerance of the bovine blastocyst through the putative modulation of ER and oxidative stress.

A Low-Protein, High-Carbohydrate Diet Exerts a Neuroprotective Effect on Mice with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson's Disease by Regulating the Microbiota-Metabolite-Brain Axis and Fibroblast Growth Factor 21.

Parkinson's disease (PD) is closely linked to lifestyle factors, particularly dietary patterns, which have attracted interest as potential disease-modifying factors. Eating a low-protein, high-carbohydrate (LPHC) diet is a promising dietary intervention against brain aging; however, its protective effect on PD remains elusive. Here, we found that an LPHC diet ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced motor deficits, decreased dopaminergic neuronal death, and increased the levels of striatal dopamine, serotonin, and their metabolites in PD mice. Levels of fibroblast growth factor 21 (FGF-21), a member of the fibroblast growth factor family, were elevated in PD mice following LPHC treatment. Furthermore, the administration of FGF-21 exerted a protective effect on MPTP-induced PC12 cells, similar to the effect of an LPHC diet in MPTP-induced mice. Sequencing of the 16S rDNA from fecal microbiota revealed that an LPHC diet normalized the gut bacterial composition imbalance in PD mice, as evidenced by the increased abundance of the genera Bifidobacterium, Ileibacterium, Turicibacter, and Blautia and decreased abundance of Bilophila, Alistipes, and Bacteroides. PICRUSt-predicted fecal microbiome function revealed that an LPHC diet suppressed lipopolysaccharide biosynthesis and the citrate cycle (TCA cycle), biosynthesis of ubiquinone and other terpenoid-quinones, and oxidative phosphorylation pathways caused by MPTP, and enhanced the biosynthesis of amino acids, carbohydrate metabolism, and biosynthesis of other secondary metabolites. A nonmetabolomic analysis of the serum and feces showed that an LPHC diet significantly increased the levels of aromatic amino acids (AAAs), including tryptophan, tyrosine, and phenylalanine. In addition, an LPHC diet elevated the serum concentrations of bile acids (BAs), particularly tauroursodeoxycholic acid (TUDCA) and taurine. Collectively, our current findings point to the potential mechanism of administering an LPHC diet in attenuating movement impairments in MPTP-induced PD mice, with AAAs, microbial metabolites (TUDCA and taurine), and FGF-21 as key mediators along the gut-microbiota-brain axis.

Experimental studies on the particulate matter emission characteristics of a lateral swirl combustion system for direct injection diesel engines.

To analyze the particulate emission characteristics of a lateral swirl combustion system (LSCS), experimental research on a single-cylinder diesel engine was done and compared against the Turbocharger-Charge Air Cooling-Diesel Particle Filter Series combustion system (TCDCS) at different conditions. Compared to the TCDCS, the LSCS presents better combustion performance and lower total particle emission characteristics: As for the LSCS, the vast majority of the particle number size distributions shifted downward, indicating a decrease in the particle number concentration. The total particle number and mass concentrations of the LSCS decreased by 8.7-62.4% and 15.2-55.6% at various loads. The number concentration of particles smaller than approximately 8 nm increased for the LSCS, which can be attributed to the higher temperature and more thorough fuel/air mixture, facilitating the oxidation of large particles into small particles. Combined with the simulation, the LSCS perfectly exerts the wall-flow-guided effect, remarkably improving the fuel/air mixing quality and reducing the local over-concentration regions, which can inhibit the formation of particles. Hence, the LSCS effectively reduces the particle number and mass concentrations, exhibiting excellent particulate emission characteristics.

Taurochenodeoxycholic acid inhibits intestinal epithelial cell proliferation and induces apoptosis independent of the farnesoid X receptor.

Bile acids, such as taurochenodeoxycholic acid (TCDCA), are considered as functional small molecules involved in nutrition regulation or acting with adjuvant therapeutic effects against metabolic or immune diseases. The homeostasis of the intestinal epithelium depends on the conventional cellular proliferation and apoptosis of cells. Herein, mice and normal intestinal epithelial cells (IPEC-J2, a widely used normal intestinal epithelial cell line derived from porcine) were used as models to explore the regulatory effect of TCDCA on the proliferation of intestinal epithelial cells (IECs). In the mouse study, the oral gavage of TCDCA led to a significant reduction in weight gain, small intestinal weight, and the villus height of the intestinal epithelium while inhibiting the gene expression of Ki-67 in the intestinal epithelial crypts of mice (P < 0.05). TCDCA significantly downregulated the expression of the farnesoid X receptor (FXR) and upregulated the expression of caspase-9 in the jejunum (P < 0.05). The results of real-time quantitative PCR (RT-qPCR) suggested that TCDCA significantly inhibited the expression of tight junction proteins zonula occludens (ZO)-1, occludin, claudin-1, and mucin-2 (P < 0.05). In terms of apoptosis-related genes, TCDCA significantly inhibited the expression of Bcl2 and increased the expression of caspase-9 (P < 0.05). At the protein level, TCDCA decreased the expression of Ki-67 and PCNA, as well as FXR (P < 0.05). Caspase inhibitor Q-VD-OPh and guggulsterone, an FXR antagonist, significantly improved the inhibition of TCDCA-induced cell proliferation. Moreover, guggulsterone enhanced TCDCA-induced cell late apoptosis through flow cytometry and significantly lowered the TCDCA-induced up-regulated gene expression of caspase 9, despite both TCDCA and guggulsterone down-regulating the expression of FXR (P < 0.05). Overall, the effect of TCDCA on the induction of apoptosis is not dependent on FXR, whereas it would function via the activation of the caspase system. This provides a new perspective for the application of TCDCA or bile acid as functional small molecules in food, additives, and medicine.

Effect of SCD probiotics supplemented with tauroursodeoxycholic acid (TUDCA) application on the aged rat gut microbiota composition.

AIMS: In this study, the effects of SCD Probiotics with tauroursodeoxycholic acid (TUDCA) application on the aged rat gut microbiota (GM) composition were investigated. METHODS AND RESULTS: Twenty-four-month-old Sprague-Dawley rats were given 300 mg/kg of TUDCA along with 3 mL (1 × 108 CFU) of SCD probiotics for 7 days. The bacterial profile was determined by the metagenome applied to the cecum content. TUDCA, SCD probiotics, and TUDCA with SCD probiotics designed GM differently. TUDCA and SCD probiotics have the most different dominant species profiles. CONCLUSIONS: SCD probiotics and TUDCA have their own unique effects on the species found in GM, and when they are evaluated together, the species found in GM are restructured differently.

Taurochenodeoxycholic acid reduces astrocytic neuroinflammation and alleviates experimental autoimmune encephalomyelitis in mice.

OBJECTIVE: Multiple sclerosis (MS) is an immune regulatory disease that affects the central nervous system (CNS). The main pathological features include demyelination and neurodegeneration, and the pathogenesis is associated with astrocytic neuroinflammation. Taurochenodeoxycholic acid (TCDCA) is one of the conjugated bile acids in animal bile, and it is not clear whether TCDCA could improve MS by inhibiting the activation of astrocytes. This study was aimed to evaluate the effects of TCDCA on experimental autoimmune encephalomyelitis (EAE)-a classical animal model of MS, and to probe its mechanism from the aspect of suppressing astrocytic neuroinflammation. It is expected to prompt the potential application of TCDCA for the treatment of MS. RESULTS: TCDCA effectively alleviated the progression of EAE and improved the impaired neurobehavior in mice. It mitigated the hyperactivation of astrocytes and down-regulated the mRNA expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the brain cortex. In the C6 astrocytic cell line induced by lipopolysaccharide (LPS), TCDCA treatment dose-dependently decreased the production of NO and the protein expression of iNOS and glial fibrillary acidic protein (GFAP). TCDCA consistently inhibited the mRNA expressions of COX2, iNOS and other inflammatory mediators. Furthermore, TCDCA decreased the protein expression of phosphorylated serine/threonine kinase (AKT), inhibitor of NFκB α (IκBα) and nuclear factor κB (NFκB). And TCDCA also inhibited the nuclear translocation of NFκB. Conversely, as an inhibitor of the G-protein coupled bile acid receptor Gpbar1 (TGR5), triamterene eliminated the effects of TCDCA in LPS-stimulated C6 cells. CONCLUSION: TCDCA improves the progress of EAE by inhibiting the astrocytic neuroinflammation, which might be exerted by the regulation of TGR5 mediated AKT/NFκB signaling pathway. These findings may prompt the potential application of TCDCA for MS therapy by suppressing astrocyte inflammation.