taurochenodeoxycholic-acid and Inflammation

In the context of obesity and its related maladies, the adipocyte plays a central role in the balance, or imbalance, of metabolic homeostasis. An obese, hypertrophic adipocyte is challenged by many insults, including surplus energy, inflammation, insulin resistance, and considerable stress to various organelles. The endoplasmic reticulum (ER) is one such vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance. Under normal conditions, the ER must function in the unique and trying environment of the adipocyte, adapting to meet the demands of increased protein synthesis and secretion, energy storage in the form of triglyceride droplet formation, and nutrient sensing that are particular to the differentiated fat cell. When nutrients are in pathological excess, the ER is overwhelmed and the unfolded protein response (UPR) is activated. Remarkably, the consequences of UPR activation have been causally linked to the development of insulin resistance through a multitude of possible mechanisms, including c-jun N-terminal kinase activation, inflammation, and oxidative stress. This review will focus on the function of the ER under normal conditions in the adipocyte and the pathological effects of a stressed ER contributing to adipocyte dysfunction and a thwarted metabolic homeostasis.

Topics: Adipocytes; Animals; Cholesterol; Endoplasmic Reticulum; Humans; Inflammation; Lipid Metabolism; Metabolic Diseases; Obesity; Phenylbutyrates; Protein Folding; Proteins; Stress, Physiological; Taurochenodeoxycholic Acid

Spinal cord injury (SCI) causes cell death and consequently the breakdown of axons and myelin. The accumulation of myelin debris at the lesion site induces inflammation and blocks axonal regeneration. Hematogenous macrophages contribute to the removal of myelin debris. In this study, we asked how the inflammatory state of macrophages affects their ability to phagocytose myelin. Bone marrow-derived macrophages (BMDM) and Raw264.7 cells were stimulated with lipopolysaccharides (LPS) or interferon gamma (IFNγ), which induce inflammatory stress, and the endocytosis of myelin was examined. We found that activation of the TLR4-NFκB pathway reduced myelin uptake by BMDM, while IFNγ-Jak/STAT1 signaling did not. Since bile acids regulate lipid metabolism and in some cases reduce inflammation, our second objective was to investigate whether myelin clearance could be improved with taurolithocholic acid (TLCA), tauroursodeoxycholic acid or hyodeoxycholic acid. In BMDM only TLCA rescued myelin phagocytosis, when this activity was suppressed by LPS. Inhibition of protein kinase A blocked the effect of TLCA, while an agonist of the farnesoid X receptor did not rescue phagocytosis, implicating TGR5-PKA signaling in the effect of TLCA. To shed light on the mechanism, we measured whether TLCA affected the expression of CD36, triggering receptor on myeloid cells-2 (TREM2), and Gas6, which are known to be involved in phagocytosis and affected by inflammatory stimuli. Concomitant with an increase in expression of tumour necrosis factor alpha, LPS reduced expression of TREM2 and Gas6 in BMDM, and TLCA significantly diminished this downregulation. These findings suggest that activation of bile acid receptors may be used to improve myelin clearance in neuropathologies.

Topics: Humans; Inflammation; Lipopolysaccharides; Macrophages; Myelin Sheath; Phagocytosis; Taurochenodeoxycholic Acid; Taurolithocholic Acid

C. difficile infection (CDI) is a highly inflammatory disease mediated by the production of two large toxins that weaken the intestinal epithelium and cause extensive colonic tissue damage. Antibiotic alternative therapies for CDI are urgently needed as current antibiotic regimens prolong the perturbation of the microbiota and lead to high disease recurrence rates. Inflammation is more closely correlated with CDI severity than bacterial burden, thus therapies that target the host response represent a promising yet unexplored strategy for treating CDI. Intestinal bile acids are key regulators of gut physiology that exert cytoprotective roles in cellular stress, inflammation, and barrier integrity, yet the dynamics between bile acids and host cellular processes during CDI have not been investigated. Here we show that several bile acids are protective against apoptosis caused by C. difficile toxins in Caco-2 cells and that protection is dependent on conjugation of bile acids. Out of 20 tested bile acids, taurine conjugated ursodeoxycholic acid (TUDCA) was the most potent inhibitor, yet unconjugated UDCA did not alter toxin-induced apoptosis. TUDCA treatment decreased expression of genes in lysosome associated and cytokine signaling pathways. TUDCA did not affect C. difficile growth or toxin activity

Topics: Anti-Bacterial Agents; Antibodies, Bacterial; Apoptosis; Bile Acids and Salts; Caco-2 Cells; Clostridioides difficile; Clostridium Infections; Humans; Inflammation; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid

Inflammation is the main cause of corneal and retinal damage in an ocular alkali burn (OAB). The aim of this study was to investigate the effect of tauroursodeoxycholic acid (TUDCA) on ocular inflammation in a mouse model of an OAB. An OAB was induced in C57BL/6j mouse corneas by using 1 M NaOH. TUDCA (400 mg/kg) or PBS was injected intraperitoneally (IP) once a day for 3 days prior to establishing the OAB model. A single injection of Infliximab (6.25 mg/kg) was administered IP immediately after the OAB. The TUDCA suppressed the infiltration of the CD45-positive cells and decreased the mRNA and protein levels of the upregulated TNF-α and IL-1β in the cornea and retina of the OAB. Furthermore, the TUDCA treatment inhibited the retinal glial activation after an OAB. The TUDCA treatment not only ameliorated CNV and promoted corneal re-epithelization but also attenuated the RGC apoptosis and preserved the retinal structure after the OAB. Finally, the TUDCA reduced the expression of the endoplasmic reticulum (ER) stress molecules, IRE1, GRP78 and CHOP, in the retinal tissues of the OAB mice. The present study demonstrated that the TUDCA inhibits ocular inflammation and protects the cornea and retina from injury in an OAB mouse model. These results provide a potential therapeutic intervention for the treatment of an OAB.

Topics: Animals; Apoptosis; Burns, Chemical; Disease Models, Animal; Endoplasmic Reticulum Stress; Inflammation; Infliximab; Mice; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; RNA, Messenger; Sodium Hydroxide; Taurochenodeoxycholic Acid; Tumor Necrosis Factor-alpha

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid derivative, which has been demonstrated to have neuroprotective effects in different neurological disease models. However, the effect and underlying mechanism of TUDCA on spinal cord injury (SCI) have not been fully elucidated. This study aims to investigate the protective effects of TUDCA in the SCI mouse model and the related mechanism involved.. We found that TUDCA attenuated axon degeneration induced by H. TUDCA treatment can alleviate secondary injury and promote functional recovery by reducing oxidative stress, inflammatory response, and apoptosis induced by primary injury, and promote axon regeneration and remyelination, which could be used as a potential therapy for human SCI recovery.

Topics: Animals; Apoptosis; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Nerve Degeneration; Nerve Regeneration; Neuroprotective Agents; Oxidative Stress; Recovery of Function; Spinal Cord Injuries; Taurochenodeoxycholic Acid

Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of dementia. According to predictions of the World Health Organization, more than 150 million people worldwide will suffer from dementia by 2050. An increasing number of studies have associated AD with type 2 diabetes mellitus (T2DM), since most of the features found in T2DM are also observed in AD, such as insulin resistance and glucose intolerance. In this sense, some bile acids have emerged as new therapeutic targets to treat AD and metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA), reduces amyloid oligomer accumulation and improves cognition in APP/PS1 mice model of AD, and also improves glucose-insulin homeostasis in obese and type 2 diabetic mice. Herein, we investigated the effect of TUDCA upon glucose metabolism in streptozotocin-induced AD mice model (Stz). The Stz mice that received 300 mg/kg TUDCA during 10 days (Stz + TUDCA), showed improvement in glucose tolerance and insulin sensitivity, reduced fasted and fed glycemia, increased islet mass and β-cell area, as well as increased glucose-stimulated insulin secretion, compared with Stz mice that received only PBS. Stz + TUDCA mice also displayed lower neuroinflammation, reduced protein content of amyloid oligomer in the hippocampus, improved memory test and increased protein content of insulin receptor β-subunit in the hippocampus. In conclusion, TUDCA treatment enhanced glucose homeostasis in the streptozotocin-induced Alzheimer's disease mice model, pointing this bile acid as a good strategy to counteract glucose homeostasis disturbance in AD pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Bile Acids and Salts; Blood Glucose; Cytokines; Disease Models, Animal; Glucose; Hippocampus; Inflammation; Insulin; Insulin-Secreting Cells; Male; Memory and Learning Tests; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Streptozocin; Taurochenodeoxycholic Acid

Osteoarthritis (OA) is considered one of the most common arthritic diseases characterized by progressive degradation and abnormal remodeling of articular cartilage. Potential therapeutics for OA aim at restoring proper chondrocyte functioning and inhibiting apoptosis. Previous studies have demonstrated that tauroursodeoxycholic acid (TUDCA) showed anti-inflammatory and anti-apoptotic activity in many models of various diseases, acting mainly via alleviation of endoplasmic reticulum (ER) stress. However, little is known about cytoprotective effects of TUDCA on chondrocyte cells. The present study was designed to evaluate potential effects of TUDCA on interleukin-1β (IL-1β) and tunicamycin (TNC)-stimulated NHAC-kn chondrocytes cultured in normoxic and hypoxic conditions. Our results showed that TUDCA alleviated ER stress in TNC-treated chondrocytes, as demonstrated by reduced CHOP expression; however, it was not effective enough to prevent apoptosis of NHAC-kn cells in either normoxia nor hypoxia. However, co-treatment with TUDCA alleviated inflammatory response induced by IL-1β, as shown by down regulation of

Topics: Anti-Inflammatory Agents; Apoptosis; Cartilage, Articular; Cell Hypoxia; Cells, Cultured; Chondrocytes; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Inflammation; Interleukin-1beta; Osteoarthritis; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Tunicamycin

In this study, we study the transplantation of tauroursodeoxycholic acid (TUDCA)-induced M2-phenotype (M2) macrophages and their ability to promote anti-neuroinflammatory effects and functional recovery in a spinal cord injury (SCI) model.. To this end, compared to the granulocyte-macrophage colony-stimulating factor (GM-CSF), we evaluated whether TUDCA effectively differentiates bone marrow-derived macrophages (BMDMs) into M2 macrophages.. The M2 expression markers in the TUDCA-treated BMDM group were increased more than those in the GM-CSF-treated BMDM group. After the SCI and transplantation steps, pro-inflammatory cytokine levels and the mitogen-activated protein kinase (MAPK) pathway were significantly decreased in the TUDCA-induced M2 group more than they were in the GM-CSF-induced M1 group and in the TUDCA group. Moreover, the TUDCA-induced M2 group showed significantly enhanced tissue volumes and improved motor functions compared to the GM-CSF-induced M1 group and the TUDCA group. In addition, biotinylated dextran amine (BDA)-labelled corticospinal tract (CST) axons and neuronal nuclei marker (NeuN) levels were increased in the TUDCA-induced M2 group more than those in the GM-CSF-induced M1 group and the TUDCA group.. This study demonstrates that the transplantation of TUDCA-induced M2 macrophages promotes an anti-neuroinflammatory effect and motor function recovery in SCI. Therefore, we suggest that the transplantation of TUDCA-induced M2 macrophages represents a possible alternative cell therapy for SCI.

Topics: Animals; Cells, Cultured; Female; Inflammation; Macrophages; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Taurochenodeoxycholic Acid

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Topics: Animals; Astrocytes; Disease Models, Animal; Humans; Inflammation; Mice; Microglia; Multiple Sclerosis; Receptors, G-Protein-Coupled; Taurochenodeoxycholic Acid

Paraquat (PQ), a widely used herbicide, could cause neurodegenerative diseases, yet the mechanism remains incompletely understood. This study aimed to investigate the direct effect of PQ on NSC in vivo and its possible mechanism. Adult C57BL/6 mice were subcutaneously injected with 2 mg/kg PQ, 20 mg/kg PQ or vehicle control once a week for 2 weeks, and sacrificed 1 week after the last PQ injection. Furthermore, extra experiments with Tauroursodeoxycholic Acid (TUDCA) intervention were performed to observe the relationship between ER stress, neuroinflammation and the neural stem cell (NSC) impairment. The results showed that 20 mg/kg PQ caused the NSC number decrease in both subgranular zones (SGZ) and subventricular zone (SVZ). Further analysis indicated that the 20 mg/kg PQ suppressed the proliferation of NSC, without affecting the apoptosis. Moreover, 20 mg/kg PQ also induced ER stress in microglia and caused neuroinflammation in SGZ and SVZ. Interestingly, the ER stress inhibitor could simultaneously ameliorate the neuroinflammation and NSC reduction. These data suggested that increased ER stress in microglia might be a possible pathway for PQ-induced neuroinflammation and NSC impairment. That is a previously unknown mechanism for PQ neurotoxicity.

Topics: Animals; Apoptosis; Endoplasmic Reticulum Stress; Herbicides; Inflammation; Lateral Ventricles; Mice; Microglia; Neural Stem Cells; Paraquat; Taurochenodeoxycholic Acid

Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.

Topics: Animals; Cell Line; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Cytokines; Humans; Inflammation; Macrophages; Rats; Receptors, G-Protein-Coupled; Signal Transduction; Taurochenodeoxycholic Acid

Endoplasmic reticulum stress (ERS) has been shown to play a crucial role in the pathogenesis of hypertension. However, the role and mechanisms of ERS on hypertension-induced cardiac functional and morphological changes remain unclear. In this study, the effect of ERS inhibition with tauroursodeoxycholic acid (TUDCA) on hypertension-induced cardiac remodelling was examined.. Hypertension was induced by deoxycorticosterone-acetate (DOCA) and salt administration in uni-nephrectomized rats for 12 weeks. TUDCA was administered for the last four weeks. Rhythmic activity and contractions of the right atrium and left papillary muscle (LPM) were recorded. In the left ventricle, the expression of various proteins was examined and histopathological evaluation was performed.. Hypertension-induced increments in systolic blood pressure and ventricular contractions were reversed by TUDCA. In the hypertensive heart, while expressions of glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated protein kinase-like ER kinase (p-PERK), sarcoplasmic reticulum Ca-ATPase-2 (SERCA2), matrix metalloproteinase-2 (MMP-2) and nuclear NF-κB p65 increased; Bcl-2 (B-cell lymphoma-2) expression decreased and the altered levels of all these markers were restored by TUDCA. In the microscopic examination, TUDCA treatment attenuated hypertension-stimulated cardiac inflammation and fibrosis.. These results suggest that ERS inhibition may ameliorate cardiac contractility through improving ERS-associated calcium mishandling, apoptosis, inflammation and fibrosis, thereby offering therapeutic potential in hypertension-induced cardiac dysfunction.

Topics: Animals; Apoptosis; Blood Pressure; Calcium; Desoxycorticosterone Acetate; Disease Models, Animal; Endoplasmic Reticulum Stress; Fibrosis; Hypertension; Inflammation; Male; Rats; Rats, Wistar; Taurochenodeoxycholic Acid

Chronic high salt intake exaggerates renal injury and inflammation, especially with the loss of functional ET. In ET. TUDCA protects against the development of glomerular and proximal tubular damage, decreases renal cell death and inflammation in the renal cortex in rats with ET

Topics: Animals; Animals, Genetically Modified; Gene Deletion; Inflammation; Kidney Diseases; Male; Random Allocation; Rats; Receptor, Endothelin B; Sodium Chloride, Dietary; Taurochenodeoxycholic Acid

Depression is a mental disease that causes severe economic and social burdens. The mechanism for the onset of depression remains largely unknown. Recently, more and more attention is being given to the role of neuroinflammation and oxidative stress in depression. Tauroursodeoxycholic acid (TUDCA), a clinically available agent used to treat cholesterol gallstone and protect neurons against neurodegeneration, has been reported to prevent neuroinflammation and oxidative stress. In this study, we investigated the effect of TUDCA on lipopolysaccharide (LPS)-induced depression-like behavior, neuroinflammation, and oxido-nitrosative stress in mice. Results showed that TUDCA pretreatment (once daily for 7 consecutive days) at the dosage of 200 and 400 mg/kg, but not 100 mg/kg, markedly attenuated LPS (0.83 mg/kg)-induced behavioral abnormalities in the tail suspension test, forced swim test, and sucrose preference test. Further analysis showed that the TUDCA pretreatment (200, 400 mg/kg) not only inhibited the production of proinflammatory cytokines induced by LPS stimulation, such as interleukin-6 and tumor necrosis factor-α, but attenuated LPS-triggered oxido-nitrosative stress in the hippocampus and prefrontal cortex. Taken together, our results provide evidence to show that the TUDCA could be a potential antidepressant, and its antidepressive mechanism may be associated with the inhibition of the neuroinflammatory response and oxido-nitrosative stress in the brain.

Topics: Animals; Antidepressive Agents; Cytokines; Depression; Disease Models, Animal; Fluoxetine; Hippocampus; Inflammation; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Nitrosative Stress; Oxidative Stress; Prefrontal Cortex; Taurochenodeoxycholic Acid; Tumor Necrosis Factor-alpha

Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.

Topics: Allergens; Animals; Asthma; Bile Acids and Salts; Chemokines; Cytokines; Female; Humans; Hypersensitivity; Inflammation; Lung; Metaplasia; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Proteostasis Deficiencies; Pyroglyphidae; Receptors, G-Protein-Coupled; Respiratory Hypersensitivity; Taurochenodeoxycholic Acid; Unfolded Protein Response

The aim of this study was to evaluate hepatic polyunsaturated fatty acids (PUFAs) and inflammatory response in an animal and cell model of endoplasmic reticulum (ER) stress. Rats were divided into control, tunicamycin (TM)-treated, and TM + tauroursodeoxycholic acid (TUDCA)-treated groups. Hepatic ER stress was induced by TM and the ER stress inhibitor TUDCA was injected 30 min before induction of ER stress. Liver THLE-3 cells were treated with TM and TUDCA was administered in advance to decrease cytotoxic effects. Necroinflammation was evaluated in liver sections, while cell viability was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay kit. ER stress was confirmed by immunofluorescence and Western blot analysis of C/EBP-homologous protein and 78-kDa glucose-regulated protein. Arachidonic acid (C20:4n-6), dihomo-γ-linolenic acid (C20:3n-6), eicosapentaenoic acid (C20:5n-3), and docosahexaenoic acid (C22:6n-3) in liver tissue and THLE-3 cells were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Phospholipase A2 (PLA2), cyclooxygenase (COX), and prostaglandin E2 (PGE2) were measured in tissue and cell samples. Hepatic ER stress was accomplished by TM and was alleviated by TUDCA. TM treatment significantly decreased PUFAs in both liver and THLE-3 cells compared to controls. PLA2, COX, and PGE2 levels were significantly increased in TM-treated rats and THLE-3 cells compared to controls. TUDCA leads to a partial restoration of liver PUFA levels and decreased PLA2, COX, and PGE2. This study reports decreased PUFA levels in ER stress and supports the use of omega-3 fatty acids in liver diseases demonstrating ER stress.

Topics: Animals; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Dinoprostone; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fatty Acids, Omega-3; Heat-Shock Proteins; Hepatocytes; Humans; Inflammation; Liver; Male; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Rats, Wistar; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Tunicamycin

Parkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Gait; Hindlimb; Homeostasis; Inflammation; Male; Mice; Mice, Inbred C57BL; Mitochondria; Motor Activity; Movement; Neostriatum; Nerve Degeneration; Neuroglia; Neuroprotective Agents; Parkinson Disease; Taurochenodeoxycholic Acid; Tremor

The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in various animal models of neuropathologies. We have previously shown the anti-inflammatory properties of TUDCA in an animal model of acute neuroinflammation. Here, we present a new anti-inflammatory mechanism of TUDCA through the regulation of transforming growth factor β (TGFβ) pathway. The bacterial lipopolysaccharide (LPS) was injected intravenously (iv) on TGFβ reporter mice (Smad-binding element (SBE)/Tk-Luc) to study in their brains the real-time activation profile of the TGFβ pathway in a non-invasive way. The activation of the TGFβ pathway in the brain of SBE/Tk-Luc mice increased 24 h after LPS injection, compared to control animals. This activation peak increased further in mice treated with both LPS and TUDCA than in mice treated with LPS only. The enhanced TGFβ activation in mice treated with LPS and TUDCA correlated with both an increase in TGFβ3 transcript in mouse brain and an increase in TGFβ3 immunoreactivity in microglia/macrophages, endothelial cells, and neurons. Inhibition of the TGFβ receptor with SB431542 drug reverted the effect of TUDCA on microglia/macrophages activation and on TGFβ3 immunoreactivity. Under inflammatory conditions, treatment with TUDCA enhanced further the activation of TGFβ pathway in mouse brain and increased the expression of TGFβ3. Therefore, the induction of TGFβ3 by TUDCA might act as a positive feedback, increasing the initial activation of the TGFβ pathway by the inflammatory stimulus. Our findings provide proof-of-concept that TGFβ contributes to the anti-inflammatory effect of TUDCA under neuroinflammatory conditions.

Topics: Animals; Anti-Inflammatory Agents; Brain; Disease Models, Animal; Inflammation; Luminescent Measurements; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Taurochenodeoxycholic Acid; Transforming Growth Factor beta

It is known that osteogenic differentiation of mesenchymal stem cells (MSCs) can be promoted by suppression of adipogenesis of MSCs. We have recently found that the chemical chaperone tauroursodeoxycholic acid (TUDCA) significantly reduces adipogenesis of MSCs. In the present study, we examined whether TUDCA can promote osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) by regulating Integrin 5 (ITGA5) associated with activation of ERK1/2 signal pathway and thereby enhance bone tissue regeneration by reducing apoptosis and the inflammatory response. TUDCA treatment promoted in vitro osteogenic differentiation of BMMSCs and in vivo bone tissue regeneration in a calvarial defect model, as confirmed by micro-computed tomography, histological staining, and immunohistochemistry for osteocalcin. In addition, TUDCA treatment significantly decreased apoptosis and the inflammatory response in vivo and in vitro, which is important to enhance bone tissue regeneration. These results indicate that TUDCA plays a critical role in enhancing osteogenesis of BMMSCs, and is therefore a potential alternative drug for bone tissue regeneration.

Topics: Animals; Apoptosis; Bone Marrow Cells; Bone Regeneration; Cell Differentiation; Inflammation; Male; MAP Kinase Signaling System; Mesenchymal Stem Cells; Mice, Inbred BALB C; Osteogenesis; Skull; Taurochenodeoxycholic Acid; X-Ray Microtomography

Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1α. Once activated, IRE1α recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-κB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.

Topics: Animals; Bacterial Outer Membrane Proteins; Brucella abortus; Cell Line; Dithiothreitol; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Endoribonucleases; Female; Humans; Immunity, Innate; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Nod1 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein; Protein Serine-Threonine Kinases; Receptors, Pattern Recognition; Signal Transduction; Taurochenodeoxycholic Acid; Thapsigargin; TNF Receptor-Associated Factor 2; Unfolded Protein Response

Ischemic-type biliary lesions (ITBL) are the most troublesome biliary complication after liver transplantation (LT) from non-heart-beating donors (NHBD) and frequently result in death or re-transplantation. In transplantation process, warm ischemia (WI) in the donor, cold ischemia and reperfusion injury in the recipient altogether inducing ischemia-reperfusion injury (IRI) is strongly associated with ITBL. This is a cascading injury process, involving in a complex series of inter-connecting events causing variety of cells activation and damage associated with the massive release of inflammatory cytokines and generation of reactive oxygen species (ROS). These damaged cells such as sinusoidal endothelial cells (SECs), Kupffer cells (KCs), hepatocytes and biliary epithelial cells (BECs), coupled with immunological injury and bile salt toxicity altogether contribute to ITBL in NHBD LT. Developed therapeutic strategies to attenuate IRI are essential to improve outcome after LT. Among them, single pharmaceutical interventions blocking a specific pathway of IRI in rodent models play an absolutely dominant role, and show a beneficial effect in some given controlled experiments. But this will likely prove ineffective in complex clinical setting in which more risk parameters are involved. Therefore, we intend to design a multidrug cocktail approach to block different pathways on more than one stage (WI, cold ischemia and reperfusion) of the process of IRI-induced ITBL simultaneously. This multidrug cocktail will include six drugs containing streptokinase, epoprostenol, thiazolidinediones (TZDs), N-Acetylcysteine (NAC), hemin and tauroursodeoxycholic acid (TUDC). These drugs show protective effects by targeting the different key events of IRI, such as anti-inflammatory, anti-fibrosis, anti-oxidation, anti-apoptosis and reduced bile salt toxicity. Ideally, the compounds, dosage, and method of application of drugs included in cocktail should not be definitive. We can consider removing or adding some drugs to the proposed cocktail based on further research. But given the multitude of different combinations, it is extremely difficult to determent which combination is the optimization design. Nevertheless, regardless of the difficulty, our multidrug cocktail approach designed to block different mechanisms on more than one stage of IRI simultaneously may represent a future preventive and therapeutic avenue for ITBL.

Topics: Acetylcysteine; Animals; Biliary Tract Diseases; Drug Therapy, Combination; Epithelial Cells; Epoprostenol; Female; Hemin; Hepatocytes; Humans; Inflammation; Ischemia; Kupffer Cells; Liver; Liver Failure; Liver Transplantation; Models, Theoretical; Organ Preservation; Reactive Oxygen Species; Reoperation; Reperfusion Injury; Streptokinase; Swine; Taurochenodeoxycholic Acid; Thiazolidinediones; Tissue Donors; Warm Ischemia

We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.

Topics: Activating Transcription Factor 4; Activating Transcription Factor 6; Animals; Blotting, Western; Brain; Cholagogues and Choleretics; Cyclooxygenase 2; Echocardiography; Endoplasmic Reticulum Stress; Heart Failure; Heat-Shock Proteins; Inflammation; Infusions, Intraventricular; Interleukin-1beta; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Paraventricular Hypothalamic Nucleus; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Signal Transduction; Subfornical Organ; Sympathetic Nervous System; Taurochenodeoxycholic Acid; Transcription Factor RelA; Tumor Necrosis Factor-alpha; X-Box Binding Protein 1

In order to investigate the possible involvement of endoplasmic reticulum (ER) stress in the developmental origins of hepatic steatosis associated with undernourishment in utero, we herein employed a fetal undernourishment mouse model by maternal caloric restriction in three cohorts; cohort 1) assessment of hepatic steatosis and the ER stress response at 9 weeks of age (wks) before a high fat diet (HFD), cohort 2) assessment of hepatic steatosis and the ER stress response on a HFD at 17 wks, cohort 3) assessment of hepatic steatosis and the ER stress response at 22 wks on a HFD after the alleviation of ER stress with a chemical chaperone, tauroursodeoxycholic acid (TUDCA), from 17 wks to 22 wks. Undernourishment in utero significantly deteriorated hepatic steatosis and led to the significant integration of the ER stress response on a HFD at 17 wks. The alleviation of ER stress by the TUDCA treatment significantly improved the parameters of hepatic steatosis in pups with undernourishment in utero, but not in those with normal nourishment in utero at 22 wks. These results suggest the pivotal involvement of the integration of ER stress in the developmental origins of hepatic steatosis in association with undernourishment in utero.

Topics: Animals; Cell Count; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Liver; Female; Hydroxyproline; Inflammation; Insulin; Lipids; Liver; Macrophages; Malnutrition; Mice, Inbred C57BL; Taurochenodeoxycholic Acid; Transaminases

Aortic valve (AV) calcification occurs via a pathophysiological process that includes lipoprotein deposition, inflammation, and osteoblastic differentiation of valvular interstitial cells. Here, we investigated the association between endoplasmic reticulum (ER) stress and AV calcification.. We identified ER stress activation in AV of patients with calcified AV stenosis. We generated an AV calcification model in hypercholesterolemic rabbits and mice, respectively, and found marked AV ER stress induction. Classical ER stress inhibitor, tauroursodeoxycholic acid, administration markedly prevented AV calcification, and attenuated AV osteoblastic differentiation and inflammation in both rabbit and mouse models of AV calcification via inhibition of ER stress. In cultured valvular interstitial cells (VICs), we found that oxidized low density lipoprotein (oxLDL) caused ER stress in a cytosolic [Ca](2+)i-dependent manner. OxLDL promoted osteoblastic differentiation via ER stress-mediated protein kinase-like ER kinase/activating transcription factor 4/osteocalcin and inositol-requiring transmembrane kinase and endonuclease-1α (IRE1α)/spliced X-box-binding protein 1/Runx2 pathway, and induced inflammatory responses through IRE1α/c-Jun N-terminal kinase and IRE1α/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in VICs. Inhibition of ER stress by either tauroursodeoxycholic acid or 4-phenyl butyric acid could both suppress oxLDL-induced osteoblastic differentiation and inflammatory responses in VICs.. These data provide novel evidence that ER stress participates in AV calcification development, and suggest that ER stress may be a novel target for AV calcification prevention and treatment.

Topics: Aged; Animals; Aortic Valve; Aortic Valve Stenosis; Apolipoproteins E; Calcinosis; Calcium; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Female; Humans; Hypercholesterolemia; Inflammation; Inflammation Mediators; Intracellular Signaling Peptides and Proteins; Lipoproteins, LDL; Male; Mice; Mice, Knockout; Middle Aged; Osteoblasts; Phenylbutyrates; Rabbits; RNA Interference; Signal Transduction; Swine; Taurochenodeoxycholic Acid; Transfection

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of nonalcoholic steatohepatitis. The ER stress response is activated in the livers of mice fed a methionine- and choline-deficient (MCD) diet, yet the role of ER stress in the pathogenesis of MCD diet-induced steatohepatitis is unknown. Using chemical chaperones on hepatic steatosis and markers of inflammation and fibrosis in mice fed a MCD diet, we aim to determine the effects of reducing ER stress. C57BL/6J mice were fed a MCD diet with or without the ER chemical chaperones 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) for 2 wk. TUDCA and PBA effectively attenuated the ER stress response in MCD diet-fed mice, as evidenced by reduced protein levels of phosphorylated eukaryotic initiation factor 2α and phosphorylated JNK and suppression of mRNA levels of CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78 kDa, and X-box binding protein 1. However, PBA and TUDCA did not decrease MCD diet-induced hepatic steatosis. MCD diet-induced hepatic inflammation, as evidenced by increased plasma alanine aminotransferase and induction of hepatic TNFα expression, was also not reduced by PBA or TUDCA. PBA and TUDCA did not attenuate MCD diet-induced upregulation of the fibrosis-associated genes tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9. ER chemical chaperones reduce MCD diet-induced ER stress, yet they do not improve MCD diet-induced hepatic steatosis, inflammation, or activation of genes associated with fibrosis. These data suggest that although the ER stress response is activated by the MCD diet, it does not have a primary role in the pathogenesis of MCD diet-induced steatohepatitis.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Cholesterol; Choline Deficiency; Diet; Endoplasmic Reticulum; Fatty Liver; Gene Expression; Inflammation; Liver; Liver Cirrhosis; Male; Methionine; Mice; Mice, Inbred C57BL; Molecular Chaperones; Phenylbutyrates; Real-Time Polymerase Chain Reaction; Stress, Physiological; Taurochenodeoxycholic Acid

Apolipoprotein (apo) E4 is a major genetic risk factor for a wide spectrum of inflammatory metabolic diseases, including atherosclerosis, diabetes, and Alzheimer disease. This study compared diet-induced adipose tissue inflammation as well as functional properties of macrophages isolated from human APOE3 and APOE4 mice to identify the mechanism responsible for the association between apoE4 and inflammatory metabolic diseases. The initial study confirmed previous reports that APOE4 gene replacement mice were less sensitive than APOE3 mice to diet-induced body weight gain but exhibited hyperinsulinemia, and their adipose tissues were similarly inflamed as those in APOE3 mice. Peritoneal macrophages isolated from APOE4 mice were defective in efferocytosis compared with APOE3 macrophages. Increased cell death was also observed in APOE4 macrophages when stimulated with LPS or oxidized LDL. Western blot analysis of cell lysates revealed that APOE4 macrophages displayed elevated JNK phosphorylation indicative of cell stress even under basal culturing conditions. Significantly higher cell stress due mainly to potentiation of endoplasmic reticulum (ER) stress signaling was also observed in APOE4 macrophages after LPS and oxidized LDL activation. The defect in efferocytosis and elevated apoptosis sensitivity of APOE4 macrophages was ameliorated by treatment with the ER chaperone tauroursodeoxycholic acid. Taken together, these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism.

Topics: Adipose Tissue; Alzheimer Disease; Animals; Apolipoprotein E3; Apolipoprotein E4; Apoptosis; Cells, Cultured; Cholagogues and Choleretics; Endoplasmic Reticulum Stress; Gene Expression Regulation; Hyperinsulinism; Inflammation; Lipopolysaccharides; Lipoproteins, LDL; Macrophages, Peritoneal; MAP Kinase Kinase 4; Metabolic Diseases; Mice; Mice, Transgenic; Phosphorylation; Polymorphism, Genetic; Signal Transduction; Taurochenodeoxycholic Acid

Adipose tissue plays a central role in maintaining metabolic homeostasis under normal conditions. Metabolic diseases such as obesity and type 2 diabetes are often accompanied by chronic inflammation and adipose tissue dysfunction. In this study, we observed that endoplasmic reticulum (ER) stress and the inflammatory response occurred in adipose tissue of mice fed a high-fat diet for a period of 16 weeks. After 16 weeks of feeding, ER stress markers increased and chronic inflammation occurred in adipose tissue. We found that ER stress is induced by free fatty acid (FFA)-mediated reactive oxygen species (ROS) generation and up-regulated gene expression of inflammatory cytokines in 3T3-L1 adipocytes. Oral administration to obese mice of chemical chaperons, which alleviate ER stress, improved chronic inflammation in adipose tissue, followed by the suppression of increased body weight and improved insulin signaling. These results indicate that ER stress plays important pathophysiological roles in obesity-induced adipose tissue dysfunction.

Topics: 3T3-L1 Cells; Adipose Tissue; Administration, Oral; Animals; Body Weight; Butylamines; Chronic Disease; Cytokines; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Acids, Nonesterified; Inflammation; Insulin; Male; Mice; Mice, Inbred C57BL; Obesity; Reactive Oxygen Species; Signal Transduction; Taurochenodeoxycholic Acid; Up-Regulation

Free-fatty acids (FFAs) are well-characterized factor for causing production of inflammatory factors and insulin resistance in adipocytes. Using cultured adipocytes, we demonstrate that FFAs can activate endoplasmic reticulum (ER) stress pathway by examination of ER stress sensor activation and marker gene expression. Chemical chaperone tauroursodeoxycholic acid (TUDCA) can reduce FFA-induced adipocyte inflammation and improve insulin signaling whereas overexpression of spliced X-box protein 1 (XBP-1s) only attenuates FFA-induced inflammation. PKR-like eukaryotic initiation factor 2α kinase (PERK) is one of the three major ER stress sensor proteins and deficiency of PERK alleviates FFA-induced inflammation and insulin resistance. The key downstream target of FFA-induced ER stress is IκB kinase β (IKKβ), a master kinase for regulating expression of inflammatory genes. Deficiency of PERK attenuates FFA-induced activation of IKKβ and deficiency of IKKβ alleviates FFA-induced inflammation and insulin resistance. Consistently, overexpression of IKKβ in 3T3-L1 CAR adipocytes causes inflammation and insulin resistance. In addition, IKKβ overexpression has profound effect on adipocyte lipid metabolism, including inhibition of lipogenesis and promotion of lipolysis. Furthermore, increased endogenous IKKβ expression and activation is also observed in isolated primary adipocytes from mice injected with lipids or fed on high-fat diet (HFD) acutely. These results indicate that ER stress pathway is a key mediator for FFA-induced inflammation and insulin resistance in adipocytes with PERK and IKKβ as the critical signaling components.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Dietary Fats; DNA-Binding Proteins; eIF-2 Kinase; Endoplasmic Reticulum; Fatty Acids, Nonesterified; I-kappa B Kinase; Inflammation; Insulin; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Regulatory Factor X Transcription Factors; Signal Transduction; Taurochenodeoxycholic Acid; Transcription Factors; X-Box Binding Protein 1

In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.

Topics: Acinar Cells; Animals; Ceruletide; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Inflammation; Male; Pancreas; Pancreatitis; Rats; Rats, Wistar; Taurochenodeoxycholic Acid; Unfolded Protein Response