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.

Tauroursodeoxycholic Acid Reverses Dextran Sulfate Sodium-Induced Colitis in Mice via Modulation of Intestinal Barrier Dysfunction and Microbiome Dysregulation.

Ulcerative colitis (UC) is an immune-mediated inflammatory disease that can lead to persistent damage and even cancer without any intervention. Conventional treatments can alleviate UC symptoms but are costly and cause various side effects. Tauroursodeoxycholic acid (TUDCA), a secondary bile acid derivative, possesses anti-inflammatory and cytoprotective properties for various diseases, but its potential therapeutic benefits in UC have not been fully explored. Mice were subjected to colitis induction using 3% dextran sulfate sodium (DSS). The therapeutic effect of TUDCA was evaluated by body weight loss, disease activity index (DAI), colon length, and spleen weight ratio. Tissue pathology was assessed using H&E staining, while the levels of pro-inflammatory and anti-inflammatory cytokines in colonic tissue were quantified via ELISA. Tight junction proteins were detected by immunoblotting and intestinal permeability was assessed using fluorescein isothiocyanate (FITC)-dextran. Moreover, the gut microbiota was profiled using high-throughput sequencing of the 16S rDNA gene. TUDCA alleviated the colitis in mice, involving reduced DAI, attenuated colon and spleen enlargement, ameliorated histopathological lesions, and normalized levels of pro-inflammatory and anti-inflammatory cytokines. Furthermore, TUDCA treatment inhibited the downregulation of intestinal barrier proteins, including zonula occludens-1 and occludin, thus reducing intestinal permeability. The analysis of gut microbiota suggested that TUDCA modulated the dysbiosis in mice with colitis, especially for the remarkable rise in Akkermansia TUDCA exerted a therapeutic efficacy in DSS-induced colitis by reducing intestinal inflammation, protecting intestinal barrier integrity, and restoring gut microbiota balance. SIGNIFICANCE STATEMENT: This study demonstrates the potential therapeutic benefits of Tauroursodeoxycholic acid (TUDCA) in ulcerative colitis. TUDCA effectively alleviated colitis symptoms in mice, including reducing inflammation, restoring intestinal barrier integrity and the dysbiosis of gut microbiota. This work highlights the promising role of TUDCA as a potentially alternative treatment, offering new insights into managing this debilitating condition.

Is TGR5 a therapeutic target for the treatment of spinal cord injury?

Bile acids, which are synthesized in liver and colon, facilitate the digestion of dietary lipids. In addition to this metabolic function, they also act as molecular signals with activities in the nervous system. These are mediated primarily by a G-protein-coupled bile acid receptor (known as TGR5). Preceded by a long tradition in Chinese medicine, bile acids are now being investigated as therapeutic options in several neuropathologies. Specifically, one bile acid, tauroursodeoxycholic acid (TUDCA), which passes the blood-brain barrier and shows anti-inflammatory and anti-apoptotic effects, has been tested in animal models of spinal cord injury (SCI). In this review, we discuss the evidence for a therapeutic benefit in these preclinical experiments. At the time of writing, 12 studies with TGR5 agonists have been published that report functional outcomes with rodent models of SCI. Most investigations found cytoprotective effects and benefits regarding the recovery of sensorimotor function in the subacute phase. When TUDCA was applied in a hydrogel into the lesion site, a significant improvement was obtained at 2 weeks after SCI. However, no lasting improvements with TUDCA treatment were found, when animals were assessed in later, chronic stages. A combination of TUDCA with stem cell injection failed to improve the effect of the cellular treatment. We conclude that the evidence does not support the use of TUDCA as a treatment of SCI. Nevertheless, cytoprotective effects suggest that different modes of application or combinatorial therapies might still be explored.

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy.

As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR-mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Tauroursodeoxycholic acid (TUDCA) is neuroprotective in a chronic mouse model of Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) is a progressive motor disease of unknown etiology. Although neuroprotective ability of endogenous bile acid, tauroursodeoxycholic acid (TUDCA), shown in various diseases, including an acute model of PD,the potential therapeutic role of TUDCA in progressive models of PD that exhibit all aspects of PD has not been elucidated. In the present study, mice were assigned to one of four treatment groups: (1) Probenecid (PROB); (2) TUDCA, (3) MPTP + PROB (MPTPp); and (3) TUDCA + MPTPp. Methods: Markers for dopaminergic function, neuroinflammation, oxidative stress and autophagy were assessed using high performance liquid chromatography (HPLC), immunohistochemistry (IHC) and western blot (WB) methods. Locomotion was measured before and after treatments. Results: MPTPp decreased the expression of dopamine transporters (DAT) and tyrosine hydroxylase (TH), indicating dopaminergic damage, and induced microglial and astroglial activation as demonstrated by IHC analysis. MPTPp also decreased DA and its metabolites as demonstrated by HPLC analysis. Further, MPTPp-induced protein oxidation; increased LAMP-1 expression indicated autophagy and the promotion of alpha-synuclein (α-SYN) aggregation. Discussion: Pretreatment with TUDCA protected against dopaminergic neuronal damage, prevented the microglial and astroglial activation, as well as the DA and DOPAC reductions caused by MPTPp. TUDCA by itself did not produce any significant change, with data similar to the negative control group. Pretreatment with TUDCA prevented protein oxidation and autophagy, in addition to inhibiting α-SYN aggregation. Although TUDCA pretreatment did not significantly affect locomotion, only acute treatment effects were measured, indicating more extensive assessments may be necessary to reveal potential therapeutic effects on behavior. Together, these results suggest that autophagy may be involved in the progression of PD and that TUDCA may attenuate these effects. The efficacy of TUDCA as a novel therapy in patients with PD clearly warrants further study.

Effect of Tauroursodeoxycholic Acid on Inflammation after Ocular Alkali Burn.

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-1ß 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.

Administration of tauroursodeoxycholic acid attenuates dexamethasone-induced skeletal muscle atrophy.

Glucocorticoids are known to induce skeletal muscle atrophy by suppressing protein synthesis and promoting protein degradation. Tauroursodeoxycholic acid (TUDCA) has beneficial effects in several diseases, such as hepatobiliary disorders, hindlimb ischemia and glucocorticoid-induced osteoporosis. However, the effects of TUDCA on glucocorticoid -induced skeletal muscle atrophy remains unknown. Therefore, in the present research, we explored the effects of TUDCA on dexamethasone (DEX)-induced loss and the potential mechanisms involved. We found TUDCA alleviated DEX-induced muscle wasting in C2C12 myotubes, identified by improved myotube differentiation index and expression of myogenin and MHC. And it showed that TUDCA activated the Akt/mTOR/S6K signaling pathway and inhibited FoxO3a transcriptional activity to decreased expression of MuRF1 and Atrogin-1, while blocking Akt by MK2206 blocked these effects of TUDCA on myotubes. Besides, TUDCA also attenuated DEX-induced apoptosis of myotubes. Furthermore, TUDCA was administrated to the mouse model of DEX-induced skeletal muscle atrophy. The results showed that TUDCA improved DEX-induced skeletal muscle atrophy and weakness (identified by increased grip strength and prolonged running exhaustive time) in mice by suppression of apoptosis, reduction of protein degradation and promotion of protein synthesis. Taken together, our research proved for the first time that TUDCA protected against DEX-induced skeletal muscle atrophy not only by improving myogenic differentiation and protein synthesis, but also through decreasing protein degradation and apoptosis of skeletal muscle.

Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice.

BACKGROUND: Burkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. However, no effective vaccine is available currently, and the drug resistance is also a major problem in the treatment of melioidosis. Therefore, finding new clinical treatment strategies in melioidosis is extremely urgent. RESULTS: We demonstrated that tauroursodeoxycholic acid (TUDCA), a clinically available endoplasmic reticulum (ER) stress inhibitor, can promote B. pseudomallei clearance both in vivo and in vitro. In this study, we investigated the effects of TUDCA on the survival of melioidosis mice, and found that treatment with TUDCA significantly decreased intracellular survival of B. pseudomallei. Mechanistically, we found that B. pseudomallei induced apoptosis and activated IRE1 and PERK signaling ways of ER stress in RAW264.7 macrophages. TUDCA treatment could reduce B. pseudomallei-induced ER stress in vitro, and TUDCA is protective in vivo. CONCLUSION: Taken together, our study has demonstrated that B. pseudomallei infection results in ER stress-induced apoptosis, and TUDCA enhances the clearance of B. pseudomallei by inhibiting ER stress-induced apoptosis both in vivo and in vitro, suggesting that TUDCA could be used as a potentially alternative treatment for melioidosis.

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

The effect of Tauroursodeoxycholic acid (TUDCA) and gut microbiota on murine gallbladder stone formation.

INTRODUCTION AND OBJECTIVES: The incidence of gallstone-related disease steadily increased in the last few years. Here, we aimed to investigate the effect of tauroursodeoxycholic acid1 (TUDCA) on preventing cholesterol gallstones formation in high-fat fed (HFD) mice. MATERIAL AND METHODS: Specific pathogen-free male C57Bl/6 mice were fed a lithogenic diet2 (LD group) alone or in combination with TUDCA (5g/kg diet) for 8 weeks. Upon sacrifice, serum, gallbladder, liver and small intestine were collected and the formation of gallstones or crystals in the gallbladder was analyzed. Additionally, the intestinal microbiota, and bile acid composition, serum lipids and hepatic lipids were studied. RESULTS: Cholesterol gallstones with cholesterol crystals formed in mice of the LD-fed group (15/15, 100%). However, only cholesterol crystals were found in three mice without the presence of any gallstone in the TUDCA-treated group. Both serum and hepatic total cholesterol levels in the TUDCA group were significantly decreased compared with the LD group. Concomitantly, mRNA expression of Abcg5 and Abcg8 was significantly lower in the liver of the TUDCA group whilst mRNA transcripts for Abcb11, Acat2, and Cyp27 were significantly increased compared with the LD group. Additionally, the gallbladder cholesterol saturation index (1.06±0.15) in the TUDCA group was significantly decreased compared with the LD group. Interestingly, the ratio of Firmicutes/Bacteroides in the TUDCA group was increased 3x fold. CONCLUSIONS: TUDCA can inhibit the absorption and synthesis of lipids in the small intestine by improving the intestinal microbiota in HFD-fed mice, thus reducing gallstone formation.

Calbindin-D9k is a Novel Risk Gene for Neurodegenerative Disease.

BACKGROUND/AIMS: Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D9k (CaBP-9k) acts as calcium modulators and sensors in various tissues. However, the neurobiological functions of CaBP-9k are unknown. METHODS: We used CaBP-9k knockout (KO) mice to investigate the roles of these gene in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We used anatomical and biochemical approaches to characterize functional abnormalities of the brain in the CaBP-9k KO mice. RESULTS: We found that the brains of CaBP-9k KO mice have increased APP/ß-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these CaBP-9k had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related proteins expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice. CONCLUSION: Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.

Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats.

BACKGROUND: Neuronal apoptosis plays a critical event in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). This study investigated the roles of Tauroursodeoxycholic acid (TUDCA) in attenuate neuronal apoptosis and underlying mechanisms after SAH. METHODS: Sprague-Dawley rats were subjected to model of SAH and TUDCA was administered via the internal carotid injection. Small interfering RNA (siRNA) for TGR5 were administered through intracerebroventricular injection 48 h before SAH. Neurological scores, brain water content, Western blot, TUNEL staining and immunofluorescence staining were evaluated. RESULTS: TUDCA alleviated brain water content and improved neurological scores at 24 h and 72 h after SAH. TUDCA administration prevented the reduction of SIRT3 and BCL-2 expressions, as well as the increase of BAX and cleaved caspase-3.Endogenous TGR5 expression were upregulated after SAH and treatment with TGR5 siRNA exacerbated neurological outcomes after SAH and the protective effects of TUDCA at 24 h after SAH were also abolished by TGR5 siRNA. CONCLUSIONS: Our findings demonstrate that TUDCA could attenuated neuronal apoptosis and improve neurological functions through TGR5/ SIRT3 signaling pathway after SAH. TUDCA may be an attractive candidate for anti-apoptosis treatment in SAH.

Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy.

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD. Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells. Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.

Review: The bile acids urso- and tauroursodeoxycholic acid as neuroprotective therapies in retinal disease.

Bile acids are produced in the liver and excreted into the intestine, where their main function is to participate in lipid digestion. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have shown antiapoptotic, anti-inflammatory, and antioxidant effects in various models of neurodegenerative diseases. However, little is known about signaling pathways and molecular mechanisms through which these bile acids act as neuroprotectors, delaying translation to the clinical setting. We review evidence supporting a potentially therapeutic role for bile acids in retinal disorders, and the mechanisms and pathways involved in the cytoprotective effects of bile acids from the liver and the enterohepatic circulation to the central nervous system and the retina. As secondary bile acids are generated by the microbiota metabolism, bile acids might be a link between neurodegenerative retinal diseases and microbiota.

Tauroursodeoxycholic acid attenuates colitis-associated colon cancer by inhibiting nuclear factor kappaB signaling.

BACKGROUND AND AIM: Inflammatory bowel diseases is associated with an increased risk for the development of colorectal cancer. However, the mechanism of immune signaling pathways linked to colitis-associated cancer (CAC) has not been fully elucidated. Tauroursodeoxycholic acid (TUDCA) exhibits anti-inflammatory and anti-cancer activities. The aim of this study is to investigate the role of TUDCA in the pathogenesis of CAC. METHODS: Colitis-associated cancer was induced in mice using azoxymethane and dextran sodium sulfate administration, and TUDCA's effect on tumor development was evaluated. HCT 116 and COLO 205 were treated with TUDCA or vehicle and then stimulated with tumor necrosis factor-α (TNF-α). Expression of interleukin (IL)-8 was determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, and IκBα phosphorylation and degradation was evaluated by immunoblot assay. The DNA-binding activity of NF-κB was assessed by electrophoretic mobility shift assay. Cell viability assay and real-time reverse transcription-polymerase chain reaction of bcl-xL, MCL1, c-FLIP-L, and VEGF were performed. RESULTS: Tauroursodeoxycholic acid significantly attenuated the development of CAC in mice. Exposure to TUDCA resulted in extensive epithelial apoptosis and reduced levels of phospho-IκB kinase in the colon. In HCT 116 cells stimulated with TNF-α, TUDCA significantly inhibited IL-8 and IL-1α expression and suppressed TNF-α-induced IκBα phosphorylation/degradation and DNA-binding activity of NF-κB. Furthermore, in both HCT 116 and COLO 205 cells, TUDCA reduced cell viability and downregulated the expression of bcl-xL, MCL1, c-FLIP-L, and VEGF. CONCLUSION: These results demonstrated that TUDCA suppresses NF-κB signaling and ameliorates colitis-associated tumorigenesis, suggesting that TUDCA could be a potential treatment for CAC.

Essential role for EGFR tyrosine kinase and ER stress in myocardial infarction in type 2 diabetes.

We previously reported that EGFR tyrosine kinase (EGFRtk) activity and endoplasmic reticulum (ER) stress are enhanced in type 2 diabetic (T2D) mice and cause vascular dysfunction. In the present study, we determined the in vivo contribution of EGFRtk and ER stress in acute myocardial infarction induced by acute ischemia (40 min)-reperfusion (24 h) (I/R) injury in T2D (db-/db-) mice. We treated db-/db- mice with EGFRtk inhibitor (AG1478, 10 mg/kg/day) for 2 weeks. Mice were then subjected to myocardial I/R injury. The db-/db- mice developed a significant infarct after I/R injury. The inhibition of EGFRtk significantly reduced the infarct size and ER stress induction. We also determined that the inhibition of ER stress (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) in db-/db- significantly decrease the infarct size indicating that ER stress is a downstream mechanism to EGFRtk. Moreover, AG1478 and TUDCA reduced myocardium p38 and ERK1/2 MAP-kinases activity, and increased the activity of the pro-survival signaling cascade Akt. Additionally, the inhibition of EGFRtk and ER stress reduced cell apoptosis and the inflammation as indicated by the reduction in macrophages and neutrophil infiltration. We determined for the first time that the inhibition of EGFRtk protects T2D heart against I/R injury through ER stress-dependent mechanism. The cardioprotective effect of EGFRtk and ER stress inhibition involves the activation of survival pathway, and inhibition of apoptosis, and inflammation. Thus, targeting EGFRtk and ER stress has the potential for therapy to overcome myocardial infarction in T2D.

Farnesoid X Receptor Agonism Protects against Diabetic Tubulopathy: Potential Add-On Therapy for Diabetic Nephropathy.

Established therapies for diabetic nephropathy (dNP) delay but do not prevent its progression. The shortage of established therapies may reflect the inability to target the tubular compartment. The chemical chaperone tauroursodeoxycholic acid (TUDCA) ameliorates maladaptive endoplasmic reticulum (ER) stress signaling and experimental dNP. Additionally, TUDCA activates the farnesoid X receptor (FXR), which is highly expressed in tubular cells. We hypothesized that TUDCA ameliorates maladaptive ER signaling via FXR agonism specifically in tubular cells. Indeed, TUDCA induced expression of FXR-dependent genes (SOCS3 and DDAH1) in tubular cells but not in other renal cells. In vivo, TUDCA reduced glomerular and tubular injury in db/db and diabetic endothelial nitric oxide synthase-deficient mice. FXR inhibition with Z-guggulsterone or vivo-morpholino targeting of FXR diminished the ER-stabilizing and renoprotective effects of TUDCA. Notably, these in vivo approaches abolished tubular but not glomerular protection by TUDCA. Combined intervention with TUDCA and the angiotensin-converting enzyme inhibitor enalapril in 16-week-old db/db mice reduced albuminuria more efficiently than did either treatment alone. Although both therapies reduced glomerular damage, only TUDCA ameliorated tubular damage. Thus, interventions that specifically protect the tubular compartment in dNP, such as FXR agonism, may provide renoprotective effects on top of those achieved by inhibiting angiotensin-converting enzyme.

Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice.

The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD.IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we studied the alterations in the fecal microbial abundance in colitic mice following the administration of secondary bile acids. Our results show that secondary bile acids reduce the severity of colitis and ameliorate colitis-associated fecal dysbiosis at the phylum level. This study indicates that secondary bile acids might act as a safe and effective drug for inflammatory bowel disease.

Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model.

Endoplasmic reticulum (ER) stress arises when excessive improperly folded proteins accumulate in the ER lumen. When ER stress occurs, the unfolded protein response (UPR) is subsequently activated to restore ER proteostasis. However, severe ER stress leads to apoptosis. Recent studies have suggested that cisplatin cytotoxicity may be related to ER stress. The purpose of this study was to determine whether ER stress participates in cochlear cell apoptosis in a cisplatin-induced ototoxicity rat model and to also determine the possible relationship between ER stress and hearing loss. Our results revealed that treatment with cisplatin upregulated the expression of active caspase-12 in cochlear cells, which is indicative of cisplatin-induced activation of ER-specific apoptosis. Increased expression of C/EBP homologous protein (CHOP) and cleaved caspase-9 suggested a close relationship between severe ER stress and mitochondria-dependent apoptosis in the cochlear cells of cisplatin-treated rats. In addition, we found that tauroursodeoxycholic acid (TUDCA), a promoter of ER proteostasis, had a protective effect on cisplatin-induced hearing loss. These results demonstrate that ER stress is involved in the cisplatin-induced apoptosis of cochlear cells in vivo.