Novel Brassinosteroid Analogues with 3,6 Dioxo Function, 24-Nor-22(S)-Hydroxy Side Chain and p-Substituted Benzoate Function at C-23-Synthesis and Evaluation of Plant Growth Effects.

Brassinosteroids (BRs) are an important group of polyhydroxylated naturally occurring steroidal phytohormones found in the plant kingdom in extremely low amounts. Due to the low concentrations in which these compounds are found, much effort has been dedicated to synthesizing these compounds or their structural analogs using natural and abundant sterols. In this work, we report the synthesis of new brassinosteroid analogs obtained from hyodeoxycholic acid, with a 3,6 dioxo function, 24-Nor-22(S)-hydroxy side chain and p-substituted benzoate function at C-23. The plant growth activities of these compounds were evaluated by two different bioassays: rice lamina inclination test (RLIT) and BSI. The results show that BRs' analog with p-Br (compound 41f) in the aromatic ring was the most active at 1 × 10-8 M in the RLIT and BSI assays. These results are discussed in terms of the chemical structure and nature of benzoate substituents at the para position. Electron-withdrawing and size effects seems to be the most important factor in determining activities in the RLIT assay. These results could be useful to propose a new structural requirement for bioactivity in brassinosteroid analogs.

Deoxycholic acid inducing chronic atrophic gastritis with colonic mucosal lesion correlated to mucosal immune dysfunction in rats.

The present study aimed to explore the underlying mechanism of bile reflux-inducing chronic atrophic gastritis (CAG) with colonic mucosal lesion. The rat model of CAG with colonic mucosal lesion was induced by free-drinking 20 mmol/L sodium deoxycholate to simulate bile reflux and 2% cold sodium salicylate for 12 weeks. In comparison to the control group, the model rats had increased abundances of Bacteroidetes and Firmicutes but had decreased abundances of Proteobacteria and Fusobacterium. Several gut bacteria with bile acids transformation ability were enriched in the model group, such as Blautia, Phascolarctobacter, and Enterococcus. The cytotoxic deoxycholic acid and lithocholic acid were significantly increased in the model group. Transcriptome analysis of colonic tissues presented that the down-regulated genes enriched in T cell receptor signaling pathway, antigen processing and presentation, Th17 cell differentiation, Th1 and Th2 cell differentiation, and intestinal immune network for IgA production in the model group. These results suggest that bile reflux-inducing CAG with colonic mucosal lesion accompanied by gut dysbacteriosis, mucosal immunocompromise, and increased gene expressions related to repair of intestinal mucosal injury.

Amphotericin B Deoxycholate Treatment of Post-Kala-Azar Dermal Leishmaniasis in India.

Post-kala-azar dermal leishmaniasis (PKDL) is widely prevalent in the endemic regions of India, but its treatment remains unsatisfactory. The WHO recommends a 12-week treatment with oral miltefosine, but its ocular toxicities are a serious concern. The late 1980s and early 1990s saw the use of sodium stibogluconate and amphotericin B (AmB) for a brief period. Both drugs had frequent adverse events and were expensive, and the duration of treatments was unacceptably long. This retrospective study evaluated, analyzed, and reported the outcomes of PKDL patients treated with a shorter course of AmB, the most effective antileishmanial drug. The hospital records of PKDL patients treated with AmB by 30 alternate-day infusions over 60 days (instead of conventional 60-80 infusions over 100-120 days) between September 2010 and August 2016 were reviewed. Only patients with confirmed parasitological diagnosis were included. Their records were studied for treatment-related adverse events, end-of-treatment parasitological status, and 12-month follow-up results. One hundred two patients were eligible for this study between September 2010 and August 2016. After therapy, 92/102 (90.2%) patients improved; 3 (2.9%) had to cease treatment owing to severe adverse effects, and one died of severe diarrhea unrelated to AmB. Six (5.9%) patients withdrew consent before the treatment was complete. At the 12-month evaluation, 89/102 (87.3%) patients attained a final cure. A 30-infusion regimen of AmB remains highly effective in PKDL. Without a shorter, safer, and more economical regimen for the treatment of PKDL, it should be used until a better regimen is available.

Robust assessment of sample preparation protocols for proteomics of cells and tissues.

In proteomic studies, the reliability and reproducibility of results hinge on well-executed protein extraction and digestion protocols. Here, we systematically compared three established digestion methods for macrophages, namely filter-assisted sample preparation (FASP), in-solution, and in-gel digestion protocols. We also compared lyophilization and manual lysis for liver tissue protein extraction, each of them tested using either sodium deoxycholate (SDC)- or RIPA-based lysis buffer. For the macrophage cell line, FASP using passivated filter units outperformed the other tested methods regarding the number of identified peptides and proteins. However, a careful standardization has shown that all three methods can yield robust results across a wide range of starting material (even starting with 1 µg of proteins). Importantly, inter and intra-day coefficients of variance (CVs) were determined for all sample preparation protocols. Thus, the median inter-day CVs for in-solution, in-gel and FASP protocols were respectively 10, 8 and 9%, very similar to the median CVs obtained for the intra-day analysis (9, 8 and 8%, respectively). Moreover, FASP digestion presented 80% of proteins with a CV lower than 25%, followed closely by in-gel digestion (78%) and in-solution sample preparation (72%) protocols. For tissue proteomics, both manual lysis and lyophilization presented similar proteome coverage and reproducibility, but the efficiency of protein extraction depended on the lysis buffer used, with RIPA buffer showing better results. In conclusion, although each sample preparation method has its own particularity, they are all suited for successful proteomic experiments if a careful standardization of the sample preparation workflow is carried out.

TGR5 deficiency in excitatory neurons ameliorates Alzheimer's pathology by regulating APP processing.

Bile acids (BAs) metabolism has a significant impact on the pathogenesis of Alzheimer's disease (AD). We found that deoxycholic acid (DCA) increased in brains of AD mice at an early stage. The enhanced production of DCA induces the up-regulation of the bile acid receptor Takeda G protein-coupled receptor (TGR5), which is also specifically increased in neurons of AD mouse brains at an early stage. The accumulation of exogenous DCA impairs cognitive function in wild-type mice, but not in TGR5 knockout mice. This suggests that TGR5 is the primary receptor mediating these effects of DCA. Furthermore, excitatory neuron-specific knockout of TGR5 ameliorates Aß pathology and cognition impairments in AD mice. The underlying mechanism linking TGR5 and AD pathology relies on the downstream effectors of TGR5 and the APP production, which is succinctly concluded as a "p-STAT3-APH1-γ-secretase" signaling pathway. Our studies identified the critical role of TGR5 in the pathological development of AD.

Bile acids and the gut microbiome are involved in the hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA).

Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia.

Disseminated Talaromyces marneffei infection initially presenting as cutaneous and subcutaneous lesion in an HIV-Negative renal transplant recipient: a case report and literature review.

BACKGROUND: The incidence of Talaromyces marneffei (T. marneffei) infection has increased in recent years with the development of organ transplantation and the widespread use of immunosuppressive agents. However, the lack of clinical suspicion leading to delay or misdiagnosis is an important reason for the high mortality rate in non-human immunodeficiency virus (HIV) and non-endemic population. Herein, we report a case of disseminated T. marneffei infection in a non-HIV and non-endemic recipient after renal transplant, who initially presented with skin rashes and subcutaneous nodules and developed gastrointestinal bleeding. CASE PRESENTATION: We describe a 54-year-old renal transplantation recipient presented with scattered rashes, subcutaneous nodules and ulcerations on the head, face, abdomen, and right upper limb. The HIV antibody test was negative. The patient had no obvious symptoms such as fever, cough, etc. Histopathological result of the skin lesion sites showed chronic suppurative inflammation with a large number of fungal spores. Subsequent fungal culture suggested T. marneffei infection. Amphotericin B deoxycholate was given for antifungal treatment, and there was no deterioration in the parameters of liver and kidney function. Unfortunately, the patient was soon diagnosed with gastrointestinal bleeding, gastrointestinal perforation and acute peritonitis. Then he rapidly developed multiple organ dysfunction syndrome and abandoned treatment. CONCLUSIONS: The risk of fatal gastrointestinal bleeding can be significantly increased in kidney transplant patients with T. marneffei infection because of the long-term side effects of post-transplant medications. Strengthening clinical awareness and using mNGS or mass spectrometry technologies to improve the detection rate and early diagnosis of T. marneffei are crucial for clinical treatment in non-HIV and non-endemic population.

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Gut Epithelial Barrier Function is Impacted by Hyperglycemia and Secondary Bile Acids in Vitro: Possible Rescuing Effects of Specific Pectins.

Gut epithelial barrier disruption is commonly observed in Western diseases like diabetes and inflammatory bowel disease (IBD). Enhanced epithelial permeability triggers inflammatory responses and gut microbiota dysbiosis. Reduced bacterial diversity in IBD affects gut microbiota metabolism, altering microbial products such as secondary bile acids (BAs), which potentially play a role in gut barrier regulation and immunity. Dietary fibers such as pectin may substitute effects of these BAs. The study examines transepithelial electrical resistance of gut epithelial T84 cells and the gene expression of tight junctions after exposure to (un)sulfated secondary BAs. This is compared to the impact of the dietary fiber pectin with different degrees of methylation (DM) and blockiness (DB), with disruption induced by calcium ionophore A23187 under both normal and hyperglycemic conditions. Unsulfated lithocholic acid (LCA) and deoxycholic acid (DCA) show a stronger rescuing effect, particularly evident under 20 mM glucose levels. DM19 with high DB (HB) and DM43HB pectin exhibit rescuing effects under both glucose conditions. Notably, DM19HB and DM43HB display higher rescue effects under 20 mM glucose compared to 5 mM glucose. The study demonstrates that specific pectins such as DM19HB and DM43HB may serve as alternatives for preventing barrier disruption in the case of disturbed DCA metabolism.

Vertical Sleeve Gastrectomy Reduces Gut Luminal Deoxycholic Acid Concentrations in Mice.

BACKGROUND: Bariatric surgery alters bile acid metabolism, which contributes to post-operative improvements in metabolic health. However, the mechanisms by which bariatric surgery alters bile acid metabolism are incompletely defined. In particular, the role of the gut microbiome in the effects of bariatric surgery on bile acid metabolism is incompletely understood. Therefore, we sought to define the changes in gut luminal bile acid composition after vertical sleeve gastrectomy (VSG). METHODS: Bile acid profile was determined by UPLC-MS/MS in serum and gut luminal samples from VSG and sham-operated mice. Sham-operated mice were divided into two groups: one was fed ad libitum, while the other was food-restricted to match their body weight to the VSG-operated mice. RESULTS: VSG decreased gut luminal secondary bile acids, which was driven by a decrease in gut luminal deoxycholic acid concentrations and abundance. However, gut luminal cholic acid (precursor for deoxycholic acid) concentration and abundance did not differ between groups. Therefore, the observed decrease in gut luminal deoxycholic acid abundance after VSG was not due to a reduction in substrate availability. CONCLUSION: VSG decreased gut luminal deoxycholic acid abundance independently of body weight, which may be driven by a decrease in gut bacterial bile acid metabolism.

Production of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism.

Alterations in gut microbiota composition are suggested to contribute to cardiometabolic diseases, in part by producing bioactive molecules. Some of the metabolites are produced by very low abundant bacterial taxa, which largely have been neglected due to limits of detection. However, the concentration of microbially produced metabolites from these taxa can still reach high levels and have substantial impact on host physiology. To explore this concept, we focused on the generation of secondary bile acids by 7α-dehydroxylating bacteria and demonstrated that addition of a very low abundant bacteria to a community can change the metabolic output dramatically. We show that Clostridium scindens converts cholic acid into the secondary bile acid deoxycholic acid (DCA) very efficiently even though the abundance of C. scindens is low, but still detectable by digital droplet PCR. We also show that colonization of germ-free female mice with a community containing C. scindens induces DCA production and affects host metabolism. Finally, we show that DCA correlates with impaired glucose metabolism and a worsened lipid profile in individuals with type 2 diabetes, which implies that this metabolic pathway may contribute to the development of cardiometabolic disease.

Inhibitory effect of doxycycline conjugated with deoxycholic acid and polyethylenimine conjugate on nasal fibroblast differentiation and extracellular production.

BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory disease affecting the sinuses or nose. Persistent inflammatory responses can lead to tissue remodeling, which is a pathological characteristics of CRS. Activation of fibroblasts in the nasal mucosal stroma, differentiation and collagen deposition, and subepithelial fibrosis have been associated with CRS. OBJECTIVES: We aimed to assess the inhibitory effects of doxycycline and deoxycholic acid-polyethyleneimine conjugate (DA3-Doxy) on myofibroblast differentiation and extracellular matrix (ECM) production in nasal fibroblasts stimulated with TGF-ß1. METHODS: To enhance efficacy, we prepared DA3-Doxy using a conjugate of low-molecular-weight polyethyleneimine (PEI) (MW 1800) and deoxycholic acid (DA) and Doxy. The synthesis of the DA3-Doxy polymer was confirmed using nuclear magnetic resonance, and the critical micelle concentration required for cationic micelle formation through self-assembly was determined. Subsequently, the Doxy loading efficiency of DA3 was assessed. The cytotoxicity of Doxy, DA3, PEI, and DA-Doxy in nasal fibroblasts was evaluated using the WST-1 assay. The anti-tissue remodeling and anti-inflammatory effects of DA3-Doxy and DA3 were examined using real-time polymerase chain reaction (Real-time PCR), immunocytochemistry, western blot, and Sircol assay. RESULTS: Both DA3 and DA3-Doxy exhibited cytotoxicity at 10 µg/ml in nasal fibroblasts. Doxy partially inhibited α-smooth muscle actin, collagen types I and III, and fibronectin. However, DA3-Doxy significantly inhibited α-SMA, collagen types I and III, and fibronectin at 5 µg/ml. DA3-Doxy also modulated TGF-ß1-induced changes in the expression of MMP 1, 2, and 9. Nonetheless, TGF-ß1-induced expression of MMP3 was further increased by DA3-Doxy. The expression of TIMP 1 and 2 was partially reduced with 5 µg/ml DA3-Doxy. CONCLUSIONS: Although initially developed for the delivery of genetic materials or drugs, DA3 exhibits inhibitory effects on myofibroblast differentiation and ECM production. Therefore, it holds therapeutic potential for CRS, and a synergistic effect can be expected when loaded with CRS treatment drugs.

Downregulation of ABCC3 activates MAPK signaling through accumulation of deoxycholic acid in colorectal cancer cells.

ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression is downregulated in colorectal cancer through the Wnt/ß-catenin signaling pathway. However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. Gene expression analysis of colorectal adenoma isolated from familial adenomatous polyposis patients revealed that genes related to bile acid secretion including ABCC3 were downregulated as early as at the stage of adenoma formation. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid, a secondary bile acid, respectively, in colorectal cancer cells. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that nonsteroidal anti-inflammatory drugs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of familial adenomatous polyposis. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling.

Comparative analysis of proteomic adaptations in Enterococcus faecalis and Enterococcus faecium after long term bile acid exposure.

BACKGROUND: All gastrointestinal pathogens, including Enterococcus faecalis and Enterococcus faecium, undergo adaptation processes during colonization and infection. In this study, we investigated by data-independent acquisition mass spectrometry (DIA-MS) two crucial adaptations of these two Enterococcus species at the proteome level. Firstly, we examined the adjustments to cope with bile acid concentrations at 0.05% that the pathogens encounter during a potential gallbladder infection. Therefore, we chose the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) as well as the secondary bile acid deoxycholic acid (DCA), as these are the most prominent bile acids. Secondly, we investigated the adaptations from an aerobic to a microaerophilic environment, as encountered after oral-fecal infection, in the absence and presence of deoxycholic acid (DCA). RESULTS: Our findings showed similarities, but also species-specific variations in the response to the different bile acids. Both Enterococcus species showed an IC50 in the range of 0.01- 0.023% for DCA and CDCA in growth experiments and both species were resistant towards 0.05% CA. DCA and CDCA had a strong effect on down-expression of proteins involved in translation, transcription and replication in E. faecalis (424 down-expressed proteins with DCA, 376 down-expressed proteins with CDCA) and in E. faecium (362 down-expressed proteins with DCA, 391 down-expressed proteins with CDCA). Proteins commonly significantly altered in their expression in all bile acid treated samples were identified for both species and represent a "general bile acid response". Among these, various subunits of a V-type ATPase, different ABC-transporters, multi-drug transporters and proteins related to cell wall biogenesis were up-expressed in both species and thus seem to play an essential role in bile acid resistance. Most of the differentially expressed proteins were also identified when E. faecalis was incubated with low levels of DCA at microaerophilic conditions instead of aerobic conditions, indicating that adaptations to bile acids and to a microaerophilic atmosphere can occur simultaneously. CONCLUSIONS: Overall, these findings provide a detailed insight into the proteomic stress response of two Enterococcus species and help to understand the resistance potential and the stress-coping mechanisms of these important gastrointestinal bacteria.

Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation.

High-fat diet (HFD) has long been recognized as risk factors for the development and progression of ulcerative colitis (UC), but the exact mechanism remained elusive. Here, HFD increased intestinal deoxycholic acid (DCA) levels, and DCA further exacerbated colonic inflammation. Transcriptome analysis revealed that DCA triggered ferroptosis pathway in colitis mice. Mechanistically, DCA upregulated hypoxia-inducible factor-2α (HIF-2α) and divalent metal transporter-1 (DMT1) expression, causing the ferrous ions accumulation and ferroptosis in intestinal epithelial cells, which was reversed by ferroptosis inhibitor ferrostatin-1. DCA failed to promote colitis and ferroptosis in intestine-specific HIF-2α-null mice. Notably, byak-angelicin inhibited DCA-induced pro-inflammatory and pro-ferroptotic effects through blocking the up-regulation of HIF-2α by DCA. Moreover, fat intake was positively correlated with disease activity in UC patients consuming HFD, with ferroptosis being more pronounced. Collectively, our findings demonstrated that HFD exacerbated colonic inflammation by promoting DCA-mediated ferroptosis, providing new insights into diet-related bile acid dysregulation in UC.

Development of porcine skeletal muscle extracellular matrix-derived hydrogels with improved properties and low immunogenicity.

Hydrogels derived from decellularized extracellular matrices (ECM) of animal origin show immense potential for regenerative applications due to their excellent cytocompatibility and biomimetic properties. Despite these benefits, the impact of decellularization protocols on the properties and immunogenicity of these hydrogels remains relatively unexplored. In this study, porcine skeletal muscle ECM (smECM) underwent decellularization using mechanical disruption (MD) and two commonly employed decellularization detergents, sodium deoxycholate (SDC) or Triton X-100. To mitigate immunogenicity associated with animal-derived ECM, all decellularized tissues were enzymatically treated with α-galactosidase to cleave the primary xenoantigen-the α-Gal antigen. Subsequently, the impact of the different decellularization protocols on the resultant hydrogels was thoroughly investigated. All methods significantly reduced total DNA content in hydrogels. Moreover, α-galactosidase treatment was crucial for cleaving α-Gal antigens, suggesting that conventional decellularization methods alone are insufficient. MD preserved total protein, collagen, sulfated glycosaminoglycan, laminin, fibronectin, and growth factors more efficiently than other protocols. The decellularization method impacted hydrogel gelation kinetics and ultrastructure, as confirmed by turbidimetric and scanning electron microscopy analyses. MD hydrogels demonstrated high cytocompatibility, supporting satellite stem cell recruitment, growth, and differentiation into multinucleated myofibers. In contrast, the SDC and Triton X-100 protocols exhibited cytotoxicity. Comprehensive in vivo immunogenicity assessments in a subcutaneous xenotransplantation model revealed MD hydrogels' biocompatibility and low immunogenicity. These findings highlight the significant influence of the decellularization protocol on hydrogel properties. Our results suggest that combining MD with α-galactosidase treatment is an efficient method for preparing low-immunogenic smECM-derived hydrogels with enhanced properties for skeletal muscle regenerative engineering and clinical applications.

Hostile bile limits anti-cancer immunity.

Various microbial metabolites promote cell transformation. In this issue of Immunity, Cong et al. show that deoxycholic acid (DCA), a microbial metabolite of bile, promotes tumor growth by suppressing antitumor CD8+ T cell responses via dysregulation of calcium efflux.

Characterization of individual bile acids in vivo utilizing a novel low bile acid mouse model.

Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1-/-/Cyp27a1-/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA, and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted toward non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.

Challenges in management of Candida auris meningitis secondary to infected ventriculoperitoneal shunt - A case report.

Meningitis in patients with ventriculo-peritoneal shunt (VP shunt) caused by various species of Candida have been widely described in literature. However, reports describing Candida auris as a cause of meningitis is limited. In this case report we describe a case of multidrug resistant Candida auris meningitis secondary to VP shunt infection successfully treated with intrathecal amphotericin B deoxycholate and intravenous liposomal amphotericin B. This is the second case report of successful treatment of Candida auris meningitis from India. More literature regarding the use of intrathecal/intraventricular echinocandins including optimal dosing and duration of therapy is needed.

Deoxycholic acid inhibits ASFV replication by inhibiting MAPK signaling pathway.

African swine fever (ASF) is an acute, febrile, highly contagious infection of pigs caused by the African swine fever virus (ASFV). The purpose of this study is to understand the molecular mechanism of ASFV infection and evaluate the effect of DCA on MAPK pathway, so as to provide scientific basis for the development of new antiviral drugs. The transcriptome analysis found that ASFV infection up-regulated the IL-17 and MAPK signaling pathways to facilitate viral replication. Metabolome analysis showed that DCA levels were up-regulated after ASFV infection, and that exogenous DCA could inhibit activation of the MAPK pathway by ASFV infection and thus inhibit viral replication. Dual-luciferase reporter assays were used to screen the genes of ASFV and revealed that I73R could significantly up-regulate the transcription level of AP-1 transcription factor in the MAPK pathway. Confocal microscopy demonstrated that I73R could promote AP-1 entry into the nucleus, and that DCA could inhibit the I73R-mediated nuclear entry of AP-1, inhibiting MAPK pathway, and I73R interacts with AP-1. These results indicated that DCA can inhibit ASFV-mediated activation of the MAPK pathway, thus inhibiting ASFV replication. This study provides a theoretical basis for research on ASF pathogenesis and for antiviral drug development.