Effects of different substrates on the growth and yield of Amorphophallus muelleri.

Seven different substrates were prepared by mixing red soil, humus and river sand in different volume ratios and the growth and yield of Amorphophallus muelleri bulbils in different substrates was investigated. The growth of A. muelleri seedlings were tracked during the reproductive period, with measurements taken of indicators such as petiole length, petiole basal diameter and leaf size during the late period of leaf expansion. Number of surviving plants, weights and sizes of corms, and leaf bulbils were recorded after lodging. The results showed that there were differences in the physical and chemical properties of the seven substrates, but all met the growth requirements of A. muelleri. T1 (river sand), T2 (river sand: humus 1:1), T3 (humus), and T7 (river sand: humus: red soil 1:1:1) had higher emergence rates, reaching 95 %. T4 (humus: red soil 1:1) and T7 had better growth, with larger petiole and leaf sizes than other substrates. T3, T4, and T7 had higher yields, with a bulbil yield of 0.30 t hm-2 and a corm yield of 22.06 t hm-2. Compared to the use of a single substrate, whether river sand, humus, or red soil, the proportional mixture of the three test materials improved the physical structure and chemical composition of the substrate, contributing to the growth of A. muelleri. T7 (river sand: humus: red soil 1:1:1) was was found to be the best nursery substrate for A. muelleri.

Coordinated action of a gut-liver pathway drives alcohol detoxification and consumption.

Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver only plays a partial role in clearing systemic AcH. Here we show that a liver-gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile flow and secretion are potential therapeutic strategies to treat AUD.

Enhanced surfactant remediation of diesel-contaminated soil using O3 nanobubbles.

Currently, nanobubbles are widely discussed in environmental research due to their unique properties, including significant specific surface area, transfer efficiency, and free radical generation. In this study, O2 and O3 nanobubbles (diameters ranging from 0 to 500 nm) were combined with conventional surfactant technology to investigate their enhanced efficacy in removing diesel contaminants from soil. The impact of various factors such as surfactant concentration, temperature, and soil aging duration on pollutant removal rates was examined across different experimental approaches (stirring/flushing). Soil samples subjected to different treatments were characterized using TG-DTG and FTIR analysis, while GC/MS was employed to assess the degradation products of diesel constituents in the soil. The results indicated that the elution efficiencies of the three surfactants (SDS, SDBS, and TX-100) for diesel in soil correlated positively with concentration (0.3-1.4 CMC) and temperature (18-60 °C), and inversely with aging time (10-300 days), with the elution capacity was SDS > SDBS > TX-100. Mechanical stirring (500 rpm) and temperature variations (18-60 °C) did not affect the stability of the nanobubbles. Upon the introduction of O3 nanobubbles to the surfactant solution, there was a consistent increase in both the removal (degraded and removed) efficiency and rate of diesel under varying experimental conditions, resulting in an enhancement of removal rates by approximately 8-15%. FTIR spectroscopy showed that surfactants containing O3 nanobubbles mitigated the impact on the primary functional groups of soil organic matter. GC/MS analyses indicated that residual pollutants were predominantly alkanes, with degradation difficulty ranking as: alkanes < alkenes < cycloalkanes < aromatic compounds. TG-DTG coupled with GC/MS analysis demonstrated that O3 nanobubbles contributed to a reduction in surfactant residues. This study significantly advances our understanding of how nanobubbles facilitate and optimize surfactant-assisted remediation of contaminated soil, thereby advancing the precise application of nanobubble technology in soil remediation.

Microbial community structure and diversity attached to the periphyton in different urban aquatic habitats.

Periphyton is a complex community composed of diverse prokaryotes and eukaryotes; understanding the characteristics of microbial communities within periphyton becomes crucial for biogeochemical cycles and energy dynamics of aquatic ecosystems. To further elucidate the community characteristics of periphyton across varied aquatic habitats, including unpolluted ecologically restored lakes, aquaculture ponds, and areas adjacent to domestic and industrial wastewater treatment plant outfalls, we explored the composition and diversity of prokaryotic and eukaryotic communities in periphyton by employing Illumina MiSeq sequencing. Our findings indicated that the prokaryotic communities were predominantly composed of Proteobacteria (40.92%), Bacteroidota (21.01%), and Cyanobacteria (10.12%), whereas the eukaryotic communities were primarily characterized by the dominance of Bacillariophyta (24.09%), Chlorophyta (20.83%), and Annelida (15.31%). Notably, Flavobacterium emerged as a widely distributed genus among the prokaryotic community. Unclassified_Tobrilidae exhibited higher abundance in unpolluted ecologically restored lakes. Chaetogaster and Nais were enriched in aquaculture ponds and domestic wastewater treatment plant outfall area, respectively, while Surirella and Gomphonema dominated industrial sewage treatment plant outfall area. The alpha diversity of eukaryotes was higher in unpolluted ecologically restored lakes. pH and nitrogen content ( NO 2 - - N , NO 3 - - N , and TN) significantly explained the variations for prokaryotic and eukaryotic community structures, respectively. Eukaryotic communities exhibited a more pronounced response to habitat variations compared to prokaryotic communities. Moreover, the association networks revealed an intensive positive correlation between dominant Bacillariophyta and Bacteroidota. This study provided useful data for identifying keystone species and understanding their ecological functions.

Causal effects of sleep traits on metabolic syndrome and its components: a Mendelian randomization study.

PURPOSE: Previous observational studies have suggested an association between sleep disturbance and metabolic syndrome (MetS). However, it remains unclear whether this association is causal. This study aims to investigate the causal effects of sleep-related traits on MetS using Mendelian randomization (MR). METHODS: Single-nucleotide polymorphisms strongly associated with daytime napping, insomnia, chronotype, short sleep, and long sleep were selected as genetic instruments from the corresponding genome-wide association studies (GWAS). Summary-level data for MetS were obtained from two independent GWAS datasets. Univariable and multivariable MR analyses were conducted to investigate and verify the causal effects of sleep traits on MetS. RESULTS: The univariable MR analysis demonstrated that genetically predicted daytime napping and insomnia were associated with increased risk of MetS in both discovery dataset (OR daytime napping = 1.630, 95% CI 1.273, 2.086; OR insomnia = 1.155, 95% CI 1.108, 1.204) and replication dataset (OR daytime napping = 1.325, 95% CI 1.131, 1.551; OR insomnia = 1.072, 95% CI 1.046, 1.099). For components, daytime napping was positively associated with triglycerides (beta = 0.383, 95% CI 0.160, 0.607) and waist circumference (beta = 0.383, 95% CI 0.184, 0.583). Insomnia was positively associated with hypertension (OR = 1.101, 95% CI 1.042, 1.162) and waist circumference (beta = 0.067, 95% CI 0.031, 0.104). The multivariable MR analysis indicated that the adverse effect of daytime napping and insomnia on MetS persisted after adjusting for BMI, smoking, drinking, and another sleep trait. CONCLUSION: Our study supported daytime napping and insomnia were potential causal factors for MetS characterized by central obesity, hypertension, or elevated triglycerides.

Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: A Mendelian randomization study.

BACKGROUND: Previous observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design. METHODS: Summary-level data for RA (N = 58,284), frailty index (FI) (N = 175,226), Fried frailty score (FFS) (N = 386,565), and 41 inflammatory cytokines (N = 8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR. RESULTS: Univariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95 % CI: 0.012, 0.03; p = 2.2 × 10-6) and FFS (beta=0.011; 95 %CI: 0.007, 0.015; p = 8.811 × 10-8). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8 % (95 %CI: 4.76 %, 19.05 %), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6 % (95 %CI: 0 %, 18.18 %) and 8.44 % (95 %CI: 0 %, 18.18 %), respectively. CONCLUSION: This study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty.

Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead.

Liver fibrosis, characterized by scar tissue formation, can ultimately result in liver failure. It's a major cause of morbidity and mortality globally, often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases. However, current treatment options are limited, highlighting the urgent need for the development of new therapies. As a reversible regulatory mechanism, epigenetic modification is implicated in many biological processes, including liver fibrosis. Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases, although the current evidence is still controversial. This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications, including DNA methylation, histone modification, and RNA modification, in liver fibrotic diseases. The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted. Finally, available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed. In summary, elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

The RIVET RCT: Rifamycin SV MMX improves muscle mass, physical function, and ammonia in cirrhosis and minimal encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) negatively affects the prognosis of cirrhosis, but treatment is not standard. Rifamycin SV MMX (RiVM) is a nonabsorbable rifampin derivative with colonic action. METHODS: In a phase 2 placebo-controlled, double-blind randomized clinical trial patients with MHE were randomized to RiVM or placebo for 30 days with a 7-day follow-up. The primary endpoint was a change in stool cirrhosis dysbiosis ratio. Gut-brain (cognition, stool/salivary microbiome, ammonia, brain magnetic resonance spectroscopy), inflammation (stool calprotectin/serum cytokines), patient-reported outcomes (sickness impact profile: total/physical/psychosocial, high = worse), and sarcopenia (handgrip, bioelectric impedance) were secondary. Between/within groups and delta (post-pre) comparisons were performed. RESULTS: Thirty patients (15/group) were randomized and completed the study without safety concerns. While cirrhosis dysbiosis ratio was statistically similar on repeated measures ANOVA (95% CI: -0.70 to 3.5), ammonia significantly reduced (95% CI: 4.4-29.6) in RiVM with changes in stool microbial α/ß-diversity. MHE status was unchanged but only serial dotting (which tests motor strength) improved in RiVM-assigned patients. Delta physical sickness impact profile (95% CI: 0.33 = 8.5), lean mass (95% CI: -3.3 to -0.9), and handgrip strength (95% CI: -8.1 to -1.0) improved in RiVM versus placebo. Stool short-chain fatty acids (propionate, acetate, and butyrate) increased post-RiVM. Serum, urine, and stool bile acid profile changed to nontoxic bile acids (higher hyocholate/ursodeoxycholate and lower deoxycholate/lithocholate) post-RiVM. Serum IL-1ß and stool calprotectin decreased while brain magnetic resonance spectroscopy showed higher glutathione concentrations in RiVM. CONCLUSIONS: RiVM is well tolerated in patients with MHE with changes in stool microbial composition and function, ammonia, inflammation, brain oxidative stress, and sarcopenia-related parameters without improvement in cognition. RiVM modulates the gut-brain axis and gut-muscle axis in cirrhosis.

Single nuclear RNA sequencing of terminal ileum in patients with cirrhosis demonstrates multi-faceted alterations in the intestinal barrier.

Patients with cirrhosis have intestinal barrier dysfunction but the role of the individual cell types in human small intestine is unclear. We performed single-nuclear RNA sequencing (snRNAseq) in the pinch biopsies of terminal ileum of four age-matched men [56 years, healthy control, compensated, early (ascites and lactulose use) and advanced decompensated cirrhosis (ascites and rifaximin use)]. Cell type proportions, differential gene expressions, cell-type specific pathway analysis using IPA, and cellular crosstalk dynamics were compared. Stem cells, enterocytes and Paneth cells were lowest in advanced decompensation. Immune cells like naive CD4 + T cells were lowest while ITGAE + cells were highest in advanced decompensation patients. MECOM had lowest expression in stem cells in advanced decompensation. Defensin and mucin sulfation gene (PAPSS2) which can stabilize the mucus barrier expression were lowest while IL1, IL6 and TNF-related genes were significantly upregulated in the enterocytes, goblet, and Paneth cells in decompensated subjects. IPA analysis showed higher inflammatory pathways in enterocytes, stem, goblet, and Paneth cells in decompensated patients. Cellular crosstalk analysis showed that desmosome, protease-activated receptors, and cadherin-catenin complex interactions were most perturbed in decompensated patients. In summary, the snRNAseq of the human terminal ileum in 4 subjects (1 control and three cirrhosis) identified multidimensional alteration in the intestinal barrier with lower stem cells and altered gene expression focused on inflammation, mucin sulfation and cell-cell interactions with cirrhosis decompensation.

Coiled-coil domain containing 159 is required for spermatid head and tail assembly in mice†.

The centrosome is critical for maintaining the sperm head-tail connection and the formation of flagellar microtubules. In this study, we found that in mouse testes, CCDC159 (coiled-coil domain-containing protein 159) is specifically localized to the head-tail coupling apparatus (HTCA) of spermatids, a structure that ensures sperm head-tail tight conjunction. CCDC159 contains a C-terminal coiled-coil domain that functions as the centrosomal localization signal. Gene knockout (KO) of Ccdc159 in mice resulted in acephalic spermatozoa, abnormal flagella, and male infertility. To explore the mechanism behind CCDC159 regulating spermatogenesis, we identified CCDC159-binding proteins using a yeast two-hybrid screen and speculated that CCDC159 participates in HTCA assembly by regulating protein phosphatase PP1 activity. Further RNA-sequencing analyses of Ccdc159 KO testes revealed numerous genes involved in male gamete generation that were downregulated. Together, our results show that CCDC159 in spermatids is a novel centrosomal protein anchoring the sperm head to the tail. Considering the limitation of KO mouse model in clarifying the biological function of CCDC159 in spermatogenesis, a gene-rescue experiment will be performed in the future.

Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2-/- mice) and elucidate the underlying mechanisms. METHODS: Mdr2-/-mice (12-14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC-MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing. RESULTS: BBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota. CONCLUSION: BBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.

[Preparation and application of rabbit polyclonal antibody against mouse IQ and ubiquitin-like domain-containing protein (IQUB)].

Objective To prepare rabbit polyclonal antibody against mouse IQ and ubiquitin-like domain-containing protein (IQUB) and detect its expression in the mouse testis. Methods Full-length coding sequence of IQUB was inserted into the pET-30a(+) vector to construct pET-30a-IQUB recombinant prokaryotic plasmid. Transformation of pET-30a-IQUB plasmid into E. coli BL21 was performed, and protein expression was induced with isopropyl-beta-D-thiogalactoside (IPTG). The protein was purified through histidine-tagged fusion protein purification column, then denatured by treatment of urea with gradient concentration. New Zealand rabbits were immunized with the denatured protein to produce IQUB polyclonal antibody. Antibody titer was detected by ELISA, and Western blot analysis and immunofluorescence assay were employed to validate the effectiveness and specificity of IQUB antibody. Results pET-30a-IQUB recombinant plasmid was constructed, and protein expression of IQUB was induced successfully with IPTG. The titer of IQUB polyclonal antibody reached 1:1 000 000. The antibody specifically recognized the endogenous IQUB protein of testis in the wild-type adult mouse. IQUB was expressed in spermatogenic cells of different stages. It was localized in the acrosome and flagellum of mature sperms. Conclusion The highly specific rabbit anti-mouse IQUB polyclonal antibody is successfully prepared, which can be used for Western blot and immunofluorescence histochemistry.

Neutrophils exacerbate acetaminophen-induced liver injury by producing cytotoxic interferon-γ.

BACKGROUND: Drug (e.g., acetaminophen, APAP)-associated hepatotoxicity is the major cause of acute liver failure. Emerging evidence shows that initial tissue damage caused by APAP triggers molecular and cellular immune responses, which can modulate the severity of hepatoxicity. The pro-inflammatory and cytotoxic cytokine interferon (IFN)-γ has been reported as a key molecule contributing to APAP-induced liver injury (AILI). However, its cellular source remains undetermined. RESULTS: In the current study, we show that elevation of serum IFN-γ in patients with drug hepatotoxicity correlates with disease severity. Neutralization of IFN-γ in a mouse model of AILI effectively reduces hepatotoxicity. Strikingly, we reveal that IFN-γ is expressed primarily by hepatic neutrophils, not by conventional immune cells with known IFN-γ-producing capability, e.g., CD8+ T cells, CD4+ T cells, natural killer cells, or natural killer T cells. Upon encountering APAP-injured hepatocytes, neutrophils secrete cytotoxic IFN-γ further causing cell stress and damage, which can be abrogated in the presence of blocking antibodies for IFN-γ or IFN-γreceptor. Furthermore, removal of neutrophils in vivo substantially decreases hepatic IFN-γ levels concomitantly with reduced APAP hepatotoxicity, whereas adoptive transfer of IFN-γ-producing neutrophils confers IFN-γ-/- mice susceptibility to APAP administration. CONCLUSIONS: Our findings uncover a novel mechanism of neutrophil action in promoting AILI and provide new insights into immune modulation of the disease pathogenesis.

Ubiquitin-like protein 5 is a novel player in the UPR-PERK arm and ER stress-induced cell death.

Biological functions of the highly conserved ubiquitin-like protein 5 (UBL5) are not well understood. In Caenorhabditis elegans, UBL5 is induced under mitochondrial stress to mount the mitochondrial unfolded protein response (UPR). However, the role of UBL5 in the more prevalent endoplasmic reticulum (ER) stress-UPR in the mammalian system is unknown. In the present work, we demonstrated that UBL5 was an ER stress-responsive protein, undergoing rapid depletion in mammalian cells and livers of mice. The ER stress-induced UBL5 depletion was mediated by proteasome-dependent yet ubiquitin-independent proteolysis. Activation of the protein kinase R-like ER kinase arm of the UPR was essential and sufficient for inducing UBL5 degradation. RNA-Seq analysis of UBL5-regulated transcriptome revealed that multiple death pathways were activated in UBL5-silenced cells. In agreement with this, UBL5 knockdown induced severe apoptosis in culture and suppressed tumorigenicity of cancer cells in vivo. Furthermore, overexpression of UBL5 protected specifically against ER stress-induced apoptosis. These results identify UBL5 as a physiologically relevant survival regulator that is proteolytically depleted by the UPR-protein kinase R-like ER kinase pathway, linking ER stress to cell death.

[Preparation and identification of rabbit anti-mouse coiled-coil domain containing 189(Ccdc189)polyclonal antibody].

Objective To prepare a rabbit anti-mouse coiled-coil domain containing 189 (Ccdc189) polyclonal antibody. Methods The pET-28a-Ccdc189 prokaryotic expression plasmid was constructed and transformed into E.coli BL21. IPTG was used to induce the expression of Ccdc189 prokaryotic protein. Adult male New Zealand rabbits were immunized with purified recombinant protein to obtain rabbit anti-mouse Ccdc189 polyclonal antibody. The specificity of the polyclonal antibody was identified by Western blot analysis, indirect ELISA and immunofluorescence histochemical staining. Results The pET-28a-Ccdc189 recombinant plasmid was successfully constructed and the expression of the Ccdc189 recombinant protein was induced. ELISA revealed that the titer of the polyclonal antibody was 1:1 000 000. Western blot and immunofluorescence staining demonstrated that the Ccdc189 polyclonal antibody could specifically identify the Ccdc189 prokaryotic protein and the Ccdc189 protein in adult wild-type mouse testis. Conclusion A polyclonal antibody with high specificity against mouse Ccdc189 was successfully created.

Integrated model simulates bigger, sweeter tomatoes under changing climate under reduced nitrogen and water input.

When simulating the response of fruit growth and quality to environmental factors and cultivation practices, the interactions between the mother plant and fruit need to be considered as a whole system. Here, we developed the integrative Tomato plant and fruit Growth and Fruit Sugar metabolism (TGFS) model by coupling equations describing the biophysical processes of leaf gas exchange, water transport, carbon allocation, organ growth and fruit sugar metabolism. The model also accounts for effects of soil nitrogen and atmospheric CO2 concentration on gaseous exchange of water and carbon by the leaf. With different nitrogen and water input values, TGFS performed well at simulating the dry mass of the tomato leaf, stem, root, and fruit, and the concentrations of soluble sugar and starch in fruit. TGFS simulations showed that increasing air temperature and CO2 concentration has positive effects on fruit growth, but not on sugar concentrations. Further model-based analyses of cultivation scenarios suggest that, in the context of climate change, decreasing N by 15%-25% and decreasing irrigation by 10%-20% relative to current levels would increase tomato fresh weight by 27.8%-36.4% while increasing soluble sugar concentration by up to 10%. TGFS provides a promising tool to optimise N and water inputs for sustainable high-quality tomatoes.

Bile acid-mediated signaling in cholestatic liver diseases.

Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.

The Dynamic Role of Endoplasmic Reticulum Stress in Chronic Liver Disease.

Chronic liver disease (CLD) is a major worldwide public health threat, with an estimated prevalence of 1.5 billion individuals with CLD in 2020. Chronic activation of endoplasmic reticulum (ER) stress-related pathways is recognized as substantially contributing to the pathologic progression of CLD. The ER is an intracellular organelle that folds proteins into their correct three-dimensional shapes. ER-associated enzymes and chaperone proteins highly regulate this process. Perturbations in protein folding lead to misfolded or unfolded protein accumulation in the ER lumen, resulting in ER stress and concomitant activation of the unfolded protein response (UPR). The adaptive UPR is a set of signal transduction pathways evolved in mammalian cells that attempts to reestablish ER protein homeostasis by reducing protein load and increasing ER-associated degradation. However, maladaptive UPR responses in CLD occur due to prolonged UPR activation, leading to concomitant inflammation and cell death. This review assesses the current understanding of the cellular and molecular mechanisms that regulate ER stress and the UPR in the progression of various liver diseases and the potential pharmacologic and biological interventions that target the UPR.