Metabolic engineering of Aspergillus niger for accelerated malic acid biosynthesis by improving NADPH availability.

Microbial production of L-malic acid from renewable carbon sources has attracted extensive attention. The reduced cofactor NADPH plays a key role in biotransformation because it participates in both biosynthetic reactions and cellular stress responses. In this study, NADPH or its precursors nicotinamide and nicotinic acid were added to the fermentation medium of Aspergillus niger RG0095, which significantly increased the yield of malic acid by 11%. To further improve the titer and productivity of L-malic acid, we increased the cytoplasmic NADPH levels of A. niger by upregulating the NAD kinases Utr1p and Yef1p. Biochemical analyses demonstrated that overexpression of Utr1p and Yef1p reduced oxidative stress, while also providing more NADPH to catalyze the conversion of glucose into malic acid. Notably, the strain overexpressing Utr1p reached a malate titer of 110.72 ± 1.91 g L-1 after 108 h, corresponding to a productivity of 1.03 ± 0.02 g L-1 h-1. Thus, the titer and productivity of malate were increased by 24.5% and 44.7%, respectively. The strategies developed in this study may also be useful for the metabolic engineering of fungi to produce other industrially relevant bulk chemicals.

The forced activation of asexual conidiation in Aspergillus niger simplifies bioproduction.

Aspergillus niger is an efficient cell factory for organic acids production, particularly l-malic acid, through genetic manipulation. However, the traditional method of collecting A. niger spores for inoculation is labor-intensive and resource-consuming. In our study, we used the CRISPR-Cas9 system to replace the promoter of brlA, a key gene in Aspergillus conidiation, with a xylose-inducible promoter xylP in l-malic acid-producing A. niger strain RG0095, generating strain brlAxylP. When induced with xylose in submerged liquid culture, brlAxylP exhibited significant upregulation of conidiation-related genes. This induction allowed us to easily collect an abundance of brlAxylP spores (>7.1 × 106/mL) in liquid xylose medium. Significantly, the submerged conidiation approach preserves the substantial potential of A. niger as a foundational cellular platform for the biosynthesis of organic acids, including but not limited to l-malic acid. In summary, our study offers a simplified submerged conidiation strategy to streamline the preparation stage and reduce labor and material costs for industrial organic acid production using Aspergillus species.

CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma.

Currently, there is still a lack of novel and effective drug targets to improve the prognosis of hepatocellular carcinoma (HCC). Additionally, the role of CHEK2 in HCC has not been reported yet. The eQTLgen database and two HCC Genome-Wide Association Study (GWAS) datasets (ieu-b-4953, ICD10 C22.0) were used to find the drug target: CHEK2. Next, Colony, Edu, ß-gal, and cell cycle analysis were facilitated to evaluate the role of CHEK2 knockout in HCC. In addition, Nultin-3 was added to evaluate the apoptosis of TP53-mutated HCC cells with CHEK2 knockout. Furthermore, MitoSox, electron microscopy, mitochondrial ATP, and NADH+/NADH levels were assessed in the CHEK2 knockout HCC cells with or without Metformin. Finally, cell-derived tumor xenograft was used to evaluate the role of CHEK2 knockout in vivo. We initially identified a potential drug target, CHEK2, through GWAS data analysis. Furthermore, we observed a significant upregulation of CHEK2 expression in HCC, which was found to be correlated with a poor prognosis. Subsequently, the results indicated that knocking out CHEK2 selectively affects the proliferation, cell cycle, senescence, and apoptosis of TP53-mutant HCC cells. Additionally, the introduction of Nultin-3 further intensified the functional impact on TP53-mutant cells. Then ClusterProfiler results showed high CHEK2 and TP53 mutation group was positively enriched in the mitochondrial ATP pathway. Then we used MitoSox, electron microscopy, mitochondrial ATP, and NADH + /NADH assay and found knockout of CHECK could induce the ATP pathway to inhibit the growth of HCC. Our research introduces a novel drug target for TP53-mutant HCC cells via mitochondrial ATP, addressing the limitation of Nultin-3 as a standalone treatment that does not induce tumor cell death.

Restricted reaction of layered double hydroxide nanoparticles with phosphate in a confined microsphere space.

Over the past decades, considerable efforts have been made to find useful solutions for phosphate pollution control. The state transition of nanomaterials from freely dispersed to encapsulated provides a realizable route for their application in phosphate elimination. The separation convenience offered by encapsulation has been widely recognized, however, the unique binding mode of nanostructures and phosphate in the confined space remains unclear, limiting its further development. Here, carboxymethyl cellulose (CMC) microspheres were used as hosts to deploy layered double hydroxide (LDH) nanoparticles. On this basis, we described an attempt to explore the adsorption behavior of LDH and phosphate in the microsphere space. Compared to their freely dispersed analogues, LDH particles exhibited higher structural stability, wider pH adaptability, and better phosphate selectivity when spatially confined in the CMC microsphere. Nevertheless, the kinetic process was severely inhibited by three orders of magnitude. Besides, the saturated phosphate adsorption capacity was also reduced to 74.6 % of the freely dispersed system. A combinative characterization revealed that the highly electronegative CMC host not only causes electrostatic repulsion to phosphate, but also extracts the electron density of the metal center of LDH, weakening its ability to act as a Lewis acid site for phosphate binding. Meanwhile, the microsphere encapsulation also hinders the ion exchange function of interlayer anions and phosphate. This study offers an objective insight into the reaction of LDH and phosphate in the confined microsphere space, which may contribute to the advanced design of encapsulation strategies for nanoparticles.

Increase in antioxidant capacity associated with the successful subclone of hypervirulent carbapenem-resistant Klebsiella pneumoniae ST11-KL64.

The acquisition of exogenous mobile genetic material imposes an adaptive burden on bacteria, whereas the adaptational evolution of virulence plasmids upon entry into carbapenem-resistant Klebsiella pneumoniae (CRKP) and its impact remains unclear. To better understand the virulence in CRKP, we characterize virulence plasmids utilizing a large genomic data containing 1219 K. pneumoniae from our long-term surveillance and publicly accessible databases. Phylogenetic evaluation unveils associations between distinct virulence plasmids and serotypes. The sub-lineage ST11-KL64 CRKP acquires a pK2044-like virulence plasmid from ST23-KL1 hypervirulent K. pneumoniae, with a 2698 bp region deletion in all ST11-KL64. The deletion is observed to regulate methionine metabolism, enhance antioxidant capacity, and further improve survival of hypervirulent CRKP in macrophages. The pK2044-like virulence plasmid discards certain sequences to enhance survival of ST11-KL64, thereby conferring an evolutionary advantage. This work contributes to multifaceted understanding of virulence and provides insight into potential causes behind low fitness costs observed in bacteria.

Anion Exchange Membranes for Hydrogen Technologies: Challenges and Progress.

Anion exchange membrane fuel cells (AEMFCs) are considered one of the most promising and efficient hydrogen conversion technologies due to their ability to use cost-effective materials. However, AEMFCs are still in the early stage of development and the lack of suitable anion exchange membranes (AEMs) is one major obstacle. In this review, we highlight three major challenges in AEMs development and discuss recent scientific advancements that address these challenges. We identify current trends and provide a perspective on future development of AEMs.

Molecular Simulation of Thermodynamic Properties of CH4/CO2 Adsorption by Coal Molecules at Different Temperatures and Moisture Contents under Variable Pressure Conditions.

In order to further elucidate the thermodynamic mechanism of CH4/CO2 adsorption by coal molecules, the adsorption behavior of a molecular model of coal (C206H128O36N2) at Wucaiwan, Zhundong was investigated by applying Materials Studio 2020 and Monte Carlo (GCMC) simulation methods, and the adsorption behavior of CH4 and CO2 was studied from the thermodynamic point of view under the conditions of different temperatures, pressures, and moisture contents. The results showed that at different temperatures or moisture contents, CH4 molecules had a low-density scattering distribution and CO2 molecules had a high-density polymerization distribution. Temperature and moisture content and adsorption constants a and b were negatively correlated. Under the same conditions, the relationship between single- and binary-component adsorption amounts was CO2 > CH4 and the relationship between heat of adsorption was CO2 > CH4. When adsorption potential energy or entropy of adsorption was the same, the adsorption capacity was CO2 > CH4. Temperatures and moisture contents were negatively correlated with the total adsorption capacity of CH4/CO2; pressure was positively correlated with the total adsorption capacity of CH4/CO2. The effect of temperature on the equivalent heat of adsorption was greater than that of pressure at different temperatures, and the entropy of adsorption was positively correlated between temperature and CH4/CO2, while the amount of adsorption was negatively correlated with the entropy of adsorption. The effect of moisture content on the equivalent heat of adsorption was greater than that of pressure at different moisture contents, and the entropy of adsorption was negatively correlated between moisture content and amount of adsorption. The adsorption entropy of CH4/CO2 was negatively correlated, and the adsorption amount was positively correlated to the adsorption entropy. At a temperature above 318 K or moisture content above 10%, the total CH4/CO2 adsorption decreased significantly and the CO2 adsorption decreased significantly. From a thermodynamic point of view, the presence of a large amount of H2O had a much greater effect on CO2 than on CH4, and an increase in temperature or moisture content was unfavorable for CO2 sequestration, CO2 stripping of CH4, and control of CH4 diffusion and desorption, whereas at low temperature, high pressure, and moisture content <1%, the effect of stripping, sequestration, and control was good.

Fluorescence-readout as a powerful macromolecular characterisation tool.

The last few decades have witnessed significant progress in synthetic macromolecular chemistry, which can provide access to diverse macromolecules with varying structural complexities, topology and functionalities, bringing us closer to the aim of controlling soft matter material properties with molecular precision. To reach this goal, the development of advanced analytical techniques, allowing for micro-, molecular level and real-time investigation, is essential. Due to their appealing features, including high sensitivity, large contrast, fast and real-time response, as well as non-invasive characteristics, fluorescence-based techniques have emerged as a powerful tool for macromolecular characterisation to provide detailed information and give new and deep insights beyond those offered by commonly applied analytical methods. Herein, we critically examine how fluorescence phenomena, principles and techniques can be effectively exploited to characterise macromolecules and soft matter materials and to further unravel their constitution, by highlighting representative examples of recent advances across major areas of polymer and materials science, ranging from polymer molecular weight and conversion, architecture, conformation to polymer self-assembly to surfaces, gels and 3D printing. Finally, we discuss the opportunities for fluorescence-readout to further advance the development of macromolecules, leading to the design of polymers and soft matter materials with pre-determined and adaptable properties.

Color-tunable luminescence based on the efficient energy transfer of a Tm-Dy system for optical thermometry and white LED lighting.

The development of phosphors with color-tunable luminescence including white emission is at the forefront of lighting and display technologies. Herein, Dy3+,Tm3+ single-doped or co-doped K3Y(PO4)2 phosphors are synthesized through the solid-state reaction method. By properly adjusting the ratio of Dy3+,Tm3+ co-doping concentrations, color-tunable luminescence from blue to yellow, including white luminescence, is realized under 359 nm excitation. The mechanism of energy transfer between Tm3+ and Dy3+ is further investigated via measuring the luminescence decay curve. Based on efficient energy transfer from Tm3+ to Dy3+, the emission of Dy3+ exhibits an abnormal thermal enhancement phenomenon as the temperature increases. The optical thermometry behaviors of various emission combinations for the Dy3+,Tm3+ co-doped system are analyzed. The maximum sensitivity can be obtained as a constant of 4.8 × 10-3 K-1, which is conducive to improve the measurement accuracy of optical temperature sensing at high temperatures. Furthermore, we also demonstrate the applicability of K3Y(PO4)2:Tm3+,Dy3+ phosphors in white LEDs, providing proof-of-concept for the lighting and display fields.

Gαs is dispensable for ß-arrestin coupling but dictates GRK selectivity and is predominant for gene expression regulation by ß2-adrenergic receptor.

ß-arrestins play a key role in G protein-coupled receptor (GPCR) internalization, trafficking, and signaling. Whether ß-arrestins act independently of G protein-mediated signaling has not been fully elucidated. Studies using genome-editing approaches revealed that whereas G proteins are essential for mitogen-activated protein kinase activation by GPCRs., ß-arrestins play a more prominent role in signal compartmentalization. However, in the absence of G proteins, GPCRs may not activate ß-arrestins, thereby limiting the ability to distinguish G protein from ß-arrestin-mediated signaling events. We used ß2-adrenergic receptor (ß2AR) and its ß2AR-C tail mutant expressed in human embryonic kidney 293 cells wildtype or CRISPR-Cas9 gene edited for Gαs, ß-arrestin1/2, or GPCR kinases 2/3/5/6 in combination with arrestin conformational sensors to elucidate the interplay between Gαs and ß-arrestins in controlling gene expression. We found that Gαs is not required for ß2AR and ß-arrestin conformational changes, ß-arrestin recruitment, and receptor internalization, but that Gαs dictates the GPCR kinase isoforms involved in ß-arrestin recruitment. By RNA-Seq analysis, we found that protein kinase A and mitogen-activated protein kinase gene signatures were activated by stimulation of ß2AR in wildtype and ß-arrestin1/2-KO cells but absent in Gαs-KO cells. These results were validated by re-expressing Gαs in the corresponding KO cells and silencing ß-arrestins in wildtype cells. These findings were extended to cellular systems expressing endogenous levels of ß2AR. Overall, our results support that Gs is essential for ß2AR-promoted protein kinase A and mitogen-activated protein kinase gene expression signatures, whereas ß-arrestins initiate signaling events modulating Gαs-driven nuclear transcriptional activity.

Konjac glucomannan/pectin/Ca-Mg hydrogel with self-releasing alkalinity to recover phosphate in aqueous solution.

The combination of polysaccharides can obtain stable, degradable, and environmentally friendly hydrogels, which have broad application prospects in adsorbents assembly. With Ca2+ and Mg2+ as crosslinkers, a new pectin/Konjac glucomannan/Ca-Mg composite hydrogel was prepared for phosphate adsorption by the alkali-thermal co-reaction method. Since Mg(OH)2 can create a suitable pH condition for phosphate adsorption by Ca, Ca and Mg synergistically promoted phosphate adsorption and remained stable in the pH range of 4 to 10. FTIR, SEM-EDS, XRD, XPS, and zero potential analysis corroborated that the hydrogel used Ca and Mg as active sites to trap pollutants by electrostatic adsorption and fix phosphate through complexation to form Mg3(PO4)2·8H2O and CaPO3(OH)2·H2O. Furthermore, it is unnecessary to separate the recovered phosphate from the hydrogel, and it can be used directly as a fertilizer. By being reused in the soil, it promoted seed germination and seedling growth. This adsorbent has the potential for recovery as a phosphorus-containing organic fertilizer after phosphorus adsorption.

Feature Selection in the Data Stream Based on Incremental Markov Boundary Learning.

Recent years have witnessed the proliferation of techniques for streaming data mining to meet the demands of many real-time systems, where high-dimensional streaming data are generated at high speed, increasing the burden on both hardware and software. Some feature selection algorithms for streaming data are proposed to tackle this issue. However, these algorithms do not consider the distribution shift due to nonstationary scenarios, leading to performance degradation when the underlying distribution changes in the data stream. To solve this problem, this article investigates feature selection in streaming data through incremental Markov boundary (MB) learning and proposes a novel algorithm. Different from existing algorithms focusing on prediction performance on off-line data, the MB is learned by analyzing conditional dependence/independence in data, which uncovers the underlying mechanism and is naturally more robust against the distribution shift. To learn MB in the data stream, the proposal transforms the learned information in previous data blocks to prior knowledge and employs them to assist MB discovery in current data blocks, where the likelihood of distribution shift and reliability of conditional independence test are monitored to avoid the negative impact from invalid prior information. Extensive experiments on synthetic and real-world datasets demonstrate the superiority of the proposed algorithm.

Acid-degradable nanocomposite hydrogel and glucose oxidase combination for killing bacterial with photothermal augmented chemodynamic therapy.

Bacterial infection often delays diabetic wound healing, and even causes serious life-threatening complications. Herein, we successfully developed a Cu2O/Pt nanocubes-dopping alginate (ALG)- hyaluronic acid (HA) hydrogel (Cu2O/Pt hydrogel) by simple assembly of the Cu2O/Pt nanocubes and the ALG-HA mixture. The Cu2O/Pt hydrogel combined with the glucose oxidase (GOx) can be used for photothermal- and starving-enhanced chemodynamic therapy (CDT) against Gram-negative and Gram-positive bacteria. The GOx can catalyze the glucose to produce gluconic acid and H2O2 for starvation therapy, following which the released Cu2O/Pt nanocubes react with H2O2 in the acidic microenvironment to generate highly cytotoxic hydroxyl radicals (·OH) for CDT. Additionally, the Cu2O/Pt hydrogel can release copper ions gradually with the decrease of pH induced by gluconic acid, which can increase the protein expression and secretion of vascular endothelial growth factor (VEGF) and promote endothelial cell proliferation, migration and angiogenesis, subsequently promoting diabetic wound healing in rats. Our results suggested that the Cu2O/Pt hydrogel combined with GOx may be a potential therapeutic approach for treating the infected diabetic wound.

Winning color-tunable upconversion luminescence and high-sensitive optical thermometry in K3Gd(PO4)2:Yb3+,Er3+,Tm3.

A series of Yb3+, Er3+, Tm3+ co-doped K3Gd(PO4)2 are prepared via the solid-state reaction method. Upon 980 nm excitation, the synthesized samples present color-tunable upconversion luminescence ranging from yellow to blue with the increment of Tm3+ doping contents. The upconversion mechanisms of Yb3+, Er3+, Tm3+ co-doped system are systematically investigated in detail. Varying contents of Tm3+ can appropriately alter the upconversion emissions of blue, green and red via possible energy transfer processes. Furthermore, the thermometric performances of phosphors associated with upconversion luminescence are analyzed in the temperature region of 300-675 K. By employing non-thermally coupled energy levels (2H11/2/4F9/2 of Er3+), the maximum relative and absolute sensitivity reaches 0.78 % K-1 and 0.168 K-1. Combining the sensitivity characteristic and repeatability of thermometer, the luminescence intensity ratio technology based on non-thermally coupled energy levels may be a more effective choice for optical thermometry. These excellent results will pave an avenue to K3Gd(PO4)2:Yb3+,Er3+,Tm3+ phosphors for the fields of color-tunable luminescence and non-contact temperature sensing.

Fluorinated Poly(aryl piperidinium) Membranes for Anion Exchange Membrane Fuel Cells.

Anion-exchange-membrane fuel cells (AEMFCs) are a cost-effective alternative to proton-exchange-membrane fuel cells (PEMFCs). The development of high-performance and durable AEMFCs requires highly conductive and robust anion-exchange membranes (AEMs). However, AEMs generally exhibit a trade-off between conductivity and dimensional stability. Here, a fluorination strategy to create a phase-separated morphological structure in poly(aryl piperidinium) AEMs is reported. The highly hydrophobic perfluoroalkyl side chains augment phase separation to construct interconnected hydrophilic channels for anion transport. As a result, these fluorinated PAP (FPAP) AEMs simultaneously possess high conductivity (>150 mS cm-1 at 80 °C) and high dimensional stability (swelling ratio <20% at 80 °C), excellent mechanical properties (tensile strength >80 MPa and elongation at break >40%) and chemical stability (>2000 h in 3 m KOH at 80 °C). AEMFCs with a non-precious Co-Mn spinel cathode using the present FPAP AEMs achieve an outstanding peak power density of 1.31 W cm-2 . The AEMs remain stable over 500 h of fuel cell operation at a constant current density of 0.2 A cm-2 .

Comparing Prognosis Associated with Partial Cystectomy and Trimodal Therapy for Muscle-Invasive Bladder Cancer Patients.

OBJECTIVE: This study aimed to compare the survival outcomes between trimodal therapy (TT) and partial cystectomy (PC) in muscle-invasive bladder cancer (MIBC) patients. METHODS: The data of 13,096 patients with MIBC diagnosed between 2004 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database. Among them, 4,041 patients underwent TT and 1,670 patients underwent PC. Propensity score matching was performed to balance the characteristics between the 2 treatment groups. A multivariate Cox regression analysis model and a competing risk model were used to evaluate overall survival (OS) and cancer-specific survival. Cumulative incidence survival curves were obtained using the Kaplan-Meier method. RESULTS: Results of multivariate Cox analysis before propensity score matching showed that the TT group had a 31% reduction in cause-specific survival relative to the PC group (HR: 0.69, 95% CI: 0.61-0.78, p < 0.001) and a 28% reduction in OS (HR: 0.72, 95% CI: 0.66-0.79, p < 0.001). After propensity score matching, the 2 groups yielded 972 patients, with 3-year cause-specific survival rates of 54.1% and 68.5% in the TT group and the PC group, respectively. CONCLUSIONS: Patients who underwent PC had a better prognosis than those who received TT. In addition, for MIBC patients who required bladder-sparing therapy, advanced age (≥80 years), pathological type of squamous cell carcinoma, and tumor stage of T3-4, N2-3, and M1 were independent poor prognostic factors.

Multilabel Feature Selection: A Local Causal Structure Learning Approach.

Multilabel feature selection plays an essential role in high-dimensional multilabel learning tasks. Existing multilabel feature selection approaches mainly either explore the feature-label and feature-feature correlations or the label-label and feature-feature correlations. A few of them are able to deal with all three types of correlations simultaneously. To address this problem, in this article, we formulate multilabel feature selection as a local causal structure learning problem and propose a novel algorithm, M2LC. By learning the local causal structure of each class label, M2LC considers three types of feature relationships simultaneously and is scalable to high-dimensional datasets as well. To tackle false discoveries caused by the label-label correlations, M2LC consists of two novel error-correction subroutines to correct those false discoveries. Through local causal structure learning, M2LC learns the causal mechanism behind data, and thus, it can select causally informative features and visualize common features shared by class labels and specific features owned by an individual class label using the learned causal structures. Extensive experiments have been conducted to evaluate M2LC in comparison with the state-of-the-art multilabel feature selection algorithms.

Multi-Target Markov Boundary Discovery: Theory, Algorithm, and Application.

Markov boundary (MB) has been widely studied in single-target scenarios. Relatively few works focus on the MB discovery for variable set due to the complex variable relationships, where an MB variable might contain predictive information about several targets. This paper investigates the multi-target MB discovery, aiming to distinguish the common MB variables (shared by multiple targets) and the target-specific MB variables (associated with single targets). Considering the multiplicity of MB, the relation between common MB variables and equivalent information is studied. We find that common MB variables are determined by equivalent information through different mechanisms, which is relevant to the existence of the target correlation. Based on the analysis of these mechanisms, we propose a multi-target MB discovery algorithm to identify these two types of variables, whose variant also achieves superiority and interpretability in feature selection tasks. Extensive experiments demonstrate the efficacy of these contributions.

Relationship between serum indirect bilirubin and prostate volume in patients with benign prostatic hyperplasia: a cross-sectional study.

Background: Due to its anti-oxidative effects, bilirubin may protect against a spectrum of diseases. However, the role of bilirubin in patients with benign prostatic hyperplasia (BPH) is poorly explored. This study aimed to investigate the cross-sectional associations between serum indirect bilirubin (IBIL) and prostate volume (PV) in patients with BPH. Methods: The medical records of 722 BPH patients were retrospectively analyzed. Body mass index (BMI) was calculated as body weight (kg)/height (m)2. PV was obtained as height (cm) × width (cm) × length (cm) × π/6. Other biochemical indexes were measured by the automatic biochemical analyzer. A univariable linear regression analysis was performed to detect confounders. The IBIL-PV relationship was examined using unadjusted and covariate-adjusted regression models. Furthermore, a segmented linear regression was conducted to analyze the linear trend of IBIL levels and PV. Finally, the sensitivity analysis was stratified by BMI and low-density lipoprotein cholesterol (LDL-C) cutoffs. Results: In this study, the mean age of the patients was 68 (range, 43-93) years. By univariable line regression test, we observed that PV was positively correlated with age, BMI, and LDL-C (ß=0.113, 0.096, and 0.135, respectively). IBIL was negatively associated with PV in full adjusted model in men age ≤75 years (ß=-1.01; 95% CI: -1.81, -0.22; P=0.01). A statistically significant inverse trend was observed between serum IBIL intervals and PV in patients aged ≤75 years (adjusted for age, BMI, and LDL-C, P for trend =0.015). In sensitivity analysis, significantly negative IBIL-PV relationship only existed in men with normal BMI (adjusted ß=-1.328; 95% CI: -2.467, -0.190; P=0.022), overweight men (adjusted ß=-1.296; 95% CI: -2.519, -0.074; P=0.038), and men with normal LDL-C level (adjusted ß=-1.017; 95% CI: -1.869, -0.164; P=0.019). Conclusions: IBIL is negatively associated with PV in the non-obese population ≤75 years with normal LDL-C. These results suggest that higher serum IBIL possibly provides a degree of protection to BPH by mitigating oxidative stress (OS) related to aging and lipid peroxidation. Nevertheless, these preliminary findings from a single-center, retrospective study have limitations and need to be confirmed by future studies.

Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment.

Bile acids (BAs) are physiological detergents that can not only promote the digestion and absorption of lipids, but also may be a potential carcinogen. The accumulation of BAs in the body can lead to cholestatic liver cirrhosis and even liver cancer. Recently, studies demonstrated that BAs are highly accumulated in metastatic lymph nodes, but not in normal healthy lymph nodes or primary tumors. Lymph node metastasis is second only to hematogenous metastasis in liver cancer metastasis, and the survival and prognosis of hepatocellular carcinoma (HCC) patients with lymph node metastasis are significantly worse than those without lymph node metastasis. Meanwhile, component of BAs was found to significantly enhance the invasive potential of HCC cells. However, it is still poorly understood how deregulated BAs fuel the metastasis process of liver cancer. The tumor microenvironment is a complex cellular ecosystem that evolves with and supports tumor cells during their malignant transformation and metastasis progression. Aberrant BAs metabolism were found to modulate tumor immune microenvironment by preventing natural killer T (NKT) cells recruitment and increasing M2-like tumor-associated macrophages (TAMs) polarization, thus facilitate tumor immune escape and HCC development. Based on these available evidence, we hypothesize that a combination of genetic and epigenetic factors in cancerous liver tissue inhibits the uptake and stimulates the synthesis of BAs by the liver, and excess BAs further promote liver carcinogenesis and HCC metastasis by inducing immunosuppressive microenvironment.