Mechanistic Understanding of Dexamethasone-Mediated Protection against Remdesivir-Induced Hepatotoxicity.

Remdesivir (RDV), a broad-spectrum antiviral agent, is often used together with dexamethasone (DEX) for hospitalized COVID-19 patients requiring respiratory support. Potential hepatic adverse drug reaction is a safety concern associated with the use of RDV. We previously reported that DEX cotreatment effectively mitigates RDV-induced hepatotoxicity and reduces elevated serum alanine aminotransferase and aspartate aminotransferase levels in cultured human primary hepatocytes (HPH) and hospitalized COVID-19 patients, respectively. Yet, the precise mechanism behind this protective drug-drug interaction remains largely unknown. Here, we show that through the activation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, RDV induces apoptosis (cleavage of caspases 8, 9, and 3), autophagy (increased autophagosome and LC3-II), and mitochondrial damages (decreased membrane potential, respiration, ATP levels, and increased expression of Bax and the released cytosolic cytochrome C) in HPH. Importantly, cotreatment with DEX partially reversed RDV-induced apoptosis, autophagy, and cell death. Mechanistically, DEX deactivates/dephosphorylates p38, JNK, and ERK1/2 signaling by enhancing the expression of dual specificity protein phosphatase 1 (DUSP1), a mitogen-activated protein kinase (MAPK) phosphatase, in a glucocorticoid receptor (GR)-dependent manner. Knockdown of GR in HPH attenuates DEX-mediated DUSP1 induction, MAPK dephosphorylation, as well as protection against RDV-induced hepatotoxicity. Collectively, our findings suggest a molecular mechanism by which DEX modulates the GR-DUSP1-MAPK regulatory axis to alleviate the adverse actions of RDV in the liver. SIGNIFICANCE STATEMENT: The research uncovers the molecular mechanisms by which dexamethasone safeguards against remdesivir-associated liver damage in the context of COVID-19 treatment.

Exploiting urine-derived induced pluripotent stem cells for advancing precision medicine in cell therapy, disease modeling, and drug testing.

The field of regenerative medicine has witnessed remarkable advancements with the emergence of induced pluripotent stem cells (iPSCs) derived from a variety of sources. Among these, urine-derived induced pluripotent stem cells (u-iPSCs) have garnered substantial attention due to their non-invasive and patient-friendly acquisition method. This review manuscript delves into the potential and application of u-iPSCs in advancing precision medicine, particularly in the realms of drug testing, disease modeling, and cell therapy. U-iPSCs are generated through the reprogramming of somatic cells found in urine samples, offering a unique and renewable source of patient-specific pluripotent cells. Their utility in drug testing has revolutionized the pharmaceutical industry by providing personalized platforms for drug screening, toxicity assessment, and efficacy evaluation. The availability of u-iPSCs with diverse genetic backgrounds facilitates the development of tailored therapeutic approaches, minimizing adverse effects and optimizing treatment outcomes. Furthermore, u-iPSCs have demonstrated remarkable efficacy in disease modeling, allowing researchers to recapitulate patient-specific pathologies in vitro. This not only enhances our understanding of disease mechanisms but also serves as a valuable tool for drug discovery and development. In addition, u-iPSC-based disease models offer a platform for studying rare and genetically complex diseases, often underserved by traditional research methods. The versatility of u-iPSCs extends to cell therapy applications, where they hold immense promise for regenerative medicine. Their potential to differentiate into various cell types, including neurons, cardiomyocytes, and hepatocytes, enables the development of patient-specific cell replacement therapies. This personalized approach can revolutionize the treatment of degenerative diseases, organ failure, and tissue damage by minimizing immune rejection and optimizing therapeutic outcomes. However, several challenges and considerations, such as standardization of reprogramming protocols, genomic stability, and scalability, must be addressed to fully exploit u-iPSCs' potential in precision medicine. In conclusion, this review underscores the transformative impact of u-iPSCs on advancing precision medicine and highlights the future prospects and challenges in harnessing this innovative technology for improved healthcare outcomes.

Human Hepatic Spheroid Coculture Model for the Assessment of Drug-Induced Liver Injury.

Accurate evaluation of potential drug risks such as drug-induced liver injury (DILI) continues to be a challenge faced by pharmaceutical industry and regulatory agencies. Preclinical testing has served as a foundation for the evaluation of the potential risks and effectiveness of investigational new drug (IND) products in humans. However, current two-dimensional (2D) in vitro human primary hepatocyte (HPH) culture systems cannot accurately depict and simulate the rich environment and complex processes observed in vivo, while animal studies present inherited species-specific differences and low throughput scales. Thus, there is a continued demand to establish new approaches that can better characterize DILI during drug discovery and development. Among others, the three-dimensional (3D) hepatic spheroid model comprising self-aggregated primary human hepatocytes cocultured with non-parenchymal cells (NPCs) appears to be a more accurate representation of the natural hepatic microenvironment with intercellular interactions between hepatocytes, stellate cells, Kupffer cells, liver sinusoidal endothelial cells (LSECs), and other cell types. This model holds the potential to improve the ability for long-term functional and toxicological studies. Here, we provide methodological details for this human hepatic spheroid coculture model system.

Ribosome heterogeneity in development and disease.

Traditionally viewed as a fixed and homogeneous machinery for protein synthesis, the ribosome is increasingly recognized for its heterogeneity, as indicated by emerging studies highlighting the functional relevance of specialized ribosomes. However, whether ribosome heterogeneity is merely an outcome limited to specific conditions or a pervasive cellular phenomenon remains unclear, and existing evidence on the extensive existence of ribosome heterogeneity is scant. Here, we leveraged existing proteomic data and employed ribosome ratio-omics (RibosomeR), which comprehensively analyzes ribosome protein stoichiometry across various biological samples exhibiting distinct functions, developmental stages, and pathological states. Using the 80S monosome proteomic data, RibosomeR analysis unveils significant ribosome heterogeneity across different tissues, including fat, spleen, liver, kidney, heart, and skeletal muscles. Furthermore, examination of testes at various stages of spermatogenesis reveals distinct RibosomeR signatures during tissue development. Analysis of the whole cell proteomic data finds that RibosomeR undergoes dynamic changes during in vitro neuronal maturation, indicating functional associations with specific molecular aspects of neurodevelopment. In pathological contexts, RibosomeR signatures in gastric tumors demonstrate functional links to pathways associated with tumorigenesis. Additionally, dynamic alterations in RibosomeR are observed in macrophages following immune challenges. Collectively, our investigation across a diverse array of biological samples underscores the presence of ribosome heterogeneity, while previous studies observed functional aspects of ribosome specialization, in cellular function, development, and disease. The RibosomeR barcode serves as a valuable tool for elucidating these complexities.

Investigation of rock genesis and geodynamic significance based on Sr-Yb granite classification and geochemical characteristics: A case study from Guangxi, China.

The intrusive bodies in the study area are categorized into two intrusive units, γπK2 and ηoπK2, based on rock structure characteristics and intrusive contact relationships. The primary lithologies are granite porphyry and quartz monzonite porphyry. Through LA-ICP-MS zircon U-Pb dating, the weighted mean ages of zircon ^206Pb/^238U for these two units were determined to be 84.09 ± 0.86 Ma and 86.10 ± 0.76 Ma, respectively. According to geochemical characteristics and Sr-Yb granite classification, the quartz monzonite porphyry is classified as Zhejiang-Fujian type granite, and the granite porphyry as Nanling type granite. The study explores the geodynamic significance of granites in the area based on Sr-Yb granite classification, identifying the lower crust metamorphic facies as amphibolite facies. The source rocks are primarily basic granulites and felsic granulites, reflecting a thermally active lower crust with poorly developed fluids. Additionally, Sr-Yb granite classification aids in determining the crustal thickness of the lower crust, which is crucial for understanding continental geological evolution. This paper discusses the optimal locations and conditions for mineralizing fluid precipitation, noting that tungsten-tin mineralization is associated with Nanling type granites and that the mineralization process generally occurs later than the diagenetic process under conditions of low pressure and low oxygen fugacity. Tungsten-tin prospecting should focus on areas where the surrounding rock temperature ranges from 300 to 500 °C, with particular attention to the contact zones of sedimentary rocks or near structural fault zones.

Characteristics, sources analysis, and risk assessment of polycyclic aromatic hydrocarbon contamination in surface sediments surrounding tourist island.

Surface sediment samples were collected from the surrounding sea areas of the two largest tourist islands in Sanya City, China, to compare and assess the sources, distribution, and ecological risks of 16 polycyclic aromatic hydrocarbons (PAHs). The total PAHs concentrations ranged from 31.16 to 163.3 ng/g, with an average concentration of 102.46 ng/g, which is still lower than the levels detected in most other sediment studies worldwide. PAHs from coal combustion (Flu, Pyr, Fl, Phe) showed positive correlations with TOC, Silt, and Clay, indicating that these PAHs are easily adsorbed in muddy and silty sediments. Sanya Bay is primarily composed of mud and silt, whereas Haitang Bay is mainly sandy. This corresponds to the significantly higher concentrations of Fl, Phe, and Pyr in Sanya Bay compared to Haitang Bay. The main industrial activities in the study area are related to power and heat production and supply. The results indicate that the primary sources of sediment PAHs are high-temperature combustion during heavy industrial production, followed by maritime transportation and petroleum sources. Overall, the PAHs pollution levels in the study area range from slight to moderate. Sediment quality assessments show that only Ace and Phe have higher individual risk values. Six stations in Sanya Bay have higher adverse impact risks, while in Haitang Bay, only HT07 poses a high risk to biological impact. These two areas require enhanced monitoring and pollution source control.

Effect of Different Edible Trichosanthes Germplasm on Its Seed Oil to Enhance Antioxidant and Anti-Aging Activity in Caenorhabditis elegans.

The seeds of various Trichosanthes L. plants have been frequently used as snacks instead of for traditional medicinal purposes in China. However, there is still a need to identify the species based on seeds from Trichosanthes germplasm for the potential biological activities of their seed oil. In this study, 18 edible Trichosanthes germplasm from three species were identified and distinguished at a species level using a combination of seed morphological and microscopic characteristics and nrDNA-ITS sequences. Seed oil from the edible Trichosanthes germplasm significantly enhanced oxidative stress tolerance, extended lifespan, delayed aging, and improved healthspan in Caenorhabditis elegans. The antioxidant activity of the seed oil exhibits a significant positive correlation with its total unsaturated fatty acid content among the 18 edible Trichosanthes germplasm, suggesting a genetic basis for this trait. The biological activities of seed oil varied among species, with T. kirilowii Maxim. and T. rosthornii Harms showing stronger effects than T. laceribractea Hayata.

Antioxidant and Neuroprotective Effects of Seed Oils from Trichosanthes kirilowii and T. laceribractea in Caenorhabditis elegans: A Comparative Analysis and Mechanism Study.

Excess reactive oxygen species (ROS) can accelerate amyloid ß (Aß) aggregation and tau protein hyperphosphorylation in neuron cells, which further leads to neurodegenerative diseases such as Alzheimer's disease (AD). Therefore, there is an urgent need to find natural and safe antioxidants for preventing or treating such neurodegenerative diseases. The seeds of Trichosanthes kirilowii Maxim and T. laceribractea Hayata have long been used for medicinal and edible purposes in China. However, the antioxidant and neuroprotective activities and underlying mechanisms of their seed oils still remain unclear. Herein, we examine the antioxidant and neuroprotective effects of seed oils extracted from different germplasms, T. kirilowii (YNHH and SDJN) and T. laceribractea (ZJQT and SXHZ), on ROS levels and neuroprotective activities in C. elegans. The results demonstrated that the seed oils significantly reduced the ROS levels in C. elegans by 17.03-42.74%, with T. kirilowii (YNHH and SDJN) exhibiting significantly stronger ROS scavenging abilities than T. laceribractea (ZJQT and SXHZ). The seed oils from T. kirilowii (YNHH and SDJN) alleviated the production and aggregation of Aß and the phosphorylation and polymerization of tau, suggesting a potential neuroprotective role. Conversely, seed oils from T. laceribractea (ZJQT and SXHZ) show minimal neuroprotective effects in C. elegans. These differential outcomes might stem from distinct mechanisms underlying antioxidant and neuroprotective effects, with the ctl-2 gene implicated as pivotal in mediating the significant neuroprotective effects of seed oils from T. kirilowii (YNHH and SDJN). Our findings have provided valuable insights into the antioxidant and neuroprotective properties of T. kirilowii seed oils, paving the way for further research aimed at elucidating the underlying mechanisms and exploring their potential therapeutic applications in combating neurodegenerative diseases.

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis.

Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, but only reduced in the DG subregion during the chronic phase. Furthermore, mRNA levels of proinflammatory cytokines ( Il1ß, Tnfα, and Ifnγ) and glial cell markers ( Gfap and Cd68) were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.

Exploring the Interfacial Hydrogen Transfer between Pt and the Siliceous Framework and Its Promotional Effect on the Isotope Catalytic Exchange.

Interfacial hydrogen transfer between metal particles and catalyst supports is a ubiquitous phenomenon in heterogeneous catalysis, and this occurrence on reducible supports has been established, yet controversies remain about how hydrogen transfer can take place on nonreducible supports, such as silica. Herein, highly dispersed Pt clusters supported on a series of porous silica materials with zeolitic or/and amorphous frameworks were prepared to interrogate the nature of hydrogen transfer and its promotional effect on H2-HDO isotope catalytic exchange. The formation of zeolitic frameworks upon these porous silica supports by hydrothermal crystallization greatly promotes the interfacial hydrogen bidirectional migration between metal clusters and supports. Benefiting from this transfer effect, the isotope exchange rate is enhanced by 10 times compared to that on the amorphous counterpart (e.g., Pt/SBA-15). In situ spectroscopic and theoretical studies suggest that the defective silanols formed within the zeolite framework serve as the reactive sites to bind HDO or H2O by hydrogen bonds. Under the electrostatic attraction interaction, the D of hydrogen-bonded HDO scrambles to the Pt site and the dissociated H on Pt simultaneously spills back to the electronegative oxygen atom of adsorbed water to attain H-D isotope exchange with an energy barrier of 0.43 eV. The reverse spillover D on Pt combines with the other H on Pt to form HD in the effluent. We anticipate that these findings are able to improve our understanding of hydrogen transfer between metal and silica supports and favor the catalyst design for the hydrogen-involving reaction.

Layer-specific mechanisms of perfluoroalkyl acid (PFAA) transport and partition in estuarine environments: Unveiling the depth-dependent differences.

Understanding of characteristics and transport of perfluoroalkyl acids (PFAAs) in heterogeneous estuarine environments is limited. Furthermore, the role of suspended particles (SPS) in different layers remains unclear. This study explores the multiphase distribution process and mechanism of PFAAs controlled by SPS across surface and bottom layers in five small estuaries. Peaks in PFAA concentrations are consistently observed at strongly stratified sites. Concentrations of the PFAAs in both surface and bottom SPS decreased as the degree of mixing increased from strongly stratified levels to well-mixed levels. The water-SPS partitioning of some short-chain PFAAs (PFBS, PFHxA, and PFHpA) is influenced by environmental factors (pH, depth, temperature, and salinity) due to electrostatic interactions, while the sorption of some long-chain PFAAs (PFOA, PFOS, and PFNA) is controlled by SPS and dissolved organic carbon (OC), driven by hydrophobic interactions. Additionally, SPS dominates OC transport in estuarine systems, except in sandy sediment environments. SPS plays a dominant role in PFAA partitioning in both surface and bottom water-SPS systems (p < 0.05), and salinity only significantly affects PFBS in bottom layer (p < 0.01). These findings are critical for understanding the drivers of PFAA partitioning and the roles of SPS in different layers, underscoring the necessity of considering particle-associated PFAA fractions in future coastal environmental management.

Haloacetamides disinfection by-products, a potential risk factor for nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by abnormal lipid deposition, with oxidative stress being a risk factor in its onset and progression. Haloacetamides (HAcAms), as unregulated disinfection by-products in drinking water, may alter the incidence and severity of NAFLD through the production of oxidative stress. We explored whether HAcAms at 1, 10, and 100-fold concentrations in Shanghai drinking water perturbed lipid metabolism in normal human liver LO-2 cells. CRISPR/Cas9 was used to construct a LO-2 line with stable NRF2 knock-down (NRF2-KD) to investigate the mechanism underlying abnormal lipid accumulation and hepatocyte damage caused by mixed exposure to HAcAms. At 100-fold real-world concentration, HAcAms caused lipid deposition and increased triglyceride accumulation in LO-2 cells, consistent with altered de novo lipogenesis. Differences in responses to HAcAms in normal and NRF2-KD LO-2 cells indicated that HAcAms caused hepatocyte lipid deposition and triglyceride accumulation by activation of the NRF2/PPARγ pathway and aggravated liver cell toxicity by inducing ferroptosis. These results indicate that HAcAms are important risk factors for NAFLD. Further observations and verifications of the effect of HAcAms on NAFLD in the population are warranted in the future.

Dendrobium officinale phenolic extract maintains proteostasis by regulating autophagy in a Caenorhabditis elegans model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and accumulating evidence suggested that proteostatic imbalance is a key feature of the disease. Traditional Chinese medicine exhibits a multi-target therapeutic effect, making it highly suitable for addressing protein homeostasis imbalance in AD. Dendrobium officinale is a traditional Chinese herbs commonly used as tonic agent in China. In this study, we investigated protection effects of D. officinale phenolic extract (SH-F) and examined its underlying mechanisms by using transgenic Caenorhabditis elegans models. We found that treatment with SH-F (50 µg/mL) alleviated Aß and tau protein toxicity in worms, and also reduced aggregation of polyglutamine proteins to help maintain proteostasis. RNA sequencing results showed that SH-F treatment significantly affected the proteolytic process and autophagy-lysosomal pathway. Furthermore, we confirmed that SH-F showing maintainance of proteostasis was dependent on bec-1 by qRT-PCR analysis and RNAi methods. Finally, we identified active components of SH-F by LC-MS method, and found the five major compounds including koaburaside, tyramine dihydroferulate, N-p-trans-coumaroyltyramine, naringenin and isolariciresinol are the main bioactive components responsible for the anti-AD activity of SH-F. Our findings provide new insights to develop a treatment strategy for AD by targeting proteostasis, and SH-F could be an alternative drug for the treatment of AD.

Diindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands.

Numerous studies have demonstrated the correlation between human gut bacteria and host physiology, mediated primarily via nuclear receptors (NRs). Despite this body of work, the systematic identification and characterization of microbe-derived ligands that regulate NRs remain a considerable challenge. In this study, we discover a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR). Using various biophysical analyses we show that their nanomolar affinities are comparable to those of synthetic CAR agonists, and that they can activate both rodent and human CAR orthologues, which established synthetic agonists cannot. We also find that the diindoles, diindolylmethane (DIM) and diindolylethane (DIE) selectively up-regulate bona fide CAR target genes in primary human hepatocytes and mouse liver without causing significant side effects. These findings provide new insights into the complex interplay between the gut microbiome and host physiology, as well as new tools for disease treatment.