Alcohol-associated liver disease - a current overview.

Alcohol-associated liver disease (ALD) remains a major and increasingly pressing concern in hepatology. ALD includes spectrum of conditions, each with unique diagnostic and therapeutic challenges. Excessive alcohol intake is a leading preventable cause of physical harm, including ALD. The pathogenesis of ALD involves oxidative stress, inflammation, and lipid metabolism disruptions, with genetic predispositions playing a major role. ALD progresses from hepatic steatosis to steatohepatitis, and finally liver cirrhosis, which is marked by severe fibrosis and impaired liver function. Advanced ALD stages, particularly alcoholic hepatitis and liver cirrhosis, are characterized by high mortality rates. Management of ALD primarily involves strict abstinence from alcohol, which can reverse early-stage disease or halt progression. Nutritional support, vitamin supplementation, and symptomatic treatment are also essential. Liver transplantation is the only definitive treatment for alcoholic liver cirrhosis, but it is difficult for patients with a history of alcohol abuse to qualify for the procedure. Epidemiological data indicate a growing burden of ALD, especially among younger populations, exacerbated by increased alcohol consumption trends and the COVID-19 pandemic's influence on drinking behaviors. Despite ALD's significant impact, current therapies are limited, highlight- ing the need for innovative treatments and comprehensive patient management strategies. Individualized care, enhanced epidemiological research, and new therapeutic approaches are crucial to improving outcomes for ALD patients.

Ultrasound Assessment of Sarcopenia in Alcoholic Liver Disease.

Malnutrition frequently affects patients with alcoholic liver disease (ALD), with important impacts on disease prognosis. Sarcopenia, the clinical phenotype of malnutrition characterized by skeletal muscle loss, is the major component responsible for adverse events in this population. The aim of this study is to assess the use of ultrasound (US) skeletal muscle performance in stratifying ALD disease severity. We recruited 43 patients with ALD and divided them into two groups: alcoholic hepatitis (AH) and alcoholic cirrhosis (AC). We evaluated disease-specific clinical and biological parameters and their relation to US Rectus Femoris muscle (RFM) measurements, including RFM thickness, stiffness (RFMS) and echogenicity (RFE). A thirty-seconds chairs stand test (30sCST) was used as the sarcopenia surrogate test. RMF thickness correlated with platelet count and serum albumin (p < 0.001). Both RFM and RFMS correlated with disease severity (p < 0.001) and 30sCST (p < 0.001, p = 0.002). Patients with AH had more severe US muscle abnormalities compared to AC (RFMS 1.78 m/s vs. 1.35 m/s, p = 0.001) and the highest prevalence of RFE (χ2 = 8.652, p = 0.003). Rectus Femoris US assessment could represent a reliable tool in the diagnosis and severity stratification of ALD-induced sarcopenia.

Therapeutic Potential of Foodborne Indole Derived from Chinese Stinky Tofu in Reducing Intestinal Inflammation and Enhancing Barrier Function to Mitigate Alcoholic Liver Injury.

Indole, a compound in Chinese stinky tofu (ST), acts as a ligand for the aryl hydrocarbon receptor (AHR). Despite extensive research on prebiotic compounds, indole's specific role in ST remains unexplored. This study used an ethanol gavage method to create an ALD (alcoholic liver disease) mouse model and investigate dietary indole's effects on the intestinal barrier. Our findings indicate that after 6 weeks of being fed ST, the indole present (2 mg/day) robustly activated the intestinal AHR, upregulating its target gene, CYP1A1 (cytochrome P450 1A1 enzyme). This activation significantly reduced intestinal permeability, mitigated alcohol-induced oxidative stress and inflammation, and restored intestinal barrier function. Consequently, the study demonstrates that foodborne indole substantially reduces alcohol absorption and lowers the expression levels of liver inflammation-related factors, thereby slowing the progression of ALD. These results highlight indole's therapeutic potential for treating ALD and its role in developing functional foods.

Multicomponent Gas Sensing Fiber Probe System Based on Platinum Coated Capillary Enhanced Raman Spectroscopy.

This paper proposes a novel multicomponent gas-sensing optical fiber probe system. It utilizes a precisely engineered Platinum-coated capillary fabricated via Atomic Layer Deposition (ALD) technology as the core for enhanced Raman spectroscopy, marking the first application of ALD in creating such a structure for gas Raman sensing. The noble metal capillary gas Raman probe demonstrates a low detection limit of 55 ppm for CO2 with a 30 s exposure time and good repeatability in multicomponent gas sensing. The capillary exhibits excellent stability, environmental resistance, and a large core diameter, enabling a rapid gas exchange rate and making it suitable for practical applications.

Fabrication of anodic and atomic layer deposition-alumina coated titanium implants for effective osteointegration applications.

Biomimicking the chemical, mechanical, and topographical properties of bone on an implant model is crucial to obtain rapid and effective osteointegration, especially for the large-area fractures of the skeletal system. Titanium-based biomaterials are more frequently preferred in clinical use in such cases and coating these materials with oxide layers having chemical/nanotopographic properties to enhance osteointegration and implantation success rates has been studied for a long time. The objective of this study is to examine the high and rapid mineralization potential of anodized aluminum oxide (AAO) coated and atomic layer deposition (ALD)-alumina coated titanium substrates on large deformation areas with difficult spontaneous healing. AAO-coated titanium (AAO@Ti) substrates were fabricated via anodization technique in different electrolytes and their osteogenic potential was analyzed by comparing them to the bare titanium surface as a control. In order to investigate the effect of the ionic characters gained by the surfaces through anodization, the oxidized nanotopographic substrates were additionally coated with an ultrathin alumina layer via ALD (ALD@AAO@Ti), which is a sensitive and conformal coating vapor deposition technique. Besides, a bare titanium sample was also coated with pure alumina by ALD (ALD@Ti) to investigate the effect of nanoscale surface morphology. XPS analysis after ALD coating showed that the ionic character of each surface fabricated by anodization was successfully suppressed. In vitro studies demonstrated that, among the substrates investigated, the mineralization capacity of MG-63 osteosarcoma cells were highest when incubated on ALD-treated and bare AAO@Ti samples that were anodized in phosphoric acid (H3PO4_AAO@Ti and ALD@H3PO4_AAO@Ti). Mineralization on these substrates also increased consistently beginning from day 2 to day 21. Moreover, immunocytochemistry for osteopontin (OPN) demonstrated the highest expression for ALD@H3PO4_AAO@Ti, followed by the H3PO4_AAO@Ti sample. Consequently, it was observed that, although ALD treatment improves cellular characteristics on all samples, effective mineralization requires more than a simple ALD coating or the presence of a nanostructured topography. Overall, ALD@H3PO4_AAO@Ti substrates can be considered as an implant alternative with its enhanced osteogenic differentiation potential and rapid mineralization capacity.

Insulin-like growth factor-binding protein7 exacerbates inflammatory response and lipid metabolism imbalance in alcohol-associated liver disease.

Alcohol-associated liver disease(ALD), caused by excessive alcohol consumption, are often associated with inflammatory outbreaks and lipid deposition in the liver. The role of Insulin-like growth factor-binding protein 7 (IGFBP7), an important metabolic regulator, in ALD, its underlying regulatory mechanism, and its potential implication in anti-ALD therapies remain unknown. We investigated the effects of IGFBP7 on hepatic inflammation and lipid metabolism disruption in a mouse model of ALD. Mice were fed by chronic ethanol feeding plus a single binge of ethanol feeding(chronic-plus-single-binge model). In addition, ethanol exposure modeling studies were performed on cultured hepatocytes to verify molecular correlations. The results showed that IGFBP7 expression was significantly elevated in the livers of mice and hepatocytes after chronic ethanol exposure. Subsequently, the results of a study by specific knockout of IGFBP7(IGFBP7-cKO) in mouse hepatocytes and lentiviral silencing of IGFBP7 in vivo suggested that IGFBP7 deletion could improve liver function levels in alcohol-fed mice; It also attenuated the outbreak of hepatitis factor and the disorder of lipid metabolism in mice.Using RNA-seq sequencing of mouse liver tissue, we found that IGFBP7 affects several downstream metabolic signaling pathways, including PPAR, MAPK, FoxO, etc. Then, we used the PPARα plasmid in hepatocytes and discovered that overexpressing PPARα reversed the impact of IGFBP7 on lipid metabolism disorders in hepatocytes. In conclusion, IGFBP7 deficiency in alcohol-associated liver disease alleviates the decline in liver function and the imbalance of lipid metabolism in mice, attenuates the inflammatory outbreak, and affects a variety of downstream lipid metabolism factors by regulating PPARα. Hence, IGFBP7 may be an effective therapeutic target in the treatment of ALD.

MicroRNAs in metabolic dysfunction-associated diseases: Pathogenesis and therapeutic opportunities.

Metabolic dysfunction-associated diseases often refer to various diseases caused by metabolic problems such as glucose and lipid metabolism disorders. With the improvement of living standards, the increasing prevalence of metabolic diseases has become a severe public health problem, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), diabetes and obesity. These diseases are both independent and interdependent, with complex and diverse molecular mechanisms. Therefore, it is urgent to explore the molecular mechanisms and find effective therapeutic targets of these diseases. MicroRNAs (miRNAs) have emerged as key regulators of metabolic homoeostasis due to their multitargets and network regulatory properties within the past few decades. In this review, we discussed the latest progress in the roles of miRNA-mediated regulatory networks in the development and progression of MASLD, ALD, diabetes and obesity.

Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.

A consistent feature of chronic liver diseases and the hallmark of pathologic repair is the so-called ductular reaction. This is a histological abnormality characterized by an expansion of dysmorphic cholangiocytes inside and around portal spaces infiltrated by inflammatory, mesenchymal, and vascular cells. The ductular reaction is a highly regulated response based on the reactivation of morphogenetic signaling mechanisms and a complex crosstalk among a multitude of cell types. The nature and mechanism of these exchanges determine the difference between healthy regenerative liver repair and pathological repair. An orchestrated signaling among cell types directs mesenchymal cells to deposit a specific extracellular matrix with distinct physical and biochemical properties defined as portal fibrosis. Progression of fibrosis leads to vast architectural and vascular changes known as liver cirrhosis. The signals regulating the ecology of this microenvironment are just beginning to be addressed. Contrary to the tumor microenvironment, immune modulation inside this "benign" microenvironment is scarcely known. One of the reasons is that both the ductular reaction and portal fibrosis have been primarily considered a manifestation of cholestatic liver disease, whereas this phenomenon is also present, albeit with distinctive features, in all chronic human liver diseases. Novel human-derived cellular models and progress in "omics" technologies are increasing our knowledge at a fast pace. Most importantly, this knowledge is on the edge of generating new diagnostic and therapeutic advances. Here, we will critically review the latest advances, in terms of mechanisms, pathophysiology, and treatment prospects. In addition, we will delineate future avenues of research including innovative translational opportunities.

Metabolic dysfunction-associated steatotic liver disease (SLD) and alcohol-associated liver disease, but not SLD without metabolic dysfunction, are independently associated with new onset of chronic kidney disease during a 10-year follow-up period.

AIMS: The new nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We aimed to elucidate the relationship between each category of SLD and chronic kidney disease (CKD). METHODS: We investigated the effects of various SLDs on the development of CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or positive for urinary protein, during a 10-year period in 12 138 Japanese subjects (men / women, 7984/4154; mean age, 48 years) who received annual health examinations including abdominal ultrasonography. RESULTS: The prevalences of SLD without metabolic dysfunction (SLD-MD[-]), MASLD, MetALD, and ALD were 1.7%, 26.3%, 4.9%, and 1.9%, respectively. During the follow-up period, 1963 subjects (16.2%) (men / women, 1374 [17.2%]/589 [14.2%]) had new onset of CKD. Multivariable Cox proportional hazard model analyses after adjustment of age, sex, eGFR, current smoking habit, diabetes mellitus, hypertension, and dyslipidemia showed that the hazard ratios (HR [95% confidence interval]) for the development of CKD in subjects with MASLD (1.20 [1.08-1.33], p = 0.001) and those with ALD (1.41 [1.05-1.88], p = 0.022), but not those with MetALD (1.11 [0.90-1.36], p = 0.332), were significantly higher than the HR in subjects with non-SLD. Interestingly, subjects with SLD-MD[-] had a significantly lower HR (0.61 [0.39-0.96], p = 0.034) than that in subjects with non-SLD. The addition of the novel classification of SLDs into traditional risk factors for the development of CKD significantly improved the discriminatory capacity. CONCLUSIONS: MASLD and ALD, but not SLD-MD[-], are independently associated with the development of CKD.

Alterations of the Fatty Acid Profile and the Expression of Genes Related to FA Metabolism in Cirrhotic Liver Tissue.

In addition to direct damage to hepatocytes, long-term ethanol consumption leads to lipid accumulation and hepatic steatosis, as well as to the dysregulation of lipid metabolism. The final step in various liver diseases is cirrhosis. The aim of this study was to compare the FA (fatty acids) profile and expression levels of genes involved in lipid metabolism in cirrhotic liver tissue and normal liver tissue. Exploring the changes in the FA profile and expression of genes related to fatty acid metabolism in cirrhotic liver tissue reveals a molecular landscape that goes beyond the surface of traditional liver function assessments. Understanding the shifts in gene expression and fatty acid composition in liver tissue opens avenues for interventions that may aid in the treatment of cirrhosis in the future.

Enhanced Thermal Stability of Conductive Mercury Telluride Colloidal Quantum Dot Thin Films Using Atomic Layer Deposition.

Colloidal quantum dots (CQDs) are valuable for their potential applications in optoelectronic devices. However, they are susceptible to thermal degradation during processing and while in use. Mitigating thermally induced sintering, which leads to absorption spectrum broadening and undesirable changes to thin film electrical properties, is necessary for the reliable design and manufacture of CQD-based optoelectronics. Here, low-temperature metal-oxide atomic layer deposition (ALD) was investigated as a method for mitigating sintering while preserving the optoelectronic properties of mercury telluride (HgTe) CQD films. ALD-coated films are subjected to temperatures up to 160 °C for up to 5 h and alumina (Al2O3) is found to be most effective at preserving the optical properties, demonstrating the feasibility of metal-oxide in-filling to protect against sintering. HgTe CQD film electrical properties were investigated before and after alumina ALD in-filling, which was found to increase the p-type doping and hole mobility of the films. The magnitude of these effects depended on the conditions used to prepare the HgTe CQDs. With further investigation into the interaction effects of CQD and ALD process factors, these results may be used to guide the design of CQD-ALD materials for their practical integration into useful optoelectronic devices.

Direct Growth of Bi2SeO5 Thin Films for High-k Dielectrics via Atomic Layer Deposition.

This study describes a modified atomic layer deposition (ALD) process for fabricating BiOxSey thin films, targeting their application as high-k dielectrics in semiconductor devices, especially for two-dimensional semiconductors. Using an intermediate-enhanced ALD technique for Bi2Se3 and a plasma-enhanced ALD process for Bi2O3, a method for the sequential deposition of Bi2SeO5 ternary films has been established. The thin film has been deposited on SiO2 and TiN substrates, exhibiting growth rates of 0.17 to 0.16 nm·cycle-1 without an incubation period, thanks to facile nucleation characteristics. The resulting film exhibited high flatness and reached 96% of its theoretical density, forming a uniform nanocrystalline structure. Electrical evaluations using metal-insulator-metal capacitors indicated the dielectric constant (∼17.6) and electrical breakdown strength (2.6 MV·cm-1), demonstrating their potential as a dielectric layer.

Key regulators of hepatic stellate cell activation in alcohol liver Disease: A comprehensive review.

Alcoholic liver disease (ALD) is a broad category of disorders that begin with liver injury, lead to liver fibrosis, and ultimately conclude in alcohol-induced liver cirrhosis, the most chronic and irreversible liver damage. Liver fibrosis (LF) is a common pathological characteristic observed in most chronic liver inflammatory conditions that involve prolonged inflammation. In this review, we have summarized ethanol-mediated hepatic stellate cell (HSCs) activation and its role in liver fibrosis progression. We highlight important molecular mechanisms that are modulated by ethanol, play a role in the activation of HSCs and the progression of liver fibrosis and identifying potential targets to ameliorate liver fibrosis.

Pathophysiology of X-Linked Adrenoleukodystrophy: Updates on Molecular Mechanisms.

X-ALD, an inherited monogenic metabolic disorder affecting the CNS and adrenal white matter, is caused by mutations in ABCD1 gene leading to defective fatty acid oxidation in the peroxisomes. This results in accumulation of very long-chain fatty acids, VLCFA, into brain, spinal cord, and body fluids. A single ABCD1mutation does not clearly explain the severity and diverse clinical spectrum of X-ALD phenotypes which suggests that not only genetic but also other modifier genes, epigenetic factors, and environmental factors play a role and contribute to neuroinflammation, mitochondrial dysfunctions, oxidative stress, and metabolic defects seen in phenotypes of ALD. In this review we discuss genotype and phenotype correlation and clinical spectra of X-ALD, previous and recent modifier genetic factors of X-ALD, including novel role of microRNAs (miRNAs) in pathology and as biomarkers. We also discuss the mechanistic interplay of miRNAs and metabolic pathways and potential of targeting miRNAs for X-ALD.

Effects of Marine Natural Products on Liver Diseases.

The prevention and treatment of liver disease, a class of disease that seriously threatens human health, has always been a hot topic of medical research. In recent years, with the in-depth exploration of marine resources, marine natural products have shown great potential and value in the field of liver disease treatment. Compounds extracted and isolated from marine natural products have a variety of biological activities such as significant antiviral properties, showing potential in the management of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), protection of the liver from fibrosis, protection from liver injury and inhibition of the growth of hepatocellular carcinoma (HCC). This paper summarizes the progress of research on marine natural products for the treatment of liver diseases in the past decade, including the structural types of active substances from different natural products and the mechanisms underlying the modulation of different liver diseases and reviews their future prospects.

Area-Selective Atomic Layer Deposition of Ru Using Carbonyl-Based Precursor and Oxygen Co-Reactant: Understanding Defect Formation Mechanisms.

Area selective deposition (ASD) is a promising IC fabrication technique to address misalignment issues arising in a top-down litho-etch patterning approach. ASD can enable resist tone inversion and bottom-up metallization, such as via prefill. It is achieved by promoting selective growth in the growth area (GA) while passivating the non-growth area (NGA). Nevertheless, preventing undesired particles and defect growth on the NGA is still a hurdle. This work shows the selectivity of Ru films by passivating the Si oxide NGA with self-assembled monolayers (SAMs) and small molecule inhibitors (SMIs). Ru films are deposited on the TiN GA using a metal-organic precursor tricarbonyl (trimethylenemethane) ruthenium (Ru TMM(CO)3) and O2 as a co-reactant by atomic layer deposition (ALD). This produces smooth Ru films (<0.1 nm RMS roughness) with a growth per cycle (GPC) of 1.6 Å/cycle. Minimizing the oxygen co-reactant dose is necessary to improve the ASD process selectivity due to the limited stability of the organic molecule and high reactivity of the ALD precursor, still allowing a Ru GPC of 0.95 Å/cycle. This work sheds light on Ru defect generation mechanisms on passivated areas from the detailed analysis of particle growth, coverage, and density as a function of ALD cycles. Finally, an optimized ASD of Ru is demonstrated on TiN/SiO2 3D patterned structures using dimethyl amino trimethyl silane (DMA-TMS) as SMI.

Structure and Selected Properties of SnO2 Thin Films.

Magnesium and its alloys are attractive temporary implants due to their biocompatibility and biodegradability. Moreover, Mg has good mechanical and osteoinductive properties. But magnesium and Mg alloys have one significant disadvantage: poor corrosion resistance in a physiological environment. Hence, a deposition of various layers on the surface of Mg alloys seems to be a good idea. The purpose of the article is to analyze the structure and morphology of two MgCa2Zn1 and MgCa2Zn1Gd3 alloys coated by SnO2 ALD (atomic layer deposition) films of various thickness. The studies were performed using scanning electron microscopy (SEM), X-ray fluorescence (XRF), and an X-ray diffractometer. The corrosion activity of the thin films and substrate alloys in a chloride-rich Ringer's solution at 37 °C was also observed. The corrosion tests that include electrochemical, immersion measurements, and electrochemical impedance spectroscopy (EIS) were evaluated. The results indicated that SnO2 had a heterogeneous crystal structure. The surfaces of the thin films were rough with visible pores. The corrosion resistance of SnO2 measured in all corrosion tests was higher for the thicker films. The observations of corrosion products after immersion tests indicated that they were lamellar-shaped and mainly contained Mg, O, Ca, and Cl in a lower concentration.

Atomic Layer Deposition of CeO2 Film with a Novel Heteroleptic Ce(III) Complex.

In this paper, four heteroleptic Ce(III) complexes, including Ce(thd)3-phen (thd = 2,2,6,6-tetramethyl-3,5-heptanedione, phen = 1, 10-phenanthroline (1), Ce(thd)3-MEDA (MEDA = N-Methylethylenediamine (2), Ce(thd)3-MOMA (MOMA = N-(2-Methoxyethyl)methylamine (3), and Ce(thd)3-DMDE (DMDE = N,N″-dimethyl ethanol amine (4), were synthesized and characterized with 1H-NMR, elemental analysis, and X-ray single-crystal diffraction. The thermogravimetric analysis and vapor pressure results indicated that the complexing ability of a nitrogen-containing bidentate ligand with a cerium ion was stronger than that of a mixed oxygen-nitrogen-containing bidentate ligand. Complex 2 was selected as an ALD precursor to deposit a CeO2 film on a SiO2/Si (100) wafer. The self-limited deposition results demonstrated that complex 2 was a potential ALD precursor.

Interface States in Gate Stack of Carbon Nanotube Array Transistors.

A deep understanding of the interface states in metal-oxide-semiconductor (MOS) structures is the premise of improving the gate stack quality, which sets the foundation for building field-effect transistors (FETs) with high performance and high reliability. Although MOSFETs built on aligned semiconducting carbon nanotube (A-CNT) arrays have been considered ideal energy-efficient successors to commercial silicon (Si) transistors, research on the interface states of A-CNT MOS devices, let alone their optimization, is lacking. Here, we fabricate MOS capacitors based on an A-CNT array with a well-designed layout and accurately measure the capacitance-voltage and conductance-voltage (C-V and G-V) data. Then, the gate electrostatics and the physical origins of interface states are systematically analyzed and revealed. In particular, targeted improvement of gate dielectric growth in the A-CNT MOS device contributes to suppressing the interface state density (Dit) to 6.1 × 1011 cm-2 eV-1, which is a record for CNT- or low-dimensional semiconductors-based MOSFETs, boosting a record transconductance (gm) of 2.42 mS/µm and an on-off ratio of 105. Further decreasing Dit below 1 × 1011 cm-2 eV-1 is necessary for A-CNT MOSFETs to achieve the expected high energy efficiency.

New advances in drug development for metabolic dysfunction-associated diseases and alcohol-associated liver disease.

Metabolic disorders are currently threatening public health worldwide. Discovering new targets and developing promising drugs will reduce the global metabolic-related disease burden. Metabolic disorders primarily consist of lipid and glucose metabolic disorders. Specifically, metabolic dysfunction-associated steatosis liver disease (MASLD) and alcohol-associated liver disease (ALD) are two representative lipid metabolism disorders, while diabetes mellitus is a typical glucose metabolism disorder. In this review, we aimed to summarize the new drug candidates with promising efficacy identified in clinical trials for these diseases. These drug candidates may provide alternatives for patients with metabolic disorders and advance the progress of drug discovery for the large disease burden.