Flavin-containing monooxygenases (FMOs) catalyze the oxygenation of a diverse range of sulfur or nitrogen-containing xenobiotics. Recently accumulated evidence has demonstrated the roles of FMOs in physiological and pathological conditions, including neurodegeneration and aging. However, the mechanisms underlying their functions are poorly understood. In this review, we summarize the expression and localization of FMOs in the brain, the endogenous chemicals and xenobiotics metabolized by FMOs, and the consequences of FMO deficiency. The understanding of FMOs activity in the brain is important for fully elucidating the roles of FMOs in pathological mechanisms.

Drug-induced liver injury (DILI) is a major cause of acute liver injury, liver failure, and liver transplantation worldwide. In recent years, immune checkpoint inhibitors have become widely used. This has led to an increase in DILI, for which pathophysiology and management methods differ significantly from the past. As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase, information about a DILI is becoming more valuable. DILI is classified into two types according to its etiology: intrinsic DILI, in which the drug or its metabolites cause liver damage that is dose-dependent and predictable; and idiosyncratic DILI, in which liver damage is also dose-independent but unpredictable. In addition, depending on the course of the disease, chronic DILI or drug-induced autoimmune hepatitis may be present. The number of DILI cases caused by antimicrobial agents is decreasing, whereas that caused by drugs for malignant tumors and health foods is increasing. The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI. Liver injury is a type of immune-related adverse event. The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular, but mixed type and bile stasis have also been reported. Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury. Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration; however, mycophenolate mofetil may be considered if the disease is refractory to steroids.

Many liver society guidelines no longer recommend single value alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) screening because of poor specificity and sensitivity. Instead, use of longitudinal AFP expression changes is recommended. However, no specific guidance has been provided as to what levels of longitudinal AFP change should be regarded as suspicious. The aim of this study was to determine whether an AFP slope cut-off value exists that could be useful for early diagnosis of HCC.

A retrospective chart review included patients with confirmed HCC as well as patients with cirrhosis but confirmed not to have HCC (control group). Trends in data points for AFP expression peaks (control group) and pre-diagnostic AFP data over time (HCC group) were compared. Additionally, aminotransferase trends were compared to AFP trends (HCC group) to account for possible confounding contribution of inflammation.

Using linear mixed effects models, the slope estimate for log (AFP) significantly differed between groups (p = 0.001), 1.21 (95% CI: 0.44–1.97, p = 0.005) in the HCC pre-diagnosis group versus the cirrhotic non-HCC controls 0.15 (95% CI: 0.08–0.23, p < 0.001). The area under the curve for sensitivity plotted against false positive rate or 1-specificity for log (AFP) of pre-diagnosis HCC was 0.844.

The results suggest that AFP trends do have clinical value compared to a single AFP cut-off. Using a log (AFP) slope cut-off of 0.32 gave a sensitivity of 89% and specificity of 70% for the diagnosis of HCC.

Nanotechnology has revolutionized and improved the potential of drug-delivery systems. Lipidic nanovesicles, termed liposomes, offer several benefits as drug-delivery carriers due to their compositional similarity with human biological membranes. Some of the advantages offered by liposomes include targeted drug delivery and improved pharmacokinetics of an entrapped drug substance, leading to enhanced bioavailability. Additionally, the reduction in the drug dose or dosing frequency, reduced drug toxicity or side effects, longer and controlled therapeutic response of a drug essential for the treatment of chronic diseases, and improved patient acceptance margins are some other benefits offered by liposomes. The easily modifiable surface of liposomes makes it an ideal vehicle for targeting a drug to the desired site. The current review provides insight on liposomes as drug-delivery carriers. This review summarizes the classification of compositional constituents of liposomes based on their chemical nature and structure. Morphology-based classification of liposomes along with methods of preparation and characterization for liposomes are also summarized. The current review emphasizes the medical applications of liposomes, specifically as delivery carriers for therapeutic and diagnostic agents. The article features detailed therapeutic applications of liposomes based on routes of administration and specific disease conditions. Diagnostic applications of liposomes for improving the efficiency of available techniques to treat diseases such as cancer are also discussed. Liposomes are thus reviewed as multifaceted nanovesicular carriers with potential therapeutic and diagnostic medical applications. The prospective multifunctional application of combining imaging functionality with therapeutic agents in a single liposome for diagnosis and real-time treatment is anticipated to be the future of liposomal formulations.

The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies.

Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors.

In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients.

Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

With the improvement of living standards in recent years, up to 90% of obese patients have nonalcoholic fatty liver disease (NAFLD). The number of nonalcoholic steatohepatitis (NASH)-related deaths will gradually increase, and NASH is expected to be the most common cause of liver-related deaths in the future. Therefore, there is an urgent need to find effective and reliable serum biomarkers to distinguish simple hepatic steatosis (SS) from NASH. Liver cell regeneration, oxidative stress-induced DNA methylation, and biliary epithelial cell proliferation were reported to increase serum alpha-fetoprotein (AFP) levels. AFP has long been used as a tool to monitor liver cancer. However, the function of AFP in NAFLD, especially NASH, has not been clarified. Moreover, whether an elevated AFP level indicates the occurrence of NASH or serves as a serum biomarker remains to be elucidated. The miRNA-122 pathway, DNA methylation and DNA damage, and activation of resident stem cells and/or progenitor cells in the liver, as well as necrosis, regeneration, and repair of liver cells, may contribute to slight increases in AFP levels in the development of NASH in patients with NAFLD. Furthermore, mildly elevated AFP levels may indicate the development of NASH. This review explores the role of elevated AFP levels in the development of NASH, with a specific focus on the underlying molecular mechanisms and the clinical significance.

Surgical site infections are the most common and significant epidemiological burden worldwide. Despite implementing modern surgical techniques, appropriate antibiotic prophylaxis, sterilization techniques, and aseptic and antiseptic practices, surgical site infections continue to pose a significant challenge. As a result, patients who experience these infections may require increased antibiotic use, extended hospital stays, and higher treatment costs. This is particularly concerning given that such infections are largely preventable. The financial and social burden imposed by the costs of surgical site infections remains a significant problem for many countries. Evidence-based preventive practices should be integrated into the preoperative, intraoperative, and postoperative periods to prevent these infections. It is estimated that approximately half of all surgical site infections can be prevented by applying evidence-based practices.

Drug-induced liver injury (DILI) can present as a chronic phenotype or acute course. However, there is a lack of research on the underlying mechanisms of chronic DILI as well as the definition of cut-off point. We aimed to profile holistic metabolic characteristics of chronic DILI and provide evidence for the cut-off point by serum metabolomics.

The sera of DILI patients were divided into Group I (0–6 months), Group II (6–12 months), and Group III (>12 months) based on the duration of liver injury. In total, 2,105 metabolites associated with the DILI duration were screened out as the holistic metabolomic signature (HMS). By unsupervised principal component analysis on the HMS dataset, the samples spontaneously represented a two-cluster pattern of the three groups, i.e., Group I as the first cluster and Group II/III as the second cluster, which suggested six months as the potential metabolomic cut-off point of DILI chronicity. Then, the differentiation ability of the metabolomic signature was validated in an independent cohort. We further screened out 23 most-associated metabolites as the metabolic fingerprint (MFP) for the DILI duration and constructed an eigenmetabolite by dimension reduction.

The eigenmetabolite was significantly different in chronic versus acute DILI and was not related to the severity grade of liver injury. Pathway enrichment analysis underlined the enhanced metabolic pathways of lipids in chronic DILI, which are associated with energy metabolism remodeling and immune regulation balance.

MFP was different between chronic and acute DILI. Six months might be the potential metabolomic cut-off point in defining chronicity of DILI.

The Bethesda System for Reporting Thyroid Cytopathology is the first reporting system established in non-gynecologic cytopathology after the Bethesda System for Reporting Cervical Cytopathology. It adopts the same concept of providing a uniform reporting system for all pathologists and clinicians to follow in thyroid cytology. The reporting system is composed of six diagnostic categories. There are defined diagnostic criteria, estimated risk of malignancy, and management recommendations for each category. The reporting system has undergone two revisions upon the emergence of a new entity, updated terminology in histology, and development and refinement of molecular testing. The third edition is soon to be published in 2023. This review will provide an updated summary of the reporting system. Potential diagnostic pitfalls and molecular testing are also discussed.

High-intensity interval training (HIIT) is a therapeutic option for people with nonalcoholic steatohepatitis (NASH). However, the perspectives and experiences of HIIT for people with NASH are unknown, limiting translation of research. We explored the experiences and perspectives of both professionally supervised and self-directed HIIT in people with NASH and evaluated participant-reported knowledge, barriers, and enablers to commencing and sustaining HIIT.

Twelve participants with NASH underwent 12 weeks of supervised HIIT (3 days/week, 4×4 minutes at 85–95% maximal heart rate, interspersed with 3 minutes active recovery), followed by 12-weeks of self-directed (unsupervised) HIIT. One-on-one, semistructured participant interviews were conducted by exercise staff prior to HIIT and following both supervised and self-directed HIIT to explore prior knowledge, barriers, enablers, and outcomes at each stage. Interviews were audio-recorded, transcribed, coded, and thematically analyzed by two independent researchers.

Four dominant themes were identified: (1) no awareness of/experience with HIIT and ambivalence about exercise capabilities; (2) multiple medical and social barriers to commencing and continuing HIIT; (3) exercise specialist support was a highly valued enabler, and (4) HIIT was enjoyed and provided holistic benefits.

People with NASH may lack knowledge of and confidence for HIIT, and experience multiple complex barriers to commencing and continuing HIIT. Exercise specialist support is a key enabler to sustained engagement. These factors need to be addressed in future clinical programs to augment the uptake and long-term sustainability of HIIT by people with NASH so they can experience the range of related benefits.

Over the past decades, cervical cancer has been a worldwide public health problem. Population-based early cancer risk detection and prevention approaches, including vaccination, cytology screening and human papilloma virus (HPV) detection, with the aligned clinical management, have formed a well-rounded high-quality implementation system for cervical cancer control, and revolutionarily improved the quality of life of women: (1) the success of cervical cancer screening practices, (2) standardization of The Bethesda system for reporting cervicovaginal cytology, (3) improvement in the understanding of HPV pathogenesis in cervical cancer, and (4) the development of appropriate management approaches have significantly decreased the disease burden of cervical cancer worldwide. This scoping review aimed to understand the evolvement of cervical cancer screening and management guidelines, describe the Bethesda cervical cytology reporting system, and HPV vaccines and tests, and highlight the key information of present policies and practices.

Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma (HCC) patients while the underlying mechanism of metastasis remains elusive. In our study, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was shown to be involved in the process of metastasis in HCC.

The Cancer Genome Atlas (TCGA) database and HCC tissue microarrays were used to evaluate the expression of genes. In vitro migration, invasion, in vivo subcutaneous tumor model and in vivo lung metastasis assays were used to determine the role of PLOD2 in tumor growth and metastasis in HCC. RNA sequencing and gene set enrichment analysis were performed to uncover the downstream factor of PLOD2 in HCC cells. A luciferase reporter assay was performed to evaluate the interaction between PLOD2 and interferon regulatory factor 5 (IRF5).

The expression of PLOD2 in HCC tissues was higher than that in adjacent tissues, and increased PLOD2 expression was often found in advanced tumors and was correlated with poor prognosis in HCC patients. In vitro experiments, knockdown of PLOD2 reduced the migration and invasion of human HCC cells. Loss of PLOD2 suppressed human HCC growth and metastasis in a subcutaneous tumor model and a lung metastasis model. Baculoviral IAP repeat containing 3 (BIRC3) was proven to be the downstream factor of PLOD2 in human HCC cells. In addition, PLOD2 was transcriptionally regulated by IRF5 in HCC cells.

High expression of PLOD2 was regulated by IRF5, which was correlated with the poor survival of HCC patients. PLOD2 enhanced HCC metastasis via BIRC3, suggesting that PLOD2 might be a valuable prognostic biomarker for HCC treatment.

Restenosis is a serious complication after percutaneous coronary intervention (PCI) for patients with coronary heart disease (CHD). This prospective clinical study was designed to investigate the effects of liposomal prostaglandin E1 (lipo-PGE1) on coronary stenosis and restenosis.

Sixty patients diagnosed with CHD and scheduled for PCI surgery in Guangdong Hospital of Traditional Chinese Medicine were enrolled in this study. The patients were divided into either the Control group (n = 30) or lipo-PGE1 treatment group (PGE group) (n = 30). Restenosis after PCI was the primary outcome, and newly increased stenosis was the secondary outcome.

In total, 54 patients finished the follow-up and were included in the final analysis (n = 30 in the Control group and n = 24 in the PGE group). Baseline comparisons of stenosis location, stenosis degree, and the number of vessels in stenosis before PCI were comparable (P > 0.05). Comparisons of implanted stents showed similar features in stent diameter and stent length during PCI between the two groups (P > 0.05). For the primary outcome, there was no obvious difference in restenosis percentage (χ2 = 1.520, P = 0.615) nor number of vessels in restenosis (χ2 = 0.070, P = 0.791) in three arteries between groups. For the secondary outcome, although there was no significant difference in the number of non-culprit vessels in increased stenosis after PCI between groups (χ2 = 3.902, P = 0.272), the percentage of increased stenosis was much lower in the right coronary artery in the PGE group than the Control group (U = 263.0, P = 0.048).

Lipo-PGE1 does not affect restenosis after PCI, but it may be effective in ameliorating newly increased stenosis in arteries.

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterised by cognitive impairment and numerous pathologies, including β-amyloid (Aβ) and Tau proteopathies, altered immune responses, and brain atrophy. Despite hundreds of years of investigations into its underlying pathogenesis, the aetiology of AD is not clearly understood. AD diagnostic criteria are not effective at identifying pre-clinical patients and current AD treatments cannot postpone or reverse disease progression. The development of non-human primate (NHP) models of AD is urgently required due to their close phylogenetic relationship to humans, similar neuroanatomy, comparable genetics, and high complexity of high-order cognitive functions, making them a better model of AD than rodents. We compared and contrasted AD-associated pathological features and behavioural alterations manifested between naturally aged spontaneous and induced NHP models of AD. Induced models of AD can be established using injections of Aβ oligomers, brain homogenates, neurotoxins, or formaldehyde. In recent decades, both spontaneous and induced NHP models of AD have been used to facilitate the development of neuroimaging tracers and therapeutic treatments, aiding in the translational application of lab discoveries into clinical trials involving human subjects. The establishment of a standardised NHP model of AD is expected by making a guideline concerning NHP species, types and doses of inducers, frequency of injections, and duration of inoculation. Its development can be facilitated by a comprehensive assessment of NHPs, including all AD-associated pathologies and a wide range of behavioural examinations. NHP models of AD have contributed to AD research and their evolution is expected to better recapitulate AD features and present greater translational potential in the near future.

Prolyl endopeptidase (PREP) is a serine endopeptidase that participates in many pathological processes including inflammation, oxidative stress, and autophagy. Our previous studies found that PREP knockout exhibited multiple benefits in high-fat diet (HFD) or methionine choline-deficient diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD). However, cumulative studies have suggested that PREP performs complex functions during disease development. Therefore, further understanding the role of PREP in MAFLD development is the foundation of PREP intervention.

In this study, an HFD-induced MAFLD model at different time points (4, 8, 12, and 16 weeks) was used to explore dynamic changes in the PREP proline-glycine-proline (PGP)/N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) system. To explore its potential value in MAFLD treatment, saline, or the PREP inhibitor, KYP-2047, was administered to HFD-induced MAFLD mice from the 10th to 16th weeks.

PREP activity and expression were increased in HFD-mice compared with control mice from the 12th week onwards, and increased PREP mainly resulted in the activation of the matrix metalloproteinase 8/9 (MMP8/9)-PREP-PGP axis rather than the thymosin β4-meprin α/PREP-AcSDKP axis. In addition, KYP-2047 reduced HFD-induced liver injury and oxidative stress, improved lipid metabolism through the suppression of lipogenic genes and the induction of β-oxidation-related genes, and attenuated hepatic inflammation by decreasing MMP8/9 and PGP. Moreover, KYP2047 restored HFD-induced impaired autophagy and this was verified in HepG2 cells.

These findings suggest that increased PREP activity/expression during MAFLD development might be a key factor in the transition from simple steatosis to steatohepatitis, and KYP-2047 might possess therapeutic potential for MAFLD treatment.

Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15–23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.

Diabetes mellitus (DM) is an established risk for biliary tract cancer (BTC). Metformin, an anti-diabetes medication, has been reported for its association with a reduced risk of BTC. However, the controversy about metformin’s benefit among epidemiological studies is unresolved. This study is to investigate metformin’s effects on the development and progression of BTC.

Literature searches were performed, without language restriction, in Pubmed, Embase, and Web of Science, from their respective inceptions to February 28, 2023. All studies were screened by two researchers using Covidence. Quality assessment was performed using the Newcastle-Ottawa Scale. Meta-analyses were performed by a fixed and random-effect model using RevMan version 5.4.

Nine observational studies met the inclusion criteria and were included in the meta-analysis. With pooled samples of 24,743,526 individuals from 4 case-control and 2 cohort studies, metformin was not associated with a decreased risk of BTC (pooled RR: 0.82, 95% CI: 0.42–1.59, p = 0.56). Sub-group analyses in each study design also revealed a null effect of metformin. Meta-analysis of 3 cohort studies reporting the association between metformin and survival of patients with BTC with a pooled sample of 1,163 patients showed a marginally significant effect of metformin on survival outcome improvement in both fixed effect models (pooled RR: 0.83, 95% CI: 0.68–1.00, p = 0.05), and random-effect model (pooled RR: 0.83, 95% CI: 0.68–1.01, p = 0.07).

Meta-analyses of available observational studies show that metformin was neither significantly associated with decreased risk nor, survival improvement for BTC patients who had DM.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common and important chronic liver diseases worldwide. Some chronic infectious diseases are associated with the risk of NAFLD. These can induce abnormal glucose and lipid metabolism, insulin resistance, inflammatory activation and other responses, which increase the risk of progression of liver fibrosis. The present study describes the pathogenesis and management of NAFLD with chronic infectious diseases, such as hepatitis B virus, hepatitis C virus, Helicobacter pylori, and human immunodeficiency virus infections.