To investigate the safety and efficacy of double plasma molecular adsorption system (DPMAS) with sequential low-dose plasma exchange (LPE) in treating early hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).

Clinical data of patients with HBV-ACLF were prospectively collected, including patients in a DPMAS with sequential LPE (DPMAS+LPE) group and those in a standard medical treatment (SMT) group. The primary endpoint was death or liver transplantation (LT) at 12 weeks of follow-up. Propensity-score matching was performed to control the effects of confounding factors on prognosis between the two groups.

After 2 weeks, total bilirubin, alanine aminotransferase, blood urea nitrogen levels, and Chinese Group on the Study of Severe Hepatitis B score, were significantly lower in the DPMAS+LPE group than those in the SMT group (p<0.05). After 4 weeks, laboratory parameters of the two groups were similar. The cumulative survival rate of the DPMAS+LPE group was significantly higher than that of the SMT group at 4 weeks (97.9% vs. 85.4%, p=0.027), but not at 12 weeks (85.4% vs. 83.3%, p=0.687). Cytokine levels were significantly lower in 12-week survival group than in the death-or-LT group (p<0.05). Functional enrichment analysis showed that downregulated cytokines were mainly involved in positive regulation of proliferation and activation of lymphocytes and monocytes, regulation of immune effect response, regulation of endotoxin response, and glial cell proliferation.

DPMAS+LPE significantly improved the 4-week cumulative survival rate, and ameliorated the inflammatory response in patients. DPMAS+LPE may be a promising modality for patients with early HBV-ACLF.

Advancements in nanomedicine have effectively overcome the issues of solubility, absorption, and cytotoxicity of conventional drugs. In recent years, phytoproducts rich in bioactive constituents have been exploited as green-, herb-, or phytosynthesized metal or nonmetal nanocarriers. Of these, alkaloids, flavonoids, polyphenols, sterols, lignans, tannins, and saponins efficiently contribute to the enhanced stability of such nanocarriers or nanoparticles by reducing metal ions. In addition, phytosynthesized silver and gold nanoparticles have received much interest due to their less hazardous, eco-friendly, and cost-effective properties. Owing to these properties, phytosynthesized silver and gold nanoparticles also have been developed as effective antiviral drug delivery carriers against human immunodeficiency virus, herpes simplex virus, influenza virus, dengue virus, chikungunya virus, hepatitis B virus, bovine diarrhea virus, and foot and mouth disease virus infections. Although experimental studies have shown that such phytonanoparticles can inhibit viral replication in infected cells, the underlying mechanism of their antiviral activities is poorly understood. Importantly, compared to herbal antivirals or metal-based antiviral nanoparticles, the novel approach of phytosynthesis of antiviral nanoparticles seems to be in its infancy. In view of the emerging viral outbreaks and pandemics like coronavirus disease 2019, this area of drug research needs special attention.

Hepatocellular carcinoma (HCC) surveillance in patients at risk is strongly recommended and usually performed by ultrasound (US) semiannually with or without alfa-fetoprotein (AFP) measurements. Quality parameters except for surveillance intervals have not been strictly defined. We aimed to evaluate surveillance success and risk factors for surveillance failure.

Patients with ≥1 US prior to HCC diagnosis performed at four tertiary referral hospitals in Germany between 2008 and 2019 were retrospectively analyzed. Surveillance success was defined as HCC detection within Milan criteria.

Only 47% of 156 patients, median age 63 (interquartile range: 57–70) years, 56% male, and 96% with cirrhosis, received recommended surveillance modality and interval. Surveillance failure occurred in 29% and was significantly associated with lower median model for end-stage liver disease (MELD) score odds ratio (OR) 1.154, 95% confidence interval (CI): 1.027–1.297, p=0.025) and HCC localization within right liver lobe (OR: 6.083, 95% CI: 1.303–28.407, p=0.022), but not with AFP ≥200 µg/L. Patients with surveillance failure had significantly more intermediate/advanced tumor stages (93% vs. 6%, p<0.001), fewer curative treatment options (15% vs. 75%, p<0.001) and lower survival at 1 year (54% vs. 75%, p=0.041), 2 years (32% vs. 57%, p=0.019) and 5 years (0% vs. 16%, p=0.009). Alcoholic and non-alcoholic fatty liver disease (OR: 6.1, 95% CI: 1.7–21.3, p=0.005) and ascites (OR: 3.9, 95% CI: 1.2–12.6, p=0.021) were independently associated with severe visual limitations on US.

US-based HCC surveillance in patients at risk frequently fails and its failure is associated with unfavorable patient-related outcomes. Lower MELD score and HCC localization within right liver lobe were significantly associated with surveillance failure.

Hepatocellular carcinoma (HCC) is one of the most common types of cancer, often resulting in death. Augmenter of liver regeneration (ALR), a widely expressed multifunctional protein, has roles in liver disease. In our previous study, we reported that ALR knockdown inhibited cell proliferation and promoted cell death. However, there is no study on the roles of ALR in HCC.

We used in vitro and in vivo models to investigate the effects of ALR in HCC as well as its mechanism of action. We produced and characterized a human ALR-specific monoclonal antibody (mAb) and investigated the effects of the mAb in HCC cells.

The purified ALR-specific mAb matched the predicted molecular weight of IgG heavy and light chains. Thereafter, we used the ALR-specific mAb as a therapeutic strategy to suppress tumor growth in nude mice. Additionally, we assessed the proliferation and viability of three HCC cell lines, Hep G2, Huh-7, and MHC97-H, treated with the ALR-specific mAb. Compared with controls, tumor growth was inhibited in mice treated with the ALR-specific mAb at 5 mg/kg, as shown by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling. Simultaneous treatment with the ALR-specific mAb and adriamycin promoted apoptosis, whereas treatment with the ALR-specific mAb alone inhibited cell proliferation.

The ALR-specific mAb might be a novel therapy for HCC by blocking extracellular ALR.

Occult HBV infection (OBI) in children has proven to be associated with their immune response to hepatitis B vaccine (HepB). This study aimed to investigate the effect of a booster HepB on OBI, which is rarely investigated.

This study enrolled 236 maternal HBsAg-positive children who were followed up annually until 8 years of age and were hepatitis B surface antigen (HBsAg) negative. Of those 100 received a booster HepB between 1 and 3 years of age (booster group), and 136 were never boosted (non-booster group). Serial follow-up data of children and baseline data of their mothers were collected and between-group differences were analyzed.

The incidence of OBI varied dynamically during follow-up, with 37.14% (78/210), 19.09% (42/220), 20.85% (44/211), 31.61% (61/193), 8.65% (18/208) and 12.71% (30/236) at 7 months, 1, 2, 3, 4, and 8 years of age. At 8 years of age, the negative conversion rate of HBV DNA in the booster group was significantly higher than that in non-booster group [57.89% (11/19) vs. 30.51% (18/59), p=0.032]. For children without OBI at 7 months old, the incidence of OBI in booster group was significantly lower than that in non-booster group [25.64% (10/39) vs. 67.74% (63/93), p<0.001].

The incidence of OBI in maternal HBsAg-positive children was high, serum HBV DNA in children with OBI was intermittently positive at low levels, and a booster HepB in infancy reduced the incidence of OBI in children with HBsAg-positive mothers.

Topoisomerase I (TOP1) participates the repair of DNA double-strand breaks (DSBs) upon radiation therapy (RT). RNF144A mediates ubiquitination of catalytic subunit of DNA protein kinase (DNA-PKcs), a critical factor in DSB repair. This study aimed to investigate the natural killer (NK) cell-mediated radiosensitization with TOP1 inhibition and the mechanism by DNA-PKcs/RNF144A.

In vitro synergism with TOP1i or cocultured NK cells and RT were evaluated in human hepatocellular carcinoma (HCC) cell lines (Huh7/PLC5) by clonogenic survivals. Orthotopic xenografts were treated with Lipotecan and/or RT. Protein expression was analyzed by western blotting, immunoprecipitation, subcellular fractionation, and confocal microscopy.

Lipotecan/RT had a superior synergistic effect to RT on HCC cells. Combined RT/Lipotecan reduced the xenograft size by 7-fold than RT (p<0.05). Lipotecan caused more radiation-induced DNA damage and DNA-PKcs signaling. The expression of major histocompatibility complex class I-related chain A and B (MICA/B) on tumor cells is associated with the sensitivity to NK cell-mediated lysis. Cocultured NK and HCC cells with Lipotecan radiosensitized HCC cells/tissues with the expression of MICA/B. RNF144A increased more in Huh7 cells with combined RT/TOP1i, and reduced the prosurvival function of DNA-PKcs. The effect was reversed by inhibiting the ubiquitin/proteasome system. In comparison, RNF144A decreased through nuclear translocation with the cumulated DNA-PKcs and radio-resistance of PLC5 cells.

TOP1i reinforces NK cell-activated anti-HCC effect of RT through RNF144A mediated DNA-PKcs ubiquitination. RNF144A provides a reason for differentiating radiosensitization effect between HCC cells.

Metabolic dysfunction and obesity commonly coexist with both alcoholic and nonalcoholic fatty liver disease (AFLD and NAFLD). The association of AFLD and NAFLD with incident diseases in individuals with different metabolic phenotypes are unclear.

UK Biobank study participants were screened for the presence of fatty liver at baseline. Body mass index and metabolic dysfunction were used to define metabolic phenotypes. Cox regression model was performed to examine the associations of AFLD and NAFLD with incident significant liver diseases (SLDs), cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), and cancers, respectively.

A total of 43,974 AFLD and 103,248 NAFLD cases were identified. Both AFLD and NAFLD were associated with an increased risk of diseases of interest. The effects were amplified by obesity and metabolic abnormalities and modified by metabolic phenotypes. Compared to individuals free of fatty liver and with phenotype of metabolically healthy-normal weight, AFLD [hazard ratio (HR) 3.27; 95% CI: 1.95–5.47)] and NAFLD (HR 2.25; 95% CI: 1.28–3.94) cases with phenotype of metabolically obese-normal weight had the greatest risk of SLDs. For CVDs, CKDs, and cancer, the greatest risks were detected in AFLD and NAFLD cases with phenotype of metabolically obese-overweight/obesity. In this subpopulation, AFLD and NAFLD conferred a 2.75-fold (95% CI: 2.32–3.25) and 4.02-fold 95% CI: (3.64–4.43) increased risk of CVDs, 4.37-fold 95% CI: (3.38–5.64) and 6.55-fold 95% CI: (5.73–7.48) increased risk of CKDs, and 1.19-fold 95% CI: (1.08–1.27) and 1.21-fold 95% CI: (1.14–1.28) increased risk of cancers, respectively.

Metabolic phenotypes modified the association of AFLD and NAFLD with intrahepatic and extrahepatic diseases.

Occlusive portal vein thrombosis (PVT) often causes portal hypertension-related complications in cirrhotic patients. Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment for this difficult problem. However, the factors influencing TIPS success and overall survival in patients with occlusive PVT are unknown. This study investigated the factors influencing TIPS success and overall survival in cirrhotic patients with occlusive PVT.

Cirrhotic patients with occlusive PVT were selected from a prospective database of consecutive patients treated with TIPS in Xijing Hospital between January 2015 and May 2021. Baseline characteristics, TIPS success rate, complications, and survival were collected, and the factors associated with the TIPS success rate and transplant-free survival were analyzed.

A total of 155 cirrhotic patients with occlusive PVT were enrolled. TIPS succeeded in 126 (81.29%) cases. The 1-year survival rate was 74%. Compared with those without, patients with portal fibrotic cord had a lower TIPS success rate (39.02% vs. 96.49%, p<0.001), shorter median overall survival (300 vs. 1,730 days, p<0.001) and more operation-related complications (12.20% vs. 1.75%, p<0.01). Logistic regression analysis found that portal fibrotic cord (odds ratio 0.024) was a risk factor for TIPS failure. Univariate and multivariate analysis showed that portal fibrotic cord was an independent predictor of death (hazard ratio 2.111; 95% CI: 1.094–4.071, p=0.026).

Portal fibrotic cord increased the TIPS failure rate and is a risk factor for poor prognosis in cirrhotic patients.

The pathogenesis of portal hypertension remains unclear, and is believed to involve dysfunction of liver sinusoidal endothelial cells (LSEC), activation of hepatic stellate cells (HSC), dysregulation of endogenous hydrogen sulfide (H2S) synthesis, and hypoxia-induced angiogenic responses. H2S, a novel gas transmitter, plays an important role in various pathophysiological processes, especially in hepatic angiogenesis. Inhibition of endogenous H2S synthase by pharmaceutical agents or gene silencing may enhance the angiogenic response of endothelial cells. Hypoxia-inducible factor-1 (HIF-1) is the main transcription factor of hypoxia, which induces hepatic angiogenesis through up-regulation of vascular endothelial growth factor (VEGF) in HSC and LSEC. H2S has also been shown to be involved in the regulation of VEGF-mediated angiogenesis. Therefore, H2S and HIF-1 may be potential therapeutic targets for portal hypertension. The effects of H2S donors or prodrugs on the hemodynamics of portal hypertension and the mechanism of H2S-induced angiogenesis are promising areas for future research.

Essential oils (EOs) are natural products with bioactive functions that are obtained from various plant species, including Lavandula angustifolia and plant parts, through extraction methods, such as hydro-distillation, steam distillation and cold pressing, which can be dated back to ancient Egyptian and Greek times. Although various EOs are effective for disease treatment, such as human infectious diseases and mental disorders, the specific pharmacological mechanisms remain unclear due to its complex composition. Previous studies have attempted to recruit pharmaceutical analysis techniques, such as HPLC and MALDI-TOF, in order to elucidate the compositions of EOs. However, these have provided limited information on the mechanism of the bioactive functions of EOs. In recent years, network pharmacology has emerged as a convenient and appropriate approach to study the molecular mechanism of traditional medicines. To date, there is a lack of updated reviews on the recent progress of network pharmacology in the field of interactions between EOs and human diseases. Therefore, the present study scrutinized recent and important literatures in the field of network pharmacology and EOs, aiming to provide a timely yet brief overview of EOs as a potential treatment for diseases via network pharmacology, and facilitating the application of EOs as a complementary medicine and therapy for human diseases.

Alzheimer’s disease (AD) is a common geriatric disease with a complex pathogenesis and challenging treatment options. Wuling capsule is a single herbal formula mainly composed of Xylaria nigripes powder, which has sedative and neuroprotective effects on the central nervous system. This study aimed to explore various potential pathways and targets of Wuling capsules for the treatment of AD.

The anti-AD mechanism of Wuling capsule was systematically analyzed by integrating multiple databases and using network pharmacology. The active ingredients of Wuling capsules were screened through the Pubchem website, the SwissADME database, and a literature search. The related targets of AD were then screened in the GeneCards database. Using Cytoscape software and STRING, the disease-drug-target interaction network and the protein-protein interaction network were visualized, and topological analysis revealed the differences in the effects of different types of compounds.

Fifty-four compounds and 284 targets were screened by network pharmacology. The main active ingredients included quercetin, xylaric acid A-D, lysine, gamma-aminobutyric acid, glutamic acid, other amino acids, trace elements, guanosine, adenosine, etc. The targets in the network cover inflammation, oxidative stress, modulation of chemical synaptic transmission, and other related proteins, including protein kinase B, tumor necrosis factor-alpha, and tumor suppressor p53. The enrichment analysis results showed that these pathways include the phosphoinositide-3-kinase/protein kinase B, mitogen-activated protein kinase, and tumor necrosis factor-alpha signaling pathways. We also explored five potential protein functional modules.

This study revealed the multi-target and multi-pathway effects of the drug-ingredient-target-disease network through network pharmacology. This systematic screening strategy provides a new concept and theoretical basis for the treatment of AD with Wuling capsules.

The quantity of Gleason pattern (GP) 4 in Grade Group 2 prostate cancer (PCa) is an important prognostic factor and may influence treatment decisions. To be impactful for patient prognosis and management, GP4 quantification must be done in a uniform and reproducible way. This study aimed to investigate the interobserver reproducibility of GP4 quantification, and whether it may be affected by any histological features, including GP4 sub-patterns and tumor size.

Glass slides containing 55 biopsy cores of various amounts of GP4 were distributed to 12 pathologists who quantified GP4 and determined the most common GP4 sub-patterns (poorly formed glands [P], fused glands [F], cribriform [C], and glomeruloid [G]) in each core.

The interobserver reproducibility for 12 pathologists to quantify GP4 in 55 biopsy cores was moderate (κ = 0.57). The κ values for cores with a PCa length ≤2 mm, 2.1–5 mm, and >5 mm were 0.51, 0.50, and 0.66, respectively. The κ values for cores with the most common sub-pattern (P, F, [C and G], no consensus) were 0.43. 0.57, 0.74, and 0.57, respectively. When the consensus of the percentages of GP4 were 41–50% and 51–60%, 35% and 41.7% of the individual measurements, respectively, were significantly different from the consensus values.

The reproducibility of quantifying GP4 PCa is moderate and significantly lower for small-sized cancer with a predominant P pattern. There is significant variability in quantifying GP4 when it is 40–60%. These findings highlight the significant limitations of GP4 quantification that pathologists and clinicians must be aware of, and argue for more training for pathologists and standardization of methodology to improve the GP4 quantification.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with an estimated prevalence of 25% globally. NAFLD is closely associated with metabolic syndrome, which are both becoming increasingly more common with increasing rates of insulin resistance, dyslipidemia, and hypertension. Although NAFLD is strongly associated with obesity, lean or nonobese NAFLD is a relatively new phenotype and occurs in patients without increased waist circumference and with or without visceral fat. Currently, there is limited literature comparing and illustrating the differences between lean/nonobese and obese NAFLD patients with regard to risk factors, pathophysiology, and clinical outcomes. In this review, we aim to define and further delineate different phenotypes of NAFLD and present a comprehensive review on the prevalence, incidence, risk factors, genetic predisposition, and pathophysiology. Furthermore, we discuss and compare the clinical outcomes, such as insulin resistance, dyslipidemia, hypertension, coronary artery disease, mortality, and progression to nonalcoholic steatohepatitis, among lean/nonobese and obese NAFLD patients. Finally, we summarize the most up to date current management of NAFLD, including lifestyle interventions, pharmacologic therapies, and surgical options.

The skin is a physical barrier that protects our body against various environmental, chemical and physical agents, and is the main organ that is easily visible as time progresses. Aging is a dynamic, progressive and undesirable biological process that unfortunately cannot be stopped, according to present knowledge. Intrinsic aging (chronological, spontaneous and biological aging) is a programmed natural process, while extrinsic aging (environmental aging and photoaging) is associated with sun exposure, smoking and malnutrition, which weakens the skin structure and functions. Over time, aging skin starts to lose elastin fibers, collagen and other proteins, which are the basic constituents that make skin healthy, bright, fit and elastic. There has been increasing interest in studies on various molecular and hormonal mechanisms, such as hormone dysfunction, changes in signaling pathways, the downregulation of mitochondrial function with cytokine increase, and mitochondrial DNA mutation. Antiaging treatment strategies can be divided into two parts: primary (basic) preventive antiaging approaches and secondary antiaging approaches after the phenotypic features of aging are revealed. The present study aims to review the literature information on the underlying causes of skin aging, healthy skin aging, and basic protective antiaging approaches. Understanding the extrinsic and intrinsic pathophysiological processes of aging would increase the effectiveness of future treatment-finding efforts.