Hepatectomy is an effective treatment for selected patients with large hepatocellular carcinoma (HCC). This study aimed to develop a nomogram incorporating non-tumoral liver volume (non-TLV) and liver function markers to predict the patients’ overall survival (OS) and disease-free survival (DFS).

Data of 198 consecutive large HCC patients who underwent hepatectomy at the Zhongshan Hospital Xiamen University were collected. Another 68 patients from the Mengchao Hepatobiliary Surgery Hospital served as an external validation cohort. The nomograms were developed based on the independent prognostic factors screened by multivariate Cox regression analyses. Concordance index (C-index), calibration curves, and time-dependent receiver operating characteristic (ROC) curves were used to measure the discrimination and predictive accuracy of the models.

High HBV DNA level, low non-TLV/ICG, vascular invasion, and a poorly differentiated tumor were confirmed as independent risk factors for both OS and DFS. The model established in this study predicted 5-year post-operative survival and DFS in good agreement with the actual observation confirmed by the calibration curves. The C-indexes of the nomograms in predicting OS and DFS were 0.812 and 0.823 in the training cohort, 0.821 and 0.846 in the internal validation cohort, and 0.724 and 0.755 in the external validation cohort. The areas under the ROC curves (AUCs) of nomograms for predicted OS and DFS at 1, 3, and 5 year were 0.85, 0.86, 0.83 and 0.76, 0.76, 0.63, respectively.

Nomograms with non-TLV/ICG predicted the prognosis of single large HCC patients accurately and effectively.

Natural products featured by an abundant molecule skeleton and structural complexity exhibit extensive pharmacological or biological activities. Thus, natural active ingredients are an important source of drug research and development. However, the inherent defects, including low solubility, low bioavailability, and unacceptable off-target toxicity, affect their development into clinical drugs. Recently, carrier-free supermolecule nanodrugs have attracted considerable attention. These nanodrugs are self-assembled by pure drugs mainly through hydrophobicity, hydrogen bond, π-π stacking, and electrostatic interaction, which possess a high drug loading capability, enhanced water solubility of the drugs, and synergistic therapeutic efficacy. In this review, natural product-based carrier-free nanoplatforms with self-assembly for efficient bioactivity were examined. These self-assembled natural products included triterpenoids, alkaloids, flavonoids, and anthraquinones. Moreover, the morphology of the formed nanoplatforms could be a nanosphere, nanofiber, nanorod, or fibrillar network, and they could exhibit several bioactivities, such as antitumor, anti-inflammatory, immunoregulation, and liver protection. Briefly, we analyzed the types and sources, formation mechanism, biological activity, and mode of action of the nanomedicine, and discussed the future of this field. We believe this review would provide a landscape of natural product-based carrier-free nanoplatforms.

In the era of antiviral therapy, the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus (HBV) replication to the pursuit of serological clearance of HBs surface antigen (HBsAg). Based on the life cycle of HBV, HBsAg originates from covalently closed circular DNA (cccDNA) and integrated HBV DNA, thus reflecting their transcriptional activity. Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA. HBsAg loss improves the recovery of abnormal immune function, which in turn, may further promote the clearance of residual viruses. Combined with functional cure and the great improvement of clinical outcomes, the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B (CHB). For many other risk factors besides HBV itself, patients with HBsAg loss still need regular monitoring. In this review, we summarized the evolution of CHB treatment, the origin of serum HBsAg, the pattern of HBsAg seroclearance, and the effect of HBsAg loss on immune function and disease outcomes. In addition, we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The mechanisms involved in NAFLD onset are complicated and multifactorial. Recent literature has indicated that altered intestinal barrier function is related to the occurrence and progression of liver disease. The intestinal barrier is important for absorbing nutrients and electrolytes and for defending against toxins and antigens in the enteric environment. Major mechanisms by which the intestinal barrier influences the development of NAFLD involve the altered epithelial layer, decreased intracellular junction integrity, and increased intestinal barrier permeability. Increased intestinal permeability leads to luminal dysbiosis and allows the translocation of pathogenic bacteria and metabolites into the liver, inducing inflammation, immune response, and hepatocyte injury in NAFLD. Although research has been directed to NAFLD in recent decades, the pathophysiological changes in NAFLD initiation and progression are still not completely understood, and the therapeutic targets remain limited. A deeper understanding on the correlation between NAFLD pathogenesis and intestinal barrier regulation must be attained. Therefore, in this review, the components of the intestinal barrier and their respective functions and disruptions during the progression of NAFLD are discussed.

The COVID-19 pandemic has impacted the care of patients with liver disease. We examined impact of COVID-19 on liver transplant (LT) activity in the USA.

LT listings in the United Network for Organ Sharing (UNOS) database (April 2018–May 2021) were analyzed to examine the impact of COVID-19 pandemic on the LT activity based on etiology: hepatitis C virus (HCV), alcohol-associated liver disease (ALD), alcoholic hepatitis (AH), and nonalcoholic steatohepatitis (NASH) complications: hepatocellular carcinoma (HCC) and acute-on-chronic liver failure (ACLF) grade 2 or 3) and Model for End-Stage Liver Disease (MELD) score. Joinpoint regression models assessed time trend changes on a log scale.

Of 23,871 recipients (8,995 in the COVID era, April 2018–February 2020), mean age 52 years, 62% men, 61% Caucasian, 32% ALD, 15% HCC, 30% ACLF grades 2–3, and mean MELD score 20.5), monthly LT changes were a decrease of 3.4% for overall LTs and 22% for HCC after September 2020, and increase of 4.5% for ALD since 11/2020 and 17% since 03/2021 for ACLF grade 2–3. Monthly MELD scores increased by 0.7 and 0.36 after June 2020 for HCV and HCC respectively.

The COVID-19 pandemic has impacted LT activity, with a decrease of LTs especially for HCC, and an increase of LTs for ALD and severe ACLF. Strategies are needed to reorganize cirrhosis patients to overcome the aftereffects of COVID-19 pandemic.

Liver transplantation (LT) is the final treatment option for patients with end-stage liver disease. The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world. Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases, which significantly reduce recipient survival. Although several clinical factors have been demonstrated to impact donor liver quality, accurate, comprehensive, and effective assessment systems to guide decision-making for organ usage, restoration or discard are lacking. In addition, the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function. Moreover, such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment. Focusing on donors and grafts, we updated potential biomarkers in donor blood, liver tissue, or perfusates that predict graft quality following LT, and summarized strategies for restoring graft function in the era of extended criteria donors. In this review, we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

Plants usually produce a large number of secondary metabolites, including antimicrobial peptides rich in cysteine. Phytopeptides, categorized into five to eight groups, exhibit varied lengths, secondary structures, and disulphide bridge patterns. Cyclotides, a specific group, possess an end-to-end cyclic structure with a knot-like disulphide bridge, which are known for their anti-nematode, anti-mollusk, and anti-trematode activities. This review provides comprehensive insights into cyclotides, covering their origin, structural and functional characteristics, therapeutic potential, biotechnological applications, and future prospects. Studies indicate that modifications in cyclotide loop regions do not alter their conformation significantly, a crucial aspect for biotechnological applications. Cyclotides, identified as peptides with a cysteine-knot motif, offer a versatile scaffold for drug delivery and combinatorial libraries due to their high tolerance for sequence variability. Molecular characterization reveals the selective targeting of G-coupled oxytocin and vasopressin receptors by the first identified cyclotide, facilitating endometrial movement during labor onset.

Hydrazone ligands along with their metal complexes exhibit important biological potential. Our objective was to synthesize new Schiff base ligands and their metal complexes which can act as vital drugs.

Metal complexes of Zn(II), Ni(II), Cu(II), Mn(II), Co(II), Hg(II), Cd(II), Sn(II), Zr(II), and Fe(II) were synthesized from a novel Schiff base (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) ligand using the condensation method. The ligand and metal complexes were characterized using analytical techniques. Their antimicrobial, antimalarial, and anti-tubercular activities were investigated.

The synthesized ligand was found to be bidentate in nature. The stoichiometry of the metal ions to ligand was 1:2. Complexes of Co(II), Cu(II), Mn(II), and Cd(II) displayed excellent antimicrobial activity. The Mn(II) complex was active against M. TuberculosisThe Cu(II) and Cd(II) complexes displayed excellent activity against malaria, moderate to good antimicrobial and anti-tubercular activity while Zn(II), Co(II), Sn(II), Ni(II), Hg(II), and Fe(II) were active against malaria.

We report the synthesis and characterization of a new (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) Schiff base bidentate ligand and metal complexes. The antitubercular, antimicrobial, and antimalarial activity of the synthesized metal complexes revealed good antimicrobial potential of Cu(II), Co(II), Mn(II), and Cd(II) complexes. The Mn(II) was remarkably active against Mycobacterium Tuberculosis.

Traumatic brain injury (TBI) can contribute to extensive dysbiosis of the gastrointestinal system, leading to worsened outcomes. The importance of nutrition in recovery is underappreciated but highly important. In this focused review, we discuss the timing of nutritional interventions with supporting data. We highlight routes of administration that are important given the extent of injury often seen in TBI. The increased energy demands can be met through these approaches. Furthermore, patients need increased vitamins, minerals, and supplements. These interventions are constantly being refined. The current standards are reviewed with an emphasis on evidence-based practices.

Interleukin (IL) 1 superfamily members are a cornerstone of a variety of inflammatory processes occurring in various organs including the liver. Progression of acute and chronic liver diseases regardless of etiology depends on the stage of hepatocyte damage, the release of inflammatory cytokines and disturbances in gut microbiota. IL1 cytokines and receptors can have pro- or anti-inflammatory roles, even dual functionalities conditioned by the microenvironment. Developing novel therapeutic strategies to block the IL1/IL1R signaling pathways seems like a reasonable option. This mode of action is now exploited by anakinra and canakinumab, which are used to treat different inflammatory illnesses, and studies in liver diseases are on the way. In this mini review, we have focused on the IL1 superfamily members, given their crucial role in liver inflammation diseases, specifically discussing their potential role in developing new treatment strategies.

Cholangiopancreatoscopy with the SpyGlass system is a direct and minimally invasive examination method in which the lesions in the pancreatic bile tract can be observed directly by inserting an ultra-fine endoscope through the biopsy channel of a duodenoscope. Compared with endoscopic retrograde cholangiopancreatography (ERCP), enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography, cholangiopancreatoscopy with the SpyGlass system has unique advantages for observing and identifying lesions originating in the pancreatic bile duct. In recent years, with the upgrading of endoscopic equipment and the improvement of operating technology, the application of cholangiopancreatoscopy is becoming more and more widespread. This article reviews the use of cholangiopancreatoscopy with the SpyGlass system for the diagnosis and treatment of pancreaticobiliary disease.

Immunomodulation is a diverse process by which immunomodulators enhance or suppress immune responses to control disease progression. Immunomodulators are a broad class of drugs that include immunosuppressants and immunostimulants. These agents have been used to fight against the dysregulated immune responses observed during tissue/organ transplantation and disorders, such as rheumatoid arthritis, ulcerative colitis, and cancers. Immunomodulators obtained from a myriad of plant sources are a major class of compounds that are known to have medicinal properties and are used for the treatment of various diseases. However, the mechanisms underlying the action of plant-derived compounds are poorly understood. Here, we discuss the major classes of plant-based immunomodulators with examples and their effects on the major signaling pathways, such as the nuclear factor kappa light chain enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin pathways. Importantly, we discuss the preclinical and clinical research to date to understand the importance of these immunomodulators. Overall, this review highlights the significance of plant-based immunomodulators as an alternative therapeutic strategy for combating various diseases.

Approximately 10% of patients with acute decompensated (AD) cirrhosis develop acute-on-chronic liver failure (ACLF) within 28 days. Such cases have high mortality and are difficult to predict. Therefore, we aimed to establish and validate an algorithm to identify these patients on hospitalization.

Hospitalized patients with AD who developed ACLF within 28 days were considered pre-ACLF. Organ dysfunction was defined according to the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) criteria, and proven bacterial infection was taken to indicate immune system dysfunction. A retrospective multicenter cohort and prospective one were used to derive and to validate the potential algorithm, respectively. A miss rate of <5% was acceptable for the calculating algorithm to rule out pre-ACLF.

In the derivation cohort (n=673), 46 patients developed ACLF within 28 days. Serum total bilirubin, creatinine, international normalized ratio, and present proven bacterial infection at admission were associated with the development of ACLF. AD patients with ≥2 organ dysfunctions had a higher risk for pre-ACLF patients [odds ratio=16.581 95% confidence interval: (4.271–64.363), p<0.001]. In the derivation cohort, 67.5% of patients (454/673) had ≤1 organ dysfunction and two patients (0.4%) were pre-ACLF, with a miss rate of 4.3% (missed/total, 2/46). In the validation cohort, 65.9% of patients (914/1388) had ≤1 organ dysfunction, and four (0.3%) of them were pre-ACLF, with a miss rate of 3.4% (missed/total, 4/117).

AD patients with ≤1 organ dysfunction had a significantly lower risk of developing ACLF within 28 days of admission and could be safely ruled out with a pre-ACLF miss rate of <5%.

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with chronic liver disease (CLD) and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and complications. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover wherein changes in various metabolic factors such as hyperammonemia, amino acid deprivation, hormonal imbalance, gut dysbiosis, insulin resistance, chronic inflammation, etc. have important roles. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α-ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Skeletal muscle is a major organ of insulin-induced glucose metabolism, and sarcopenia is closely linked to insulin resistance and metabolic syndrome. Patients with liver cirrhosis are in a hypermetabolic state that is associated with catabolism and depletion of amino acids, particularly branched-chain amino acids. Sarcopenia can have significant implications for nonalcoholic fatty liver disease, the most common form of CLD worldwide, because of the close link between metabolic syndrome and sarcopenia. This review discusses the potential metabolic derangement as a cause or effect of sarcopenia in CLD, as well as interorgan crosstalk, which that might help identifying a novel therapeutic strategies.

Generally acceptable prognostic models for hepatocellular carcinoma (HCC) are not available. This study aimed to establish a prognostic model for HCC by identifying immune-related differentially expressed genes (IR-DEGs) and to investigate the potential role of NR6A1 in the progression of HCC.

Bioinformatics analysis using The Cancer Genome Atlas and ImmPort databases was used to identify IR-DEGs. Lasso Cox regression and multivariate Cox regression analysis were used to establish a prognostic model of HCC. Kaplan-Meier analysis and the receiver operating characteristic (ROC) curves were used to evaluate the performance of the prognostic model, which was further verified in the International Cancer Genome Consortium (ICGC) database. Gene set enrichment analysis was used to explore the potential pathways of NR6A1. Cell counting kit 8, colony formation, wound healing, and Transwell migration assays using Huh7 cells, and tumor formation models in nude mice were conducted.

A prognostic model established based on ten identified IR-DEGs including HSPA4, FABP6, MAPT, NDRG1, APLN, IL17D, LHB, SPP1, GLP1R, and NR6A1, effectively predicted the prognosis of HCC patients, was confirmed by the ROC curves and verified in ICGC database. NR6A1 expression was significantly up-regulated in HCC patients, and NR6A1 was significantly associated with a low survival rate. Gene set enrichment analysis showed the enrichment of cell cycle, mTOR, WNT, and ERBB signaling pathways in patients with high NR6A1 expression. NR6A1 promoted cell proliferation, invasiveness, migration, and malignant tumor formation and growth in vitro and in vivo.

An effective prognostic model for HCC, based on a novel signature of 10 immune-related genes, was established. NR6A1 was up-regulated in HCC and was associated with a poor prognosis of HCC. NR6A1 promoted cell proliferation, migration, and growth of HCC, most likely through the cell cycle, mTOR, WNT, and ERBB signaling pathways.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the human body mainly through the nasal epithelial cells. The cell entry of SARS-CoV-2 needs to be preactivated via S1/S2 boundary furin motif cleavage by furin and/or relevant proteases. Therefore, it is important to locally block the SARS-CoV-2 S1/S2 site cleavage caused by furin and other relevant protease activity in the nasal cavity. The objective of this study is to evaluate the efficacy of hypertonic saline and aprotinin in inhibiting the furin-mediated cleavage of the SARS-CoV-2 S1/S2 site in both wild-type and mutant strains

With synthesized peptides containing a wild-type or mutant furin cleavage motif and by using SARS-CoV-2 specific furin site cleavage assay, we tested the hypertonic saline and aprotinin-based blockage of the SARS-CoV-2 specific furin site cleavage by furin, trypsin, and nasal swab samples containing nasal proteases.

The results showed that hypertonic saline and aprotinin could block SARS-CoV-2 specific furin site cleavage, and a hypertonic saline and aprotinin combination could reduce 99% of the furin site cleavage in the SARS-CoV-2 wild-type, 90% in the P681R mutant, and 83% in the N679K/P681H mutants, respectively by inhibition of the nasal protease activity.

Our findings preliminarily elucidated that the combination of hypertonic saline and aprotinin significantly blocked the furin site cleavage in both the SARS-CoV-2 wild-type and mutants (P681R and N679K/P681H), which could represent a simple, economical, and practical feasible approach in locally controlling viral activation and entry into cells to replicate.

The world is now in the third year of the COVID-19 pandemic. As such, enormous volumes of virological, immunological, and epidemiological knowledge pertaining to the SARS-CoV-2 infection have been obtained during these years. The SARS-CoV-2 Omicron variant is currently causing the latest wave of infection globally presumably due to its ability to transmit with ease among individuals and to escape from the existing neutralizing antibodies. Fortunately, numerous treatment agents as well as prophylactic vaccines are now available, thus providing people with a better chance to control this infectious disease. This review will discuss the Omicron variant of concern as well as the available treatments and vaccines for COVID-19.

Acute variceal bleeding (AVB) is associated with significant short-term morbidity and mortality. Pre-emptive transjugular intrahepatic portosystemic shunt (p-TIPSS) is recommended to prevent rebleeding in AVB patients with a high risk of rebleeding. Despite the benefit of preventing rebleeding and de-novo ascites, the uptake of p-TIPSS remains low because logistic challenges in the real-world setting. In this review, we summarize the current evidence and controversies on p-TIPSS including patient selection for p-TIPSS, particularly in the setting of NASH cirrhosis and acute-on-chronic liver failure, the role of sarcopenia, renal impairment in the setting of p-TIPSS. Finally, we summarize both pharmacological and nonpharmacological strategies to optimize outcomes in patients undergoing p-TIPSS.

Natural products from plants and their biological potentialities have increased environmental concerns. This study aimed to evaluate the phenolic composition, along with the antioxidant, antimicrobial, and insecticidal activities of Ziziphus spina-christi leaf extracts using LC-MS.

Leaves of Z. spina-christi were collected from three Tunisian localities (Metlaoui, Degueche, and Tozeur) and processed for chemical analysis. After drying and milling, leaf powders were macerated in methanol, and the extracts were concentrated and filtered. Chemical assays determined total phenolic, flavonoid, and tannin contents using spectrophotometric methods. LC-ESI-MS analysis quantified specific phenolic compounds. Biological activities were assessed through antioxidant, antimicrobial, and insecticidal evaluations. The antioxidant capacity was measured via the DPPH assay, while antimicrobial effects against selected bacterial and fungal strains were determined using agar diffusion and MIC assays. Finally, insecticidal activity was tested on Tribolium castaneum, with mortality rates and lethal concentrations calculated.

The leaf extracts contained phenols (8.157 mg GAE/DW), flavonoids (4.42 mg Quercetin Eq/gDW), and tannins (1.62 mg Cat Eq. g−1). LC-MS analysis identified the rutin compound at a rate between 1.3 ± 0.005 µg/mL (Dgueche) and 2 ± 0.005 µg/mL (Metlaoui) while 3 ± 0.005 µg/mL in the extracts from the Tozeur. The extracts from the Tozeur had the highest antioxidant activity with a concentration for 50% inhibition of 0.125 mg/mL and the highest antibacterial activity against Streptococcus agalactiae specie with a superior diameter of zone inhibition of about 27.5 mm and against Staphylococcus aureus specie with a diameter of 16 mm. In contrast, the extracts from the Deguech displayed stronger activity against Escherchia coli specie with a diameter of 13.5 mm. There were only two Tozeur extracts that exhibited activity against Candida albicans and Candida Sake species. Furthermore, treatment with methanolic extracts caused 66.60% mortality in Tribolium castaneum.

This study showed that Ziziphus spina-christi extracts contained several components that had potent antioxidant and antibacterial activities against some types of bacteria. Hence, these extracts or their components may be recommended as an eco-friendly alternative for synthetic insecticides and used as natural antioxidants in phototherapy.