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.

Strategies for detection of early hepatocellular carcinoma (HCC) are still limited. The GALAD score is a serum biomarker-based model designed to predict the probability of having HCC. We aimed to assess the ability of GALAD score to diagnose early HCC and its validity to follow patients after local ablation therapy.

This multicenter prospective study included 108 patients in two groups, 58 HCC patients (67 focal lesions) with local ablative therapy (study group), and a control group of 50 patients with liver cirrhosis. The GALAD scores of the study and control groups, and of the HCC patients before and after ablative therapy were compared.

Most patients were men (74.1% in study group and 76% in controls) with hepatitis C virus infection (98.30% in the study group, and 94% in controls). GALAD scores were significantly higher in HCC patients than in those with benign cirrhosis (2.65 vs. −0.37, p=0.001). Ablative therapy was successful in 94.4% of focal lesions <2 cm, and in 86.10% of 2–5 cm lesions. The GALAD score was also significantly lower at 1 month after ablation in patients with well-ablated tumors (2.19 vs. 0.98, p=0.001). The best cutoff values of GALAD score for diagnosis of early HCC, and for prediction of well ablation of HCC were 0.74 and ≤3.31 (areas under the curve of 0.92 and 0.75, sensitivities of 84.48% and 76.19%, specificities of 89.13% and 83.33%, positive predictive values of 90.74% and 94.1%, and negative predictive values of 82% and 35.7% respectively).

The GALAD score was effective for the diagnosis of early HCC and for follow-up after ablative therapy.

The most often encountered kind of liver cancer is hepatocellular carcinoma (HCC), in which distant metastases (DM) continue to result in a worse prognosis. The present study aims to determine the prognostic and predictive factors of DM in patients with HCC, and generate two nomograms to assess the occurrence probability of DM and prognosis of HCC patients with DM.

From 2010 to 2015, the data of patients who were diagnosed with HCC in the Surveillance, Epidemiology and End Results (SEER) database were retrospectively reviewed. The multivariate and univariate logistic regression analyses were assessed to determine the risk factors correlated to the occurrence of DM in patients with HCC. Then, the multivariate and univariate analyses of the Cox regression were assessed to determine prognostic risk factors of DM in HCC patients, and two nomograms were constructed.

The present study included 14,508 participants with HCC. Gender, T stage, N stage and tumor size were determined as independent risk factors correlated to the occurrence of DM in HCC patients, while T stage, N stage, surgery, radiation and chemotherapy were determined as independent prognostic factors in HCC patients with DM. The AUC for the diagnostic nomogram was 0.766 in the training group and 0.776 in the testing group. At 6, 9 and 12 months, the AUC for the prognostic nomogram was 0.732, 0.727 and 0.719, respectively, in the training group, and 0.697, 0.722 and 0.731, respectively, in the testing group.

The two nomograms developed to assess the occurrence of DM in HCC patients and prognosis of HCC patients with DM may benefit clinician decision-making and clinical patient prognosis.

The huge burden of type 1 diabetes mellitus (T1DM) has been a source of concern globally since the Industrial Revolution in the 18th–19th centuries. To this end, studies have shown that certain environmental changes that accompanied the Revolution may have increased the risk and burden of the disease in genetically predisposed individuals. However, documented studies that synthesize these environmental triggers are scarce. As a result, the current study was conceived to synthesize the environmental triggers of T1DM to boost public awareness. Relevant information was retrieved from reputable academic databases; namely, Scopus, PubMed, SpringerLink, and Embase. The results showed that chemical exposure, viral infection, gut microbiome disruption, vitamin and mineral deficiencies, inadequate or exclusive breastfeeding, as well as early exposure to infant feeding formulas could increase the risk and burden of T1DM in genetically predisposed individuals. As a consequence, these triggers could compromise the expression of certain genes involved in insulin synthesis and immune function, such as the human leukocyte antigen (HLA), insulin (INS), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes. This would result in a dysfunctional immune system in which immune cells, such as T-cells and B-cells and molecules, such as cytokines would attack self-tissues, thus causing autoimmunity of the pancreatic beta cells. Environmental triggers could also induce the T1DM pathophysiology by modifying the epigenome of the mentioned genes. Furthermore, some epigenetic changes could be reversed, which would infer that treatment procedures that would include the pathophysiology of the environmental triggers could be more effective.

Patients with persistent positive hepatitis B surface antigen (HBsAg), even with a low HBV-DNA load, have a higher risk of hepatocellular carcinoma (HCC) than those without HBV infection. Given that tumor stemness has a critical role in the occurrence and maintenance of neoplasms, this study aimed to explore whether HBsAg affects biological function and stemness of HCC by regulating microRNA, and to explore underlying mechanisms.

We screened out miR-203a, the most significant down-regulated microRNA in the microarray analysis of HBsAg-positive samples and focused on that miRNA in the ensuing study. In vitro and in vivo functional experiments were performed to assess its regulatory function. The effect of miR-203a on stemness and the possible correlation with BMI1 were analyzed in this study.

MiR-203a was significantly down-regulated in HBsAg-positive HCC with the sharpest decrease shown in microarray analysis. The negative correlation between miR-203a and HBsAg expression was confirmed by quantitative real-time PCR after stimulation or overexpression/knockdown of HBsAg in cells. We demonstrated the function of miR-203a in inhibiting HCC cell proliferation, migration, clonogenic capacity, and tumor development in vivo. Furthermore, the overexpression of miR-203a remarkably increases the sensitivity of tumor cells to 5-FU treatment and decreases the proportion of HCC cells with stem markers. In concordance with our study, the survival analysis of both The Cancer Genome Atlas database and samples in our center indicated a worse prognosis in patients with low level of miR-203a. We also found that BMI1, a gene maintains the self-renewal capacity of stem cells, showed a significant negative correlation with miR-203a in HCC specimen (p<0.001). Similarly, opposite BMI1 changes after overexpression/knockdown of miR-203a were also confirmed in vitro. Dual luciferase reporting assay suggested that miR-203a may regulate BMI1 expression by direct binding.

HBsAg may promote the development of HCC and tumor stemness by inhibiting miR-203a, resulting in poor prognosis. miR-203a may serve as a crucial treatment target in HBsAg-positive HCC. More explicit mechanistic studies and animal experiments need to be conducted as a next step.

In May 2022, the UK International Health Regulations National Focal Point notified World Health Organization of 176 cases of severe acute hepatitis of unknown etiology in children under 10 years of age. From that moment on, cases of severe acute hepatitis of unknown origin in children began to be reported in several countries. As of June 17, 2022, a total of 991 cases had been reported in 35 countries worldwide, 50 children needed a liver transplant and 28 patients died. According to information published by ECDC, 449 cases have been detected in 21 EU countries. The children were between 1 month and 16 years of age. Adenovirus was detected in 62.2% of the analyzed samples. So far, the cause of these cases is unknown and many hypotheses remain open, but hepatitis A–E viruses and COVID-19 vaccines have been ruled out. A possible hypothesis has been published to explain the cause of these cases of severe hepatitis, according to which it could be a consequence of adenovirus infection in the intestine in healthy children previously infected with SARS-CoV-2. No other clear epidemiological risk factors have been identified to date. Thus, at this time, the etiology of the current cases of hepatitis remains under active investigation.

Immune checkpoint inhibitors (ICIs) suppress the function of immune checkpoints, which are involved in downregulating immune responses. These lead to an increased activation of the function of T cells, increased release of cytokines, and decreased activity of regulatory T cells. This allows for a more significant and less regulated immune response and subsequent enhanced cytotoxic activity against cancer cells. A number of cancers are now being treated with these agents and this increased use has resulted in more reports of toxicity. While almost every organ can be affected, the skin, gastrointestinal tract, liver, and endocrine glands are most commonly involved. It is necessary that gastroenterologists and hepatologists familiarize themselves with diagnostic steps and management plan in patients with these undesirable outcomes. When assessing for possible ICIs induced hepatotoxicity, it is of utmost importance to use a formal scoring system such as the Roussel Uclaf causality assessment method (RUCAM) to assess for risk factors, alternative causes, and response to cessation and re-exposure of a given drug. While this review is based on studies with and without RUCAM, the conclusions were carefully established mainly from studies that used RUCAM. The aim of this review is to provide information on the epidemiology, risk factors, clinical presentation, diagnostic tools, and management plan based on the most recent studies of immunotherapy-induced hepatotoxicity.

Intravenous infusions of magnesium-containing solutions were routinely applied in Russia as treatment of alcohol withdrawal syndrome and other alcohol-related conditions. However, this indiscriminate approach is unfounded and may cause more harm than benefit. Magnesium deficiency is associated with certain circulatory, neuropsychiatric and metabolic conditions. The frequency of hypomagnesemia is enhanced in cases of chronic alcoholism. However, moderate deficiency does not necessarily require parenteral magnesium supplementation. Iatrogenic hypermagnesemia is associated with adverse effects. Endovascular manipulations in conditions of suboptimal procedural quality assurance can cause transmission of viral hepatitis. To decide if an intravenous magnesium supplementation is indicated, it should first be determined whether there is a deficiency and, if so, whether it can be compensated by diet or by oral intake of magnesium-containing drugs.

Functional cure (FC) is characterized by the clearance of the hepatitis B surface antigen from the serum of patients with chronic hepatitis B (CHB). However, the level of intrahepatic covalently closed circular DNA (cccDNA) and hepatitis B virus (HBV) integration remains unclear. We conducted this study to determine them and reveal their value in the treatment of CHB.

There were two sessions to elucidate the changes in intrahepatic cccDNA and HBV integration after antiviral therapy. In the first session, 116 patients were enrolled and divided into FC, non-functional cure (NFC), and CHB groups, including 48 patients with functionally cured CHB, 27 with CHB without functional cure after antiviral treatment, and 41 with treatment-naïve CHB. Patients were tested for both intrahepatic cccDNA and other viral markers. All patients in the FC group were followed up for at least 24 weeks to observe relapse. In the second session, another ten patients were included for in-depth whole-genome sequencing to analyze HBV integration.

Thirteen patients in the FC group were negative for intrahepatic cccDNA. Intrahepatic cccDNA was much higher in the CHB group compared with the FC group. Seven patients had HBsAg seroreversion, including two with virological relapse. Integration of HBV was detected in one (33.3%) functionally cured patients and in seven (100%) with CHB. 28.0% of the HBV breakpoints were assigned in the 1,500 nt to 1,900 nt range of the HBV genome.

After achieving an FC, the rate of intrahepatic cccDNA and HBV integration was significantly reduced in patients with CHB. For those patients who cleared intrahepatic cccDNA, the chances of developing virological relapse were even lower.

Portal hypertension in nonalcoholic fatty liver disease (NAFLD) mostly occur in cirrhotic stage. However, several experimental and clinical studies showed evidence of portal hypertension in NAFLD without significant or advance fibrosis. This early development of portal hypertension in NAFLD is associated with liver sinusoidal contraction by hepatocellular lipid accumulation and ballooning, which is also accompanied by capillarization and dysfunction of liver sinusoidal endothelial cells. Both of these impaired mechanical and molecular components can cause an increase in intrahepatic vascular resistance which lead to the increase of portal pressure in the absence of significant liver fibrosis. Extrahepatic factors such as insulin resistance and gut dysbiosis may also contribute to liver sinusoidal endothelial dysfunction and early portal hypertension in NAFLD. The clinical impact of early portal hypertension in NAFLD is still unclear. However, clinical tools for diagnosis and monitoring of portal hypertension in NAFLD are being investigated to predict high-risk patients and to guide therapy.