Psoralea corylifolia L. (PCL) is widely used in clinical practice and is commonly used in the treatment of osteoporosis, tumors, and dermatosis. However, in recent years, adverse reactions of PCL and its related preparations have been frequently reported, and there are even case reports of acute liver injury caused by taking PCL alone, which seriously affects the safe and rational clinical application of PCL. In this paper, the main chemical components, pharmacology, and toxicology of PCL are analyzed and summarized, and the effect-toxicity relationship of PCL and its main active components are sorted out and compared. On this basis, the active components of PCL for treating osteoporosis and causing hepatotoxicity are further systematically compared and summarized, to clarify its effect-toxicity relationship, reduce the toxicity risk of PCL, increase the benefit/risk ratio and provide evidence for the safe clinical application of PCL.

Hepatocellular carcinoma (HCC) is becoming one of the major health problems, and the leading cause of cancer-related mortality globally. Its multifactorial risk factors remain as paramount challenges to the treatment of this deadly disease. The conventionally known risk factors that trigger HCC include hepatitis C virus (HCV), hepatitis B virus (HBV), excess alcohol consumption, and environmental toxins, such as aflatoxin, aristolochic acid, etc. All these risk factors activate the oncogenic signaling in the liver, and transform the normal liver into an HCC liver. Recently, globalization and the Western sedentary lifestyle have newly emerged as risk factors for HCC, which include obesity, metabolic syndrome, and associated clinical and pathological modalities. In addition, a number of cellular signaling pathways are derailed in HCC, and these pathways, which are altered in HCC, are known to be directly controlled by oncogenes, such as KRAS, BRAF, c-MYC, astrocyte elevated gene-1 (AEG-1), staphylococcal nuclease domain containing 1 (SND1), late SV40 factor (LSF), apoptosis-antagonizing transcription factor (AATF), WNT/β-catenin, TGF-β, etc. All these oncogenes activate the oncogenic signaling in HCC, and suppress the important cellular tumor suppressor protein activity, playing a prominent role in hepatocarcinogenesis, and its development and progression. The present review established a novel interconnected network between all these oncogene-associated proteins, in order to determine its role in deregulating normal cellular signaling pathways, and transforming these into oncogenic signaling. A number of these oncogenes regulate the miRNA-RISC-associated oncogenic signaling, and trigger oncogenic miRNA singling by downregulating various tumor suppressor genes. Therefore, therapeutically targeting these oncogenes and associated proteins would aid in the development of new drugs to treat HCC.

Hepatocellular carcinoma (HCC) is among the most common malignant tumors globally. Circular RNAs (circRNAs), as a type of noncoding RNAs, reportedly participate in various tumor biological processes. However, the role of circHDAC1_004 in HCC remains unclear. Thus, we aimed to explore the role and the underlying mechanisms of circHDAC1_004 in the development and progression of HCC.

Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect circHDAC1_004 expression (circ_0005339) in HCC. Sanger sequencing and agarose gel electrophoresis were used to determine the structure of circHDAC1_004. In vitro and in vivo experiments were used to determine the biological function of circHDAC1_004 in HCC. Herein, qRT-PCR, RNA immunoprecipitation, western blotting, and a luciferase reporter assay were used to explore the relationships among circHDAC1_004, miR-361-3p, and NACC1.

circHDAC1_004 was upregulated in HCC and significantly associated with poor overall survival. circHDAC1_004 promoted HCC cell proliferation, stemness, migration, and invasion. In addition, circHDAC1_004 upregulated human umbilical vein endothelial cells (HUVECs) and promoted angiogenesis through exosomes. circHDAC1_004 promoted NACC1 expression and stimulated the epithelial-mesenchymal transition pathway by sponging miR-361-3p.

We found that circHDAC1_004 overexpression enhanced the proliferation, stemness, and metastasis of HCC via the miR-361-3p/NACC1 axis and promoted HCC angiogenesis through exosomes. Our findings may help develop a possible therapeutic strategy for HCC.

Primary melanomas of the penis are extremely rare, accounting for 0.18% of all melanomas and less than 2% of all primary penile malignancies. We present a case of primary mucosal melanoma of the penile urethra in an 82-year-old man. His partial penectomy revealed sheets of spindling and epithelioid tumor cells with pale eosinophilic granular cytoplasm and indistinct cell borders, which invaded the corpus spongiosum. Multi-foci of melanoma in situ was identified at the mucosal surface of the urethra meatus. Both positron emission tomography (PET) and magnetic resonance imaging (MRI) scan one month after the partial penectomy showed no evidence of metastatic disease. Five months later, an F18-fluorodeoxyglucose-PET/computed tomography scan demonstrated mildly increased F18-fluorodeoxyglucose avidity along the ventral penis and a marked avidity of a right inguinal lymph node. Subsequent excision confirmed an ulcerated melanoma and a metastatic melanoma in one inguinal lymph node, respectively. Molecular analysis revealed a unique BRAF c.1780G>A mutation, resulting in the D594N alteration, which is the first report in penile urethral melanoma. The patient was miserable from the first infusion of immunotherapy (Keytruda), and a PET scan showed that the tumor continued to grow, with extensive metastatic pulmonary disease leading to massive pleural effusion. Unfortunately, the patient died of the disease 18 months after his first presentation.

Cirrhosis is the precursor lesion for most hepatocellular carcinoma (HCC) cases. However, no biomarker effectively predicted HCC initiation before diagnosis by imaging. We aimed to investigate the hallmarks of immune microenvironments in healthy, cirrhotic livers and HCC tumor tissues and to identify immune biomarkers of cirrhosis-HCC transition.

Expression matrices of single-cell RNA sequencing studies were downloaded and integrated with Seurat package vignettes. Clustering was performed to analyze the immune cell compositions of different sample types.

The cirrhotic liver and HCC tumors had distinct immune microenvironments, but the immune landscape of cirrhotic livers was not markedly modified compared with healthy livers. Two subsets of B cells and three subsets of T cells were identified in the samples. Among the T cells, naïve T cells were more prominent in the cirrhotic and healthy liver samples than in the HCC samples. In contrast, the neutrophil count was lower in cirrhotic livers. Two macrophage clusters were identified, one that actively interacted with T cells and B cells and was enriched in cirrhotic blood compared with HCC blood samples.

Decreased naïve T cell infiltration and increased neutrophil infiltration in the liver may indicate the development of HCC in cirrhotic patients. Alterations in blood-resident immune cells may also be a sign of HCC development in cirrhotic patients. The dynamics of the immune cell subsets may serve as novel biomarkers to predict the transition from cirrhosis to HCC.

The liver has a vital role in many metabolic and regulatory processes in the body. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens. At this time there is no definitive cure for PBC; however, ursodeoxycholic acid (UDCA) has been shown to reduce injury when administered as the first line of treatment. Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression. Currently, a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus. This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

Lung cancer (LC), with its high incidence and less effective treatment strategies, is often not detected until it is in an advanced stage, which contributes to its high mortality rate. Hence, screening the DNA and RNA content in exosomes offers a promising method for its early diagnosis. New technologies for the early detection of LC are absolutely necessary to improve patient outcomes. Such an approach could be the exploitation of exosomes and their content. Exosomes contain DNA, different RNA species, proteins, ceramides, and cholesterol. They can transport their oncogenetic cargo derived from tumor cells to healthy cells over a range of distances to help propagate genetic information that could contribute to the initiation of cancer. This review provides an overview of the involvement of exosomes and their DNA/RNA together with cell-free DNA, summarizes potential biomarkers and describes the application of technologies for the characterization of exosomes with their possible tumor markers. Current radiological and scanning methods for the early detection of LC are also described and compared with nucleic acid analysis. The strengths and weaknesses of both approaches are considered.

We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1.

IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p.

Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33–deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent.

IL-33–ST2–GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.

A functional cure, or hepatitis B virus (HBV) surface antigen (HBsAg) loss, is difficult to achieve in patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B. The HBV vaccine and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been reported to help reduce HBsAg levels and promote HBsAg loss. In this prospective randomized trial, we evaluated HBsAg loss in patients receiving pegylated interferon-α2b (PEGIFN-α2b) and tenofovir disoproxil fumarate (TDF), with and without GM-CSF and HBV vaccination.

A total of 287 patients with HBeAg positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment were assigned randomly to three treatment groups for 48 weeks, TDF alone (control), PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine. The primary endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks.

The cumulative HBsAg loss rates in the control, PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine groups at week 48 were 0.0%, 28.3%, and 41.1%, respectively. The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%, 21.7%, and 33.9%, respectively. Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss (p=0.017) and seroconversion (p=0.030).

In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment, immunomodulatory/antiviral treatment regimens effectively improved HBsAg loss, and the regimen including GM-CSF and HBV vaccination was most effective.

Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is the primary cause of chronic HBV infection worldwide. MTCT prevention and antiviral treatment of infected individuals could eliminate this public health burden. Antiviral treatment of hepatitis B surface antigen (HBsAg)-positive pregnant women and immunoprophylaxis with HBV vaccine and hepatitis B immune globulin are the most effective strategies to interfere with MTCT of HBV. However, for worldwide application of those strategies, feasibility, availability, cost, safety, and effectiveness should be considered. Cesarean section and breastfeeding avoidance in hepatitis B e antigen-positive mothers with a high viral load and without antiviral therapy during pregnancy could be an option, but more supporting evidence is needed. HBsAg screening of all pregnant women is recommended when initiating antiviral therapy and immunoprophylaxis for MTCT prevention, except in areas with limited resources. Timely HBV vaccination series administered soon after birth might be the mainstay of prevention. This review aimed to provide a concise update on the effectiveness of available strategies to prevent MTCT of HBV.

Chinese government lifted its “Zero COVID-19” policy in December 2022. The estimated COVDI-19 new cases and deaths after the policy change are 167–279 million (about 12.0% to 20.1% of the Chinese population) and 0.68–2.1 million, respectively. Recent data also revealed continuous drops in fertility rate and historically lowest growth in gross domestic production in China. Thus, balancing COVID-19 control and economic recovery in China is of paramount importance yet very difficult. Supply chain disruption, essential service reduction and shortage of intensive care units have been discussed as the challenges associated with lifting “Zero COVID-19” policy. The additional challenges may include triple epidemic of COVID-19, respiratory syncytial virus and influenza, mental health issues of healthcare providers, care givers and patients, impact on human mobility, lack of robust genomic and epidemiological data and long COVID-19. However, the policy-associated opportunities and other challenges are largely untouched, but warrant attention of and prompt reactions by the policy makers, healthcare providers, public health officials and other stakeholders. The associated benefits are quick reach of herd immunity, boost of economy and business activities and increase in social activities. At this moment, we must embrace the policy change, effectively mitigate its associated problems and timely and effectively maximize its associated benefits.

Previous trials comparing cyclosporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclosporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tacrolimus based on trough level (T0) after LT, with similar treated biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. Therefore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT.

Patients after first LT were randomized to C2 or T0. tBPAR, patient- and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan–Meier survival analysis and log-rank test.

In intention-to-treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months (p=0.104), and 21.9% vs. 9.7% at 6 and 12 months (p=0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% (p=0.049) and graft loss 23.8% vs. 9.4% (p=0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% (p≤0.001), with no other differences in safety and tolerability.

In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.

We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis. To our knowledge, this is the first well-documented case of this association. A 46-year-old male patient who was repeatedly infused with red blood cells for anemia secondary to osteopetrosis suffered from refractory ascites. The serum-ascites albumin gradient was 29.9 g/L. Abdominal computed tomography (CT) showed a large amount of ascites, hepatomegaly, and splenomegaly. Bone marrow biopsy showed a small bone marrow cavity with no hematopoietic tissue. A peripheral blood smear showed tear drop red blood cells and metarubricytes. Serum ferritin was 8,855.0 ng/mL. Therefore, we considered that the ascites resulted from portal hypertension caused by hemochromatosis secondary to osteopetrosis. We simultaneously performed the transjungular intrahepatic portal-systemic shunt (TIPS) and obtained a transjungular liver biopsy. The portal pressure gradient before TIPS was 28 mmHg, and iron staining was strongly positive on liver biopsy, which confirmed our diagnosis. After TIPS, both abdominal distention and ascites gradually resolved, and no recurrence as observed after the 12-month postoperative follow-up was observed. This case indicated that regular monitoring of iron load is important for patients with osteopetrosis. TIPS is safe and effective for portal hypertension complications due to osteopetrosis.

This work aimed to evaluate the phenolic profile and antioxidant capacity of water extracts of three different date seed varieties i.e., Aseel, Karbalaen and Khupro. Date (Phoenix dactylifera L.) seeds are available in bulk quantities after manufacturing of pitted dates or syrup and are considered as waste stream.

Total phenolic content in date seeds was determined with Folin-Ciocalteu’s phenol reagent. The phenolic compounds profile was determined by high performance liquid chromatography. Antioxidant capacity of each variety was investigated by 2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), oxygen radical absorbance capacity, ferric reducing antioxidant power assay and 2,2-diphenyl-1-picryl-hydrazyl-hydrate assays.

Eight phenolics including gallic acid, caffeic acid, p-coumaric acid, vanillic acid, catechin, epicatechin, chlorogenic acid and sinapic acid were detected in date seeds. The highest content of phenolics was found in Aseel, followed by Karbalaen and Khupro date seeds respectively. Furthermore, the phenolic profile also correlated with the antioxidant capacity of these samples.

Date seeds contain significant level of phenolics and possess high antioxidant activity. Therefore, date seeds could be promising candidates for biomedical applications, functional foods and fortification to increase the shelf life of food products.

This study aimed to analyze the influence of alloferon on the Epstein-Barr virus (EBV) DNA copy number in saliva samples and the changes of natural killer (NK) cell content, cytotoxic activity of killer cells, and production of interferon alpha and gamma in patients suffering chronic EBV infection (CEBVI) at 6 weeks after therapy completion.

One hundred CEBVI patients (69 females and 31 males were divided into two groups: alloferon (n = 70; nine injections s/c, 1.0 mg every alternate day) and valacyclovir (n = 30; 500 mg two times/day, orally). The EBV DNA quantity in the saliva samples, the number of killer cells in the blood, and the cytotoxic activity of killer cells via spontaneous and induced expression of CD107a, a marker of degranulation, were determined after treatment with alloferon. The dynamics of interferon alpha and gamma production before and after alloferon therapy were also assessed.

At 6 weeks after therapy completion, EBV DNA was not found in 38 (54.28%) patients in the alloferon group and in 9 (30.0%) patients in the valacyclovir group (p = 0.001). In addition, a reliable increase of the NK cell content and stimulation of cytotoxic activity of NK cells were detected in the CEBVI patients. Moreover, alloferon treatment did not lead to a reliable increase of interferon alpha or gamma production at 6 weeks after therapy completion.

Alloferon significantly reduces the EBV DNA copy number in saliva samples and induces the expansion of NK cells and cytotoxic activity of NK cells in CEBV patients. Alloferon also significantly affects the clinical complaints of CEBVI patients.

Natural vaginal delivery and breastfeeding favor the development of a strong immune system in infants, and the immune response of infants to vaccines is closely related to their immune system. This large prospective cohort study aimed to explore the effects of delivery and feeding mode on infant’s immune response to hepatitis B vaccine (HepB).

A total of 1,254 infants who completed the whole course of HepB immunization and whose parents were both HBsAg negative were enrolled from infants born in Jinchang City during 2018–2019 by cluster sampling method.

Twenty (1.59%) of the 1,254 infants were nonresponders to HepB. Among the other 1,234 infants, 10.05% (124/1,234), 81.69% (1,008/1,234) and 8.27% (102/1,234) of infants had low, medium, and high responses to HepB, respectively. Logistic regression analysis showed that cesarean section (OR: 8.58, 95% CI: 3.11–23.65, p<0.001) and birth weight <3.18 kg (OR: 5.58, 95% CI: 1.89–16.51, p=0.002) were independent risk factors for infant nonresponse to HepB, and cesarean section (OR: 7.63, 95% CI: 4.64–12.56, p<0.001), formula feeding (OR: 4.91, 95% CI: 1.47–16.45, p=0.001), maternal anti-HBs negativity (OR: 27.2, 95% CI: 10.67–69.35, p<0.001), paternal non-response history of HepB (OR: 7.86, 95% CI: 2.22–27.82, p=0.014) and birth weight <3.22 kg (OR: 4.00, 95% CI: 2.43–6.59, p<0.001) were independent risk factors for infant low response to HepB. In cases where birth weight and genetic factors are unmodifiable and maternal anti-HBs effects are controversial, it makes sense to enhance infant response by changing delivery and feeding patterns.

Natural vaginal delivery and breastfeeding are beneficial to the infant’s immune response to HepB.