Recent genome-wide association studies have shown that low-density lipoprotein receptor (LDLR) rs1433099 polymorphism is associated with cardiovascular disease (CVD) risk in many countries. However, the association of LDLR rs1433099 with CVD in China has not been reported yet. There are no studies on LDLR rs1433099 and non-alcoholic fatty liver disease (NAFLD) as well. The purpose of this study was to investigate whether LDLR rs1433099 is related to CVD or NAFLD in the Chinese population.

LDLR rs1433099 polymorphism was genotyped in 507 individuals, including 140 healthy controls, 79 NAFLD patients, 185 CVD patients, and 103 patients with NAFLD combined with CVD. The expression of LDLR was tested by the sequence detection system, and clinical parameters were assessed by biochemical tests and physical examination.

The genotype distribution of LDLR rs1433099 was not statistically different among the NAFLD group, the CVD group, the combined group, and the healthy control group (p>0.05). There was no significant correlation of LDLR rs1433099 genotypic distribution or allele frequency and the risk of NAFLD, CVD or NAFLD combined with CVD (p>0.05). In the CVD group, T allele carriers had higher alkaline phosphatase and gamma-glutamyl transpeptidase than non-carriers (p<0.05).

Our study demonstrated that the LDLR rs1433099 polymorphism is not a risk factor of NAFLD. The LDLR rs1433099 polymorphism may increase the risk of CVD through a mechanism involving alkaline phosphatase and gamma-glutamyl transpeptidase.

Photodynamic therapy (PDT) for the inactivation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a valuable therapy for the treatment of coronavirus disease 2019 (COVID-19) disease. The spread of the SARS-CoV-2 virus has caused the COVID-19 pandemic, resulting in the death of many people worldwide due to the lack of effective treatments. FDA has recently approved two mRNA-based vaccines for emergency use, but still vaccine supply is limited. Therefore, it is imperative to discover new therapeutic strategies for the management of COVID-19 patients. PDT has been used to deactivate microorganisms for many years and might be an effective and promising therapy for COVID-19 patients. The PDT procedure is composed of a photosensitizer, light, and oxygen, which generate a local spurt of reactive oxygen species that can inactivate enveloped viruses and microorganisms. PDT is a safe, faster, cost-effective, and simple method to inactivate microorganisms. In addition, there have been no reports of resistance, unlike other antibiotics and antiviral drugs. This review aims to update the advancement of PDT and the findings could attract clinical attention in future clinical trials.

Chronic hepatitis B virus (HBV) infection is a global public health challenge. HBV reactivation usually occurs in cancer patients after receiving cytotoxic chemotherapy or immunosuppressive therapies. Romidepsin (FK228) and vorinostat (SAHA) are histone deacetylase inhibitors (HDACi) approved by the Food and Drug Administration as novel antitumor agents. The aim of this study was to explore the effects and mechanisms of HDACi treatment on HBV replication.

To assess these effects, human hepatoma cell lines were cultured and cell viability after FK228 or SAHA treatment was measured by the CCK-8 cell counting kit-8 assay. Then, HBV DNA and RNA were quantified by real-time PCR and Southern blotting. Furthermore, analysis by western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and flow cytometry was performed.

FK228/SAHA treatment significantly promoted HBV replication and biosynthesis in both HBV-replicating cells and HBV-transgenic mouse model. Flow cytometry assay indicated that FK228/SAHA enhanced HBV replication by inducing cell cycle arrest through modulating the expression of cell cycle regulatory proteins. In addition, simultaneous inhibition of HDAC1/2 by FK228 promoted HBV replication more effectively than the broad spectrum HDAC inhibitor SAHA.

Overall, our results demonstrate that cell cycle blockage plays an important role in FK228/SAHA-enhanced HBV replication, thus providing a potential avenue for rational use of HDACi in patients with chronic hepatitis B.

To compare the efficacy and safety of physical thermal ablation (PTA), including radiofrequency ablation (RFA) and microwave ablation (MWA), combined with sorafenib and physical thermal ablation alone for the control and treatment of hepatocellular carcinoma (HCC) according to the available literature.

Comprehensive searches were performed on PubMed, Embase, CNKI, the Cochrane Library, China Biomedical Literature Database (known as CBM), Weipu Journal, and Wanfang Database. Meta-analysis was performed using Revman 5.3 software.

A total of 15 studies, consisting of 2,227 HCC patients, were selected and included in this meta-analysis. Compared with the RFA-alone group, the patients in the RFA+sorafenib group had longer 1-, 2-, and 3-year overall survival (all p<0.05), better overall efficacy (p<0.0001), longer radiofrequency interval (p<0.001), and lower 2-year recurrence rate (p=0.02). The 1-year overall survival (p=0.003) and overall efficacy (p=0.002) of the MWA+sorafenib group were also higher than those of the MWA-alone group. The incidences of adverse reactions in the RFA+sorafenib group, such as hand-foot skin reactions (p<0.001), diarrhea and constipation (p=0.0001), hypertension (p=0.009), and alopecia (p<0.001), were significantly higher than those in the RFA-alone group.

RFA or MWA combined with sorafenib has produced a better therapeutic effect on HCC than physical thermal ablation alone; however, adverse reactions have been obvious. It is necessary to evaluate the safety of combination therapy, and pay close attention to the adverse reactions that develop in patients.

Lipid accumulation is the major characteristic of non-alcoholic fatty liver disease, the prevalence of which continues to rise. We aimed to investigate the effects and mechanisms of icaritin on lipid accumulation.

Cells were treated with icaritin at 0.7, 2.2, 6.7, or 20 µM for 24 h. The effects on lipid accumulation in L02 and Huh-7 cells were detected by Bodipy and oil red O staining, respectively. Mitochondria biogenesis of L02 cells was detected by MitoTracker Orange staining. Glucose uptake and adenosine triphosphate content of 3T3-L1 adipocytes and C2C12 myotubes were detected. The expression levels of proteins in the adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway, biomarkers of autophagy, and mitochondria biogenesis were measured by western blotting. LC3 puncta were detected by immunofluorescence.

Icaritin significantly attenuated lipid accumulation in L02 and Huh-7 cells and boosted the mitochondria biogenesis of L02 cells. Icaritin enhanced glucose uptake, decreased adenosine triphosphate content, and activated the AMPK signaling pathway in 3T3-L1 adipocytes and C2C12 myotubes. Icaritin boosted autophagy and also enhanced the initiation of autophagic flux in 3T3-L1 preadipocytes and C2C12 myoblasts. However, icaritin decreased autophagy and promoted mitochondria biogenesis in 3T3-L1 adipocytes and C2C12 myotubes.

Icaritin attenuates lipid accumulation by increasing energy expenditure and regulating autophagy by activating the AMPK pathway.

Tumor microenvironment plays an essential role in cancer development and progression. Cancer immunotherapy has become a promising approach for the treatment of hepatocellular carcinoma (HCC). We aimed to analyze the HCC immune microenvironment characteristics to identify immune-related genetic changes.

Key immune-relevant genes (KIRGs) were obtained through integrating the differentially expressed genes of The Cancer Genome Atlas, immune genes from the Immunology Database and Analysis Portal, and immune differentially expressed genes determined by single-sample gene set enrichment analysis scores. Cox regression analysis was performed to mine therapeutic target genes. A regulatory network based on KIRGs, transcription factors, and immune-related long non-coding RNAs (IRLncRNAs) was also generated. The outcomes of risk score model were validated in a testing cohort and in clinical samples using tissue immunohistochemistry staining. Correlation analysis between risk score and immune checkpoint genes and immune cell infiltration were investigated.

In total, we identified 21 KIRGs, including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), and found IKBKE, IL2RG, EDNRA, and IGHA1 may be equally important to PD-1 or CTLA4. Meanwhile, KIRGs, various transcription factors, and IRLncRNAs were integrated to reveal that the NRF1-AC127024.5-IKBKE axis might be involved in tumor immunity regulation. Furthermore, the immune-related risk score model was established according to KIRGs and key IRLncRNAs, and verified more obvious discriminating power in the testing cohort. Correlation analysis indicated TNFSF4 , LGALS9 , KIAA1429 , IDO2, and CD276 were closely related to the risk score, and CD4 T cells, macrophages, and neutrophils were the primary immune infiltration cell types.

Our results highlight the importance of immune genes in the HCC microenvironment and further unravel the underlying molecular mechanisms in the development of HCC.

The gut microbiome plays a key role in the health-disease balance in the human body. Although its composition is unique for each person and tends to remain stable throughout lifetime, it has been shown that certain bacterial patterns may be determining factors in the onset of certain chronic metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic-associated fatty liver disease (MAFLD), and metabolic syndrome. The gut-liver axis embodies the close relationship between the gut and the liver; disturbance of the normal gut microbiota, also known as dysbiosis, may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation. Regulation of gut microbiota is fundamental to maintaining gut integrity, as well as the bile acids composition. In the present review, we summarize the current knowledge regarding the microbiota, bile acids composition and their association with MAFLD, obesity, T2DM and metabolic syndrome.

Although ursodeoxycholic acid (UDCA) treatment in primary biliary cholangitis is effective in many patients, there are still many people who respond poorly to it. Identifying and intervening these patients early is important. Therefore, exploring the risk factors and proposing a predictor index to predict the UDCA treatment nonresponse earlier among primary biliary cholangitis patients were the aims of this research.

A total of 135 primary biliary cholangitis patients treated with UDCA (13–15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on Paris I criteria. The univariate and logistic multivariate regression analyses were adopted to determine the independent risk factors and propose a predictor index. Receiver operating characteristic curve was used to evaluate the predictive ability of the predictor index.

Total bilirubin, albumin, globulin, immunoglobin M, and aspartate aminotransferase-to-platelet ratio index were the five independent risk factors associating with early biochemical nonresponse to UDCA treatment. Based on these factors, we established a predictor index with the predictive value being 0.886 (sensitivity: 82.80%, specificity: 84.40%).

We developed a predictor index that had an accurate prediction of the early biochemical nonresponse to UDCA treatment, which is expected to provide valuable information for the high-risk group before treatment begins.

An unprecedented outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection appeared in Wuhan, Hubei Province, China, in December 2019. On 11 February 2020, the World Health Organization (WHO) officially attributed the disease to infection with SARS-COV-2 as coronavirus disease 2019 (COVID-19). SARS-COV-2 is highly contagious, and people are generally susceptible to infection. Since the outbreak of the pandemic, which has changed the way most people live and work, the Chinese government and scientific community have acted quickly and taken measures to contain the pandemic. This review aims to look at the psychological impact of the outbreak on a specific segment of the population (e.g., students, recent college graduates, medical staff, older people, pregnant women, children, the general public, and others), and to isolate the mechanisms by which social isolation could cause loneliness, to improve our understanding of the emerging epidemic’s impact on people’s mental health, and therefore, to focus attention on mental health care.

Recurrence and metastasis are the foremost causes of morbidity and mortality for breast cancer (BC). Recent studies have highlighted the critical role of the tumor microenvironment, in particular, because it is related to tumor-associated macrophages (TAMs), in metastasis of BC. TAMs are mainly derived from macrophages that are recruited by C-C motif chemokine ligand 5, which are secreted by cancer cells and cancer-related stromal cells. Although E-cigarettes (E-cigs) were originally proposed as a healthy substitute for conventional cigarette smoking, clinical and experimental evidence has highlighted the potentially lethal effects of this alternative. Several studies have illustrated the immune or macrophage activation and DNA damaging effects of E-cigs. However, the potentially pivotal role of TAM-BC crosstalk during BC progression and metastasis for E-cig vaping has not been explored. This review discussed the significant effect that E-cig use had on the BC tumor microenvironment, which ultimately led to enhanced tumor malignancy and metastasis, with an emphasis on the extent that E-cig uses had on the crosstalk between cancer and immune cells, as well as the potential underlying mechanisms that drive this aggressive phenotype of BC. This review advances our understanding of this matter and provides scientific evidence that could highlight risks associated with vaping and suggest a potential intervention for the treatment of aggressive BCs that present an increased risk of metastasis.

Growing evidence suggests that metabolic-related genes have a significant impact on the occurrence and development of hepatocellular carcinoma (HCC). However, the prognostic value of metabolic-related genes for HCC has not been fully revealed.

mRNA sequencing and clinical data were obtained from The Cancer Genome Atlas and the GTEx Genotype-Tissue Expression comprehensive database. Differentially expressed metabolic-related genes in tumor tissues (n=374) and normal tissues (n=160) were identified by the Wilcoxon test. Time-dependent receiver operating characteristic curve analysis, univariate multivariate Cox regression analysis and Kaplan-Meier survival analysis were used to evaluate the predictive effectiveness and independence of the prognostic model. Two independent cohorts (International Cancer Genome Consortiums and GSE14520) were applied to verify the prognostic model.

Our study included a total of 793 patients with HCC. We constructed a risk score consisting of five metabolic-genes (BDH1, RRM2, CYP2C9, PLA2G7, and TXNRD1). For the overall survival rate, the low-risk group had a considerably higher rate than the high-risk group. Univariate and multivariate Cox regression analyses indicated that the risk score was an independent predictor for the prognosis of HCC.

We constructed and validated a novel prognostic model, which may provide support for the precise treatment of HCC.

Coronavirus disease 2019 (COVID-19) has infected over 93 million people worldwide as of January 14, 2021. Various studies have gathered data on liver transplant patients infected with COVID-19. Here, we discuss the presentation of COVID-19 in immunosuppressed patients with prior liver transplants. We also evaluate patient outcomes after infection.

We searched the PubMed database for all studies focused on liver transplant patients with COVID-19.

We identified eight studies that evaluated COVID-19 infection in liver transplant patients (n=494). Hypertension was the most prevalent comorbidity in our cohort. Calcineurin inhibitors were the most common immunosuppressant medications in the entire cohort. The average time from liver transplant to COVID-19 infection in our cohort was 74.1 months. Fever and cough, at 70% and 62% respectively, were the most common symptoms in our review. In total, 50% of the patients received hydroxychloroquine as treatment for COVID-19. The next most prevalent treatment was azithromycin, given to 30% of patients in our cohort. In total, 80% of the patients were admitted to a hospital and 17% required intensive care unit-level care, with 21% having required mechanical ventilation. Overall mortality was 17% in our review.

Given the immunocompromised status of liver transplant patients, more intensive surveillance is necessary for severe cases of COVID-19 infection. As liver transplantations have been restricted during the COVID-19 pandemic, further investigation is warranted for studying the risk of COVID-19 infection in liver transplant patients.

In Europeans, variants in the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene impact liver histology in metabolic-associated fatty liver disease (MAFLD). The impact of these variants in ethnic Chinese is unknown. The aim of this study was to investigate the potential associations in Chinese patients.

In total, 427 Han Chinese with biopsy-confirmed MAFLD were enrolled. Two single nucleotide polymorphisms in HSD17B13 were genotyped: rs72613567 and rs6531975. Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.

In our cohort, the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis [odds ratio (OR): 2.93 (1.20–7.17), p=0.019 for the additive model; OR: 3.32 (1.39–7.91), p=0.007 for the recessive model], representing an inverse association as compared to the results from European cohorts. In contrast, we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant [OR: 0.48 (0.24–0.98), p=0.043 for the additive model; OR: 0.62 (0.40–0.94), p=0.025 for the dominant model]. HSD17B13 variants were only associated with fibrosis but no other histological features. Furthermore, HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.

HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans. These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.

Endothelial dysfunction plays a crucial role in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and has recently been proposed to be connected with acute thrombosis, hyper-inflammation, cytokine storm syndrome, immune cell recruitment, platelet aggregation, vasoconstriction and endothelial apoptosis. Importantly, certain mediators and pro-inflammatory cytokines such as galectin (Gal) 1, Gal3 and Gal8 act in a concerted manner through the N- and O-linked glycans located on the SARS-CoV-2 S protein. We hypothesize that the presence of these factors may cause the ACE2 receptor, integrin β1, and CD44 to generate a Gal-glycan lattice on the surface of SARS-CoV-2 virus. This lattice, in addition to endothelial cells (ECs), may not only influence EC behavior and the inflammatory response, but may also induce conformational changes in the viral structure that can facilitate attachment and entry into the ECs. We believe that further basic science research is necessary to elucidate the composition and role of the Gal-glycan lattices in the SARS-CoV-2 infection.

The rearrangement during transfection (RET) encodes a receptor tyrosine kinase (RTK), which is involved in the development of various tissues and cells. The rearrangements and mutations of RET contribute to the development of a variety of human malignancies. Therefore, RET alterations are novel therapeutic targets. Inhibitors for RET and other kinases have been approved for the treatment of RET-altered tumors and have demonstrated their benefits for some types of cancer patients in clinics. However, due to off-target effects, these inhibitors have some adverse effects and dose-limiting toxicity. Therefore, long-term treatment with these inhibitors has potential limitations. Novel highly selective inhibitors (pralsetinib and selpercatinib) that target the RET pathway are well tolerated and have significant and long-lasting antitumor activity. They have been accelerated for approval by the FDA. This article will focus on the role of highly selective inhibitors targeting the RET and their efficacy and safety in therapy for RET-associated cancers.

Patients with cirrhosis and acute-on-chronic liver failure (ACLF) may have bleeding complications and need for invasive procedures. Point-of-care (POC) coagulation tests like thromboelastography (TEG) and Sonoclot may be better for guiding patient management than the standard coagulation tests (SCTs), like prothrombin time, platelet count and international normalized ratio.

We prospectively compared and validated the POC tests and SCTs in 70 persons with ACLF and 72 persons with decompensated cirrhosis who had clinical bleeding and checked for episodes of re-bleeding and transfusion requirements. We assessed pre-procedure requirement of blood components when correction was done based on an SCT or POC strategy.

Episodes of bleeding were seen in 45% and 28% of ACLF and cirrhosis patient, respectively (p=0.036), with the major site of bleeding being gastrointestinal (31% and 16%, respectively). Platelet counts correlated with TEG-maximum amplitude in cirrhosis (p=0.045) and prothrombin time correlated positively with TEG-reaction (R) time (p=0.032), TEG-Clot kinetics (K) time (p=0.042), Son-activated clotting time (p=0.038) and negatively with clot rate (p=0.043) in ACLF, making these correctable target variables in POC transfusion algorithms. Of 223 procedures, transfusion of fresh frozen plasma and platelet concentrate was reduced by 25% (p=0.035) and 20.8% (p=0.045) by using a POC strategy in 76 patients. Correction of deranged Son-activated clotting time and TEG-reaction time was noted in 68% and 72% after 24 h of fresh frozen plasma transfusion in ACLF and 85% and 80% in cirrhosis, respectively.

Our study clinically validates that POC tests can better detect coagulation defects and transfusion thresholds in ACLF and cirrhosis, whereas use of conventional tests appear to be less suitable in patients with clinical bleeding.

NCT04332484.

Plants are a rich source of bio-functional phytochemicals. The present study was designed to investigate the methanol extracts of selected plants for their phytochemicals, antioxidant activity, urease and acetylcholine esterase (AChE) inhibitory potential.

Crude methanol extracts of selected ethnopharmacological plants were prepared by a simple maceration procedure. Antioxidant assays, total phenolic and total flavonoid content were determined using colorimetric methods. The urease and AChE inhibitory potential of the extract was investigated using spectroscopy techniques.

Most of the extracts tested positive for alkaloids, saponin, glycosides and terpenoids. The total phenolic and flavonoid content in the extracts ranged from 62.7 ± 6.07 – 172.25 ± 11.8 µg gallic acid equivalent (GAE) and 9.7–60.1 µg quercetin equivalent (QE) per gram dry weight (DW). The maximum GAE and QE content was found in Coruns officinalis and Prunus armeniaca, at 164.9 ± 5.6 and 60 ± 0.65 g/mg DW, respectively. All medicinal plants showed significant antioxidant activity. M. kobus exhibited significant antiradical (DPPH) potential (IC50 = 30.77 µg/ml). F. koreana showed the maximum total antioxidant capacity when expressed as ascorbic acid equivalent (AAE) (119.1 µg AAE/mg DW). The extracts were evaluated for their inhibitory potential against urease and AChE enzymes. Among all plants, G. biloba and P. mume exhibited the maximum urease and AChE inhibitory activity with IC50 of 45.25 and 16.58 µg/mL, respectively.

The present study showed that methanol extracts of plants can be considered as potential sources of pharmacological importance in terms of phyto-constituents for the treatment of oxidative stress associated ailments, ulcer and Alzheimer’s disease.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.