The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve, emerging novel variants with spike protein mutations. Although most mutations emerged in the SARS-CoV-2 genome are neutral or mildly deleterious, a small number of mutations can affect virus phenotype that confers the virus a fitness advantage. These mutations can enhance viral replication, raise the risk of reinfection and blunt the potency of neutralizing antibodies triggered by previous infection and vaccination. Since December 2020, the SARS-CoV-2 has emerged five quickly spreading strains, designated variants of concern (VOCs), including the Alpha (B.1.1.7) variant, the Beta (B.1.351) variant, the Gamma (P.1) variant, the Delta (B.1.617.2) variant and the Omicron (B.1.1.529) variant. These variants have a high number of the mutations in the spike protein that promotes viral cell entry through the angiotensin-converting enzyme -2 (ACE2). Mutations that have arisen in the receptor binding domain (RBD) of the spike protein are of great concern due to their potential to evade neutralizing antibodies triggered by previous infection and vaccines. The Alpha variant emerged in the United Kingdom in the second half of 2020 that has spread quickly globally and acquired the E484K mutation in the United Kingdom and the United States. The Beta and Gamma variants emerged in South Africa and Brazil, respectively, that have additional mutations at positions E484 and K417 in the RBD. SARS-CoV-2 variants containing the combination of N501Y, E484K, and K417N/T mutations exhibit remarkably decreased sensitivity to neutralizing antibodies mediated by vaccination or previous infection. The Gamma variant may result in more severe disease than other variants do even in convalescent individuals. The Delta variant emerged in India in December 2020 and has spread to many countries including the United States and the United Kingdom. The Delta variant has 8 mutations in the spike protein, some of which can influence immune responses to the key antigenic regions of RBD. In early November 2021, the Omicron (B.1.1.529) variant was first detected in Botswana and South Africa. The Omicron variant harbors more than 30 mutations in the spike protein, many of which are located within the RBD, which have been associated with increased transmissibility and immune evasion after previous infection and vaccination. Additionally, the Omicron variant contains 3 deletions and one insertion in the spike protein. Recently, the Omicron variant has been classified into three sublineages, including BA.1, BA.2, and BA.3, with strikingly different genetic characteristics. The Omicron BA.2 sublineage has different virological landscapes, such as transmissibility, pathogenicity and resistance to the vaccine-induced immunity compared to BA.1 and BA.3 sublineages. Mutations emerged in the RBD of the spike protein of VOCs increase viral replication, making the virus more infectious and more transmissible and enable the virus to evade vaccine-elicited neutralizing antibodies. Unfortunately, the emergence of novel SARS-CoV-2 VOCs has tempered early optimism regarding the efficacy of COVID-19 vaccines. This review addresses the biological and clinical significance of SARS-CoV-2 VOCs and their impact on neutralizing antibodies mediated by existing COVID-19 vaccines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease 2019 (COVID-19), has been identified in China in late December 2019. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA betacoronavirus of the Coronaviridae family. Coronaviruses have genetic proofreading mechanism that corrects copying mistakes and thus SARS-CoV-2 genetic diversity is extremely low. Despite lower mutation rate of the virus, researchers have detected a total of 12,706 mutations in the SARS-CoV-2 genome, the majority of which were single nucleotide polymorphisms. Sequencing data revealed that the SARS-CoV-2 accumulates two-single nucleotide mutations per month in its genome. Recently, an amino acid aspartate (D) to glycine (G) (D614G) mutation due to an adenine to guanine nucleotide change at position 23,403 at the 614th amino-acid position of the spike protein in the original reference genotype has been identified. The SARS-CoV-2 viruses that carry the spike protein D614G mutation have become dominant variant around the world. The D614G mutation has been found to be associated with 3 other mutations in the spike protein. Clinical and pseudovirus experimental studies have demonstrated that the spike protein D614G mutation alters the virus phenotype. However, the impact of the mutation on the rate of transmission between people, disease severity and the vaccine and therapeutic development remains unclear. Three variants of SARS-CoV-2 have recently been identified. They are B.1.1.7 (UK) variant, B.1.351 (N501Y.V2, South African) variant and B.1.1.28 (Brazilian) variant. Epidemiological data suggest that they have a higher transmissibility than the original variant. There are reports that some vaccines are less efficacious against the B.1.351 variant. This review article discusses the effects of novel mutations in the SARS-CoV-2 genome on transmission, clinical outcomes and vaccine development.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death globally. Tumor cells recruit and remodel various types of stromal and inflammatory cells to form a tumor microenvironment (TME), which encompasses cellular and molecular entities, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), immune cells, myeloid-derived suppressor cells (MDSCs), immune checkpoint molecules and cytokines that promote cancer cell growth, as well as their drug resistance. HCC usually arises in the context of cirrhosis, which is always associated with an enrichment of activated fibroblasts that are owed to chronic inflammation. CAFs are a major component of the TME, providing physical support in it and secreting various proteins, such as extracellular matrices (ECMs), hepatocyte growth factor (HGF), insulin-like growth factor 1/2 (ILGF1/2) and cytokines that can modulate tumor growth and survival. As such, CAF-derived signaling may increase the pool of resistant cells, thus reducing the duration of clinical responses and increasing the degree of heterogeneity within tumors. Although CAFs are often implicated to be associated with tumor growth, metastasis and drug resistance, several studies have reported that CAFs have significant phenotypic and functional heterogeneity, and some CAFs display antitumor and drug-sensitizing properties. Multiple studies have highlighted the relevance of crosstalk between HCC cells, CAFs and other stromal cells in influence of HCC progression. Although basic and clinical studies partially revealed the emerging roles of CAFs in immunotherapy resistance and immune evasion, a better understanding of the unique functions of CAFs in HCC progression will contribute to development of more effective molecular-targeted drugs. In this review article, molecular mechanisms involved in crosstalk between CAFs, HCC cells and other stromal cells, as well as the effects of CAFs on HCC-cell growth, metastasis, drug resistance and clinical outcomes, are comprehensively discussed.