Current Status and Challenges in Anti-Hepatitis B Virus Agents Based on Inactivation/Inhibition or Elimination of Hepatitis B Virus Covalently Closed Circular DNA.

There has been over half a century since the discovery of hepatitis B virus (HBV) to now, but approximately 300 million patients with chronic hepatitis B (CHB) still live in the world, resulting in about one million deaths every year. Although currently approved antivirals (e.g., nucleoside analogues) are effective at reducing HBV replication, they have almost no impact on the existing HBV covalently closed circular DNA (cccDNA) reservoir. HBV cccDNA is a critical obstacle to the complete elimination of the virus via antiviral therapy. The true cure of HBV infection requires the eradication of viral cccDNA from HBV-infected cells; thus, the development of new agents directly or indirectly targeting HBV cccDNA is urgently needed due to the limitations of current available drugs against HBV infection. In this regard, it is the major focus of current anti-HBV research worldwide via different mechanisms to either inactivate/inhibit (functional cure) or eliminate (complete cure) HBV cccDNA. Therefore, this review discussed and summarized recent advances and challenges in efforts to inactivate/silence or eliminate viral cccDNA using anti-HBV agents from different sources, such as small molecules (including epigenetic drugs) and polypeptides/proteins, and siRNA or gene-editing approaches targeting/attenuating HBV cccDNA via different mechanisms, as well as future directions that may be considered in efforts to truly cure chronic HBV infection. In conclusion, no breakthrough has been made yet in attenuating HBV cccDNA, although a number of candidates have advanced into the phase of clinical trials. Furthermore, the overwhelming majority of the candidates function to indirectly target HBV cccDNA. No outstanding candidate directly targets HBV cccDNA. Relatively speaking, CCC_R08 and nitazoxanide may be some of the most promising agents to clear HBV infection in small molecule compounds. Additionally, CRISPR-Cas9 systems can directly target HBV cccDNA for decay and demonstrate significant anti-HBV activity. Consequently, gene-editing approaches targeting HBV cccDNA may be one of the most promising means to achieve the core goal of anti-HBV therapeutic strategies. In short, more basic studies on HBV infection need to be carried out to overcome these challenges.

Improved Lithium Storage Performance of a TiO2 Anode Material Doped by Co.

TiO2 is a promising anode material for lithium-ion batteries (LIBs) due to its low cost, suitable operating voltage, and excellent structural stability. The inherent poor electron conductivity and low ion diffusion coefficient, however, severely limit its application in lithium storage. Here, Co-doped TiO2 is synthesized by a hydrothermal method as an anode material since Co@TiO2 possesses a large specific surface area and high electronic conductivity. Thanks to the Co dopants, the ion diffusion and electron transport are both greatly improved, which is very beneficial for cycle stability, coulombic efficiency (CE), reversible capacity, and rate performance. As a result, Co@TiO2 shows a high reversible capacity of 227 mAh g-1 at 3 C, excellent rate performance, and cycling stability with a capacity of about 125 mAh g-1 at 10C after 600 cycles (1 C = 170 mA g-1).

Availability, Functionality, and Safety as well as Quality Control of Hepatocytes as Seeding Cells in Liver Regenerative Medicine: State of the Art and Challenges.

Hepatic disease is one of the most common causes of death worldwide and has become a global health problem. Liver transplantation is the only effective treatment strategy for patients with hepatic function failure, but the insufficient number of donated healthy livers is the main obstacle limiting this process. To alleviate the demand for donor's livers, alternative approaches are being actively explored using liver tissue engineering principles. Liver tissue engineering consists of three elements, including seeding cells, extracellular matrix, and bioreactors. Among them, seeding cell is the most key factor. In this regard, hepatocyte-based tissue engineering can overcome the above shortages for tissue repair and regeneration in hepatic disorders. Primary human hepatocytes in liver regenerative medicine are the most preferred seeding cells, although limited access to a sufficient number of functional hepatocytes are a major issue due to the difficulties in long-term function maintenance of hepatocyte as well as the lack of availability of healthy donors. Hepatocyte-like cells (HLCs), derived from various stem cells, including non-liver-derived stem cells and liver-derived stem cells, as well as trans-differentiation of other cell types, may provide adequate cell sources and could replace primary human hepatocytes as seeding cells. However, it is still a great difficulty that HLCs generated by stem cell differentiation meet the quality required for clinical therapy. Furthermore, none of the standardized protocols to generate high-quality HLCs is available. Whether primary hepatocytes or HLCs are from various sources, preventing the functional deterioration of hepatocytes or generating fully functional hepatocytes is also a big challenge, respectively. In addition, the adoptions of three-dimensional co-culture systems and some small-molecule compounds contribute to maintaining the hepatic functionality of primary hepatocytes and enhancing the liver-specific functions of HLCs. In short, hepatocyte-based liver regenerative medicine is an attractive alternative strategy for liver diseases, notwithstanding some challenges still exist from bench to bedside. This review summarizes the current status, issues, and challenges in availability, functionality, and safety, as well as quality control of seeding hepatocytes with regard to liver tissue engineering in regenerative medicine for the treatment of liver disorders.