Sequential drug delivery for liver diseases.

Nonalcoholic fatty liver disease (NAFLD), the major reason for abnormal liver function in the Western world, is associated with obesity and diabetes and is characterized by insulin resistance (IR). IR is regulated by mediators released from cells of the immune system or adipocytes and proinflammatory cytokines such as tumor necrosis factor-α (TNFα). The importance of TNFα in human and animal fatty liver diseases, both caused by genetic manipulation and overnutrition, has been shown convincingly. Furthermore, neutralization of TNFα activity improves IR and fatty liver disease in animals. Adiponectin is a potent TNFα-neutralizing and anti-inflammatory adipokine and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are exerted both by suppressing TNFα synthesis and by induction of anti-inflammatory cytokines such as interleukin-10 or interleukin-1–receptor antagonist. Therefore, the balance between various mediators, either derived from the immune system or adipose tissue, appears to play an important role in hepatic and systemic insulin action and in the development of fatty liver disease.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

Epidemiology of non-alcoholic fatty liver disease in China

Controlled drug delivery systems, that include sequential and/or sustained drug delivery, have been utilized to enhance the therapeutic effects of many current drugs by effectively delivering drugs in a time-dependent and repeatable manner. In this study, with the aid of 3D printing technology, a novel drug delivery device was fabricated and tested to evaluate sequential delivery functionality. With an alginate shell and a poly(lactic-co-glycolic acid) (PLGA) core, the fabricated tubes displayed sequential release of distinct fluorescent dyes and showed no cytotoxicity when incubated with the human embryonic kidney (HEK293) cell line or bone marrow stromal stem cells (BMSC). The controlled differential release of drugs or proteins through such a delivery system has the potential to be used in a wide variety of biomedical applications from treating cancer to regenerative medicine.

A pH-responsive polycarbonate nanoplatform enables sequential drug release for enhanced apoptotic cascade synergy in non-small cell lung cancer therapy.

Cancer is a major public health problem and one of the leading causes of death. However, traditional cancer therapy may damage normal cells and cause side effects. Many targeted drug delivery platforms have been developed to overcome the limitations of the free form of therapeutics and biological barriers. The commonly used cancer cell surface targets are CD44, matrix metalloproteinase-2, folate receptors, etc. Once the drug enters the cell, active delivery of the drug molecule to its final destination is still preferred. The subcellular targeting strategies include using glucocorticoid receptors for nuclear targeting, negative mitochondrial membrane potential and N-acetylgalactosaminyltransferase for Golgi apparatus targeting, etc. Therefore, the most effective way to deliver therapeutic agents is through a sequential drug delivery system that simultaneously achieves cellular- and subcellular-level targeting. The dual-targeting delivery holds great promise for improving therapeutic effects and overcoming drug resistance. This review classifies sequential drug delivery systems based on final targeted organelles. We summarize different targeting strategies and mechanisms and gave examples of each case.

IL-6: a magic potion for liver transplantation?

Contribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease

Are patients with elevated liver tests at increased risk of drug-induced liver injury?

The needs of surveillance of metabolic associated fatty liver disease in Taiwan

Stem Cells and Liver Regeneration

Controlled and sequential drug delivery is a strategy to enhance the therapeutic effectiveness of drugs in a variety of biological processes and disease states. While many different drug delivery systems are developed recently, most cannot generate temporally complex delivery profiles of multiple therapeutics. These temporally complex profiles are critical for applications such as bone regeneration and cancer chemotherapy, where an orchestrated delivery of multiple drugs is required for an optimal outcome. Here, we developed three distinct biomaterial systems that each enable on-demand controlled or sequential drug release. These systems are based on varying external stimulus such as magnetic stimulation, radiofrequency heating, and near infrared (NIR) laser irradiation. The first system is a dual compartment hydrogel composed of an outer gelatin partition and an inner alginate ferrogel. While the outer compartment could be loaded with a recruitment factor to recruit and harbor cells, the inner compartment was capable of retaining and releasing a differentiation factor on-demand. The inner compartment was a biphasic ferrogel and stimulation was conducted using a custom magnetic stimulation set up. It was shown that delayed differentiation factor delivery can enhance mMSCs’ osteo-differentiation outcomes using 2D and 3D cell cultures. The second system is a magnetoliposome (ML) integrated hydrogel system. In this design, different sizes of magnetic iron oxide nanoparticles (IONPs) were used to develop two different MLs: ML-A and ML-B. Cationic and zwitterionic lipids were used to form positively charged liposomes that could electrostatically adsorb the IONPs on their surfaces and form MLs. The ratio of IONP/lipid was optimized to form stable ML-A and ML-B structures. These structures were integrated within 3D alginate hydrogels to enhance stability and provide localized drug delivery. As the different MLs could be stimulated at different frequencies, complex delivery profiles could be generated using these MLs in hydrogels. Controlled and delayed releases of a model drug (FITC-Dextran) from ML-A and ML-B in hydrogels were demonstrated. The third system is a single-walled carbon nanotube (SWCNT) liposome complex (CLC) integrated hydrogel. Here, unique NIR absorbance properties of SWCNTs were used to achieve drug release from liposomal structures. DNA sequences were used to wrap SWCNTs to uniformly disperse them in an aqueous solution and provide negative charge on their surface. These DNA-SWCNTs were then mixed with cationic liposomes to form CLCs. Optimal SWCNT to lipid ratio to form stable CLCs were determined. CLCs were then integrated within hydrogel structures and drug release was controlled using

The changing epidemiology of liver diseases in Asia.

Fatty liver disease associated with metabolic dysfunction has emerged as a significant global health challenge. This condition often coexists with other liver diseases, such as alcohol-related liver disease and viral hepatitis, complicating both diagnosis and management. To address the limitations of the non-alcoholic fatty liver disease (NAFLD) classification, two alternative frameworks have been proposed: metabolic dysfunction-associated fatty liver disease (MAFLD) in 2020 and metabolic dysfunction-associated steatotic liver disease (MASLD) in 2023. A key difference between these definitions is how they consider fatty liver disease in relation to the coexistence of other liver conditions. MAFLD adopts a dual etiology concept, creating a unified classification system that aligns with contemporary clinical and epidemiological needs. In contrast, MASLD introduces a new term, MetALD (metabolic and alcohol-related/associated liver disease), to describe patients who have both metabolic dysfunction and excessive alcohol intake. This review critically examines the clinical, research, and epidemiological implications of the differing approaches of MAFLD and MASLD, offering insights into their potential to enhance the understanding and management of multi-etiology liver diseases.

The Negative Bidirectional Interaction Between Climate Change and the Prevalence and Care of Liver Disease: A Joint BSG, BASL, EASL, and AASLD Commentary