Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis

Kumar, Virender; Xin, Xiaoqing; Ma, Jingyi; Tan, Chalet; Osna, Natalia A.; Mahato, Ram I.

doi:10.1016/j.addr.2021.113888

Cited by 90 publications

(63 citation statements)

References 310 publications

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“…[88][89][90] The benefits of circadian medicine specific to the liver may be possible with the advancement of hepatic-specific drug delivery systems such as liposomes, polyethylenimine/small interfering ribonucleic acid complex, and adeno-associated viruses. 91 In addition, noncore clock targets may be highly circadian in their expression, and there is proof of concept for chronotherapy of liver targets, 44 in which the timing of therapy is rationally linked to the expression of the target. Finally, studies of time-restricted eating suggest that intake of the same amount of calories at different times may allow further control of body weight, insulin sensitivity, and lipid accumulation, all of which affect the liver.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the triglyceride lowering effects of drugs that target PPAR are dependent upon hepatic expression of the target (44,87), whereas drugs in clinical use such as fibrates affect PPAR in all tissues, which may contribute to their side effect profile (88)(89)(90). The benefits of circadian medicine specific to the liver may be possible with the advancement of hepatic-specific drug delivery systems such as liposomes, polyethylenimine (PEI)/siRNA complex, and adeno-associated viruses (91). In addition, non-core clock targets may be highly circadian in their expression, and there is proof of concept for chronotherapy of liver targets (44), in which the timing of therapy is rationally linked to the expression of the target.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Circadian Regulation of Gene Expression and Metabolism in the Liver

Guan

Lazar

2022

Semin Liver Dis

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Circadian rhythms are approximately 24-hour cycles of variation in physiological processes, gene expression, and behavior. They result from the interplay of internal biological clocks with daily environmental rhythms, including light/dark and feeding/fasting. 24-hour rhythms of liver metabolic processes have been known for almost 100 years. Modern studies reveal that, like metabolism, hepatic gene expression is highly rhythmic. Genetic or environmental changes can disrupt the circadian rhythms of the liver, leading to metabolic disorders and hepatocellular carcinoma. In this review, we summarize the current understanding of mechanisms regulating rhythmic gene expression in liver, highlighting the roles of transcription factors that comprise the core clock molecular as well as noncanonical regulators. We emphasize the plasticity of circadian rhythms in the liver as it responds to multiple inputs from the external and internal environments as well as the potential of circadian medicine to impact liver-related diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Circadian Regulation of Gene Expression and Metabolism in the Liver

Guan

Lazar

2022

Semin Liver Dis

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“…As well as coupling with polyethylene glycerol and dextran, deimmunization by depleting T-cell epitopes on the protein can be a good way to reduce immunogenicity in designing ITs [ 140 ]. Recent studies showed that the clearance of partially unfolded or oxidized proteins by non-target cells such as hepatic Kupffer cells may also affect the cytotoxicity and tolerance of TCS [ 141 , 142 , 143 ]. Strategies to improve specificity, such as targeting the protein delivery system [ 144 ], show potential to overcome this problem.…”

Section: Discussionmentioning

confidence: 99%

A Sixty-Year Research and Development of Trichosanthin, a Ribosome-Inactivating Protein

Lü

Wong

Shaw

2022

Toxins

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Tian Hua Fen, a herbal powder extract that contains trichosanthin (TCS), was used as an abortifacient in traditional Chinese medicine. In 1972, TCS was purified to alleviate the side effects. Because of its clinical applications, TCS became one of the most active research areas in the 1960s to the 1980s in China. These include obtaining the sequence information in the 1980s and the crystal structure in 1995. The replication block of TCS on human immunodeficiency virus in lymphocytes and macrophages was found in 1989 and started a new chapter of its development. Clinical studies were subsequently conducted. TCS was also found to have the potential for gastric and colorectal cancer treatment. Studies on its mechanism showed TCS acts as an rRNA N-glycosylase (EC 3.2.2.22) by hydrolyzing and depurinating A-4324 in α-sarcin/ricin loop on 28S rRNA of rat ribosome. Its interaction with acidic ribosomal stalk proteins was revealed in 2007, and its trafficking in mammalian cells was elucidated in the 2000s. The adverse drug reactions, such as inducing immune responses, short plasma half-life, and non-specificity, somehow became the obstacles to its usage. Immunotoxins, sequence modification, or coupling with polyethylene glycerol and dextran were developed to improve the pharmacological properties. TCS has nicely shown the scientific basis of traditional Chinese medicine and how its research and development have expanded the knowledge and applications of ribosome-inactivating proteins.

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“…Other biomolecules and pathways most recently identified as potential therapeutic targets in NAFLD have been highlighted in many comprehensive review articles [ 246 , 247 , 248 , 249 ]. Of those, the sirtuins, a family of highly conserved histone and protein deacetylases, can be considered of special interest regarding future therapeutic concepts for NAFLD.…”

Section: Future Directionsmentioning

confidence: 99%

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

2022

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Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.

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Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis

Cited by 90 publications

References 310 publications

Circadian Regulation of Gene Expression and Metabolism in the Liver

Circadian Regulation of Gene Expression and Metabolism in the Liver

A Sixty-Year Research and Development of Trichosanthin, a Ribosome-Inactivating Protein

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

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