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A Sirna-Based Targeted Therapy For Treating Metabolic Dysfunction-Associated Steatotic Liver Disease: A Precision Medicine Approach
No full textBackground: Metabolic dysfunction-associated steatotic liver disease (MASLD) now affects 30% of the global population. Without intervention, patients with liver steatosis may further develop inflammation and fibrosis, i.e., metabolic-associated steatohepatitis (MASH). Currently, there is only one FDA-approved drug in the treatment of MASH, with no drug targeting the causal factors of MASLD/MASH. Among several genes identified by genome-wide associations studies (GWAS), the role of patatin-like phospholipase domain containing 3 (PNPLA3) gene in MASLD and MASH is well established, with its single nucleotide polymorphism I148M being the single largest genetic risk factor for MASLD and MASH. The increased risk for MASLD attributed to the PNPLA3-148M allele relies on overrepresentation of the PNPLA3-148M isoform. The aim of our study is to validate a liver-specific, oligonucleotide-based therapeutic specifically targeting the PNPLA3-148M isoform as a potential treatment strategy for MASLD and MASH. To this end, both a prototype siRNA and antisense oligo (ASO) were to examine for their efficacy and safety profiles in vivo.Methods: Our group has designed, screened, and patented a few siRNAs that demonstrated highly selective knock-down activity to down-regulate the expression of PNPLA3-148M isoform in hepatocytes. The Liu lab have also successfully developed a transgenic human PNPLA3 mouse model carrying the human PNPLA3-148I or PNPLA3-148M isoform. We examined the effectiveness and safety profiles of our prototype siRNA and ASO in our transgenic mice (n=8 per genotype group) fed with a high sucrose diet for 15 weeks. The two candidates and scrambled control siRNA were conjugated with N-acetylgalactosamine (GalNAc) and subcutaneously (s.c.) injected at week 9 and continued for 6 weeks. The pharmacological and toxicological profiles were assessed. Results: Among mice received the scramble control siRNA, the transgenic PNPLA3-148M (Tg- PNPLA3-148M) mice exhibited significantly increased hepatic steatosis and triglycerides (TG) content compared to the transgenic PNPLA3-148I (Tg-PNPLA3-148I) mice or the non-transgenic wildtype (WT) mice. The prototype siRNA injection significantly reduced hepatic steatosis and hepatic TG content in the Tg-PNPLA3-148M group to the levels similar to that in the Tg-PNPLA3- 148I and WT groups. The ASO-injected Tg-PNPLA3-148M mice exhibited a trend of decreased hepatosteatosis and TG content but was not statistically significant. Both the siRNA and ASO treatment significantly reduced hepatic expression level of PNPLA3-148M but not PNPLA3-148I. The injection of siRNA was revealed to be safe based on the comprehensive evaluation of the physiological data (body weight, fat/lean composition, serum levels of glucose, TG, total cholesterol, ALT, AST, bilirubin, cytokines and chemokines, hepatic transcriptome, as well as hepatic and serum metabolomes) collected throughout the entire trial. The reduced hepatosteatosis and TG content in the siRNA injected Tg-PNPLA3-148M mice was associated with a metabolic reprograming e.g. increased fatty acids β-oxidation, increased cholesterol-bile acids conversion, etc. Also, the knockdown of PNPLA3-148M partially reversed the expression changes of a group of inflammatory genes altered by the phenotype. Although the RNA-seq data reveals that the prototype siRNA might have an off-target knockdown effect on the transcripts of Abgl5 gene in the mouse, it was further confirmed with no knockdown effect on the human ABGL5. In contrast, the ASO has a limited pharmacological effect and is revealed with concerns on its safety profile that is more likely associated with ASO itself regardless of the genotype. The ASO injection induced liver injuries as indicated by the elevated level of liver function markers AST and ALT, as well as the hepatic fibrosis marker αSMA. Moreover, it might be associated with the jeopardized mitochondrial function, which leads to the blockage of fatty acid oxidation and accumulated acylcarnitine. There is also evidence demonstrating over-breakdown of lean mass along with elevated serum creatinine level, suggesting a potential harm to the kidney function. Conclusion: Our PNPLA3-148M targeting siRNA demonstrated promising specificity, efficacy, and safety in treating MASLD, warranting further development for MASH treatment
Star Wars and Gender in 1980s America
No full textThis research paper examines the role of gender in the franchise Star Wars. With the first installment of the trilogy released in 1977, many expected this film would turn out like many before. However, the world that George Lucas created was an instant hit and continues to be today. This paper focuses on how the franchise was set apart from other science fiction films based on a defiance of typical gender roles that were prevalent in the late twentieth century, specifically focusing on the two leading roles, Luke Skywalker and Leia Organa, and employing analysis of the films, cast interviews, promotional posters, and several secondary sources
Piracy and Patriotism: The Forces of Resistance in Viet Nam’s Video Game Industry During the 2000s to the Early 2010s Through the Case of 7554
No full textThis paper examines cultural resistance in Viet Nam’s video game industry through the case of 7554, the country’s first indie, first-person shooter. Piracy, normalized by economic hardship and distrust of capitalist systems, both enabled access and undermined domestic creativity. Viet Nam’s shifting intellectual property laws reflected broader balancing between socialist sovereignty and global economic integration. By situating 7554 within Viet Nam’s historical context from colonial resistance to socio-economic reforms, this study argues that piracy functioned not only as economic necessity but also as a decolonial practice shaping cultural sovereignty
Supporting the Next Generation of Developmental Scientists
No full textThe purpose of this issue is to encourage and support the next generation of developmental scientists. The following pages contain original reports of empirical research by aspiring young undergraduate students working closely with their faculty mentors. Most of the studies reported here were conducted as undergraduate thesis projects. All articles in this issue underwent the same submission and review procedures (e.g., revision and resubmission following blind peer review) as the journal’s regular submissions
Crowd Choreographies: Spike Lee’s BlacKkKlansman (2018) and the Politics of (Post)Cinematic Assembly
No full textChronic Illness Education 2025: Resources to Improve Incidence of Atherosclerotic Cardiovascular Disease
No full textChronic Illness Education 2025: Addressing Adolescent Depression Through Community and Systems-Based Care
Get PDFChronic Illness Education 2025: Lifestyle Modification Resources for Cardiovascular Disease Risk Reduction
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On Inventions of a Present: The Novel in Its Crisis of Globalization
Get PDFA review of Inventions of a Present: The Novel in Its Crisis of Globalization by Fredric Jameson. London: Verso, 2024. Pp. 272. $34.95, hardcover