Several ATP-Binding Cassette (ABC) transporters, including ABCG1 and the related ABCG4, are essential regulators of cellular lipid homeostasis. ABCG1 is expressed ubiquitously and is functional in the context of atherosclerosis. However, ABCG4 is expressed almost exclusively in brain and has been linked to Alzheimer’s disease (AD). These transporters are highly regulated post-translationally by E3 ubiquitin ligases, with the ligase NEDD4-1 (Neural precursor cell-expressed developmentally downregulated gene 4) implicated in their protein stability. In this study, we investigated interacting partners of ABCG1 using peptide-mass spectrometry and identified the potential adaptor protein, Alix (apoptosis-linked gene 2-interacting protein X). In this paper, we hypothesized and investigated whether Alix could facilitate the interaction between NEDD4-1 and the ABC transporters. We showed that Alix and NEDD4-1 proteins were co-expressed in several commonly used cell lines. Knockdown of Alix in cells overexpressing ABCG1 or ABCG4 increased transporter protein expression while co-immunoprecipitation experiments showed interaction between NEDD4-1, Alix, and ABC transporters. In summary, we provide evidence that Alix serves as a co-factor for the interaction between the E3-ubiquitin ligase NEDD4-1 and the ABC transporter targets, ABCG1 and ABCG4.

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Background: Isorhamnetin is a flavonoid that is found in medical plants. Several studies showed that isorhamnetin has anti-inflammatory and anti-obesity effects. This study aims to investigate the anti-diabetic effects of isorhamnetin in a high-fat diet and Streptozotocin-(HFD/STZ)-induced mice model of type 2 diabetes. Materials and Methods: Mice were fed with HFD followed by two consecutive low doses of STZ (40 mg/kg). HFD/STZ diabetic mice were treated orally with isorhamnetin (10 mg/kg) or (200 mg/kg) metformin for 10 days before sacrificing the mice and collecting plasma and soleus muscle for further analysis. Results: Isorhamnetin reduced the elevated levels of serum glucose compared to the vehicle control group (p < 0.001). Isorhamnetin abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control mice (p < 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in diabetic mice treated with isorhamnetin compared to the vehicle controls. Fasting glucose level was significantly lower in diabetic mice treated with isorhamnetin during the intraperitoneal glucose tolerance test (IPGTT) (p < 0.001). The skeletal muscle protein contents of GLUT4 and p-AMPK-α were upregulated following treatment with isorhamnetin (p > 0.01). LDL, triglyceride, and cholesterol were reduced in diabetic mice treated with isorhamnetin compared to vehicle control (p < 0.001). Isorhamnetin reduced MDA, and IL-6 levels (p < 0.001), increased GSH levels (p < 0.001), and reduced GSSG levels (p < 0.05) in diabetic mice compared to vehicle control. Conclusions: Isorhamnetin ameliorates insulin resistance, oxidative stress, and inflammation. Isorhamnetin could represent a promising therapeutic agent to treat T2D.

The term ‘cancer’ refers to >100 disorders that progressively manifest over time and are characterized by uncontrolled cell division. Although malignant growth can occur in virtually any human tissue, the underlying mechanisms underlying all forms of cancer are consistent. The International Agency for Research on Cancer's annual GLOBOCAN 2020 report provided an update on the global cancer incidence and mortality. Excluding non-melanoma skin cancer, the report predicts that there will be 19.3 million new cancer cases and >10 million cancer-related fatalities in 2023. Lung, prostate, and colon cancers are the most prevalent and lethal cancers in males. It was recognized that post-translational modifications (PTMs) of proteins are necessary for almost all cellular biological processes, as well as in cancer development and metastasis to other bodily organs. Thus, PTMs have a considerable impact on how proteins behave. Various PTMs may have harmful roles by affecting the hallmarks of cancer, metabolism and the regulation of the tumor microenvironment. PTMs and genetic changes/mutations are essential in carcinogenesis and cancer development. A pivotal PTM mechanism is protein ubiquitination. Of note, the rate-limiting stage of the protein ubiquitination cascade is hypothesized to be E3-ligase-mediated ubiquitination. Numerous studies revealed that the neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) E3 ligase is among the E3 ubiquitin ligases that have essential roles in cellular processes. It regulates protein degradation and substrate ubiquitination. In addition, it has been shown that NEDD4 primarily functions as an oncogene in various malignancies but can also act as a tumor suppressor in certain types of tumor. In the present review, the roles of NEDD4 as an anticancer protein in various high-incidence male malignancies and the significance of NEDD4 as a potential cancer therapeutic target are discussed. In addition, the targeting of NEDD4 as a therapeutic strategy for the treatment of human malignancies is explored.

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