Isthmin-1 promotes growth and progression of colorectal cancer through the interaction with EGFR and YBX-1.

While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.

Cryptotanshinone protects skin cells from ultraviolet radiation-induced photoaging via its antioxidant effect and by reducing mitochondrial dysfunction and inhibiting apoptosis.

The integrity of skin tissue structure and function plays an important role in maintaining skin rejuvenation. Ultraviolet (UV) radiation is the main environmental factor that causes skin aging through photodamage of the skin tissue. Cryptotanshinone (CTS), an active ingredient mianly derived from the Salvia plants of Lamiaceae, has many pharmacological effects, such as anti-inflammatory, antioxidant, and anti-tumor effects. In this study, we showed that CTS could ameliorate the photodamage induced by UV radiation in epidermal keratinocytes (HaCaT) and dermal fibroblasts (HFF-1) when applied to the cells before exposure to the radiation, effectively delaying the aging of the cells. CTS exerted its antiaging effect by reducing the level of reactive oxygen species (ROS) in the cells, attenuating DNA damage, activating the nuclear factor E2-related factor 2 (Nrf2) signaling pathway, and reduced mitochondrial dysfunction as well as inhibiting apoptosis. Further, CTS could promote mitochondrial biosynthesis in skin cells by activating the AMP-activated protein kinase (AMPK)/sirtuin-1 (SIRT1)/peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) signaling pathway. These findings demonstrated the protective effects of CTS against UV radiation-induced skin photoaging and provided a theoretical and experimental basis for the application of CTS as an anti-photodamage and anti-aging agent for the skin.

Hrd1-mediated ACLY ubiquitination alleviate NAFLD in db/db mice.

BACKGROUND: The functions of Acly in regulating nonalcoholic fatty liver disease (NAFLD) have been identified; however, the dynamic control of Acly expression under the pathological state of metabolic disorders has not been fully elucidated. Previous studies reported an ubiquitin-proteasome-mediated degradation of Acly, but the mechanism is still largely unknown. METHODS: Co-IP-based mass spectrum (MS/MS) assays were performed in HepG2 and Hepa1-6 hepatocytes and mouse liver tissue. The protein-protein interaction and ubiquitin modification of Hrd1 on Acly were confirmed by co-IP based immuno-blotting. Acetyl-CoA levels and lipogenesis rates were determined. The roles of Hrd1 on NAFLD and insulin resistance were tested by adenovirus-mediated overexpression in db/db mice or in separated primary hepatocytes. RESULTS: Hrd1, a subunit of the endoplasmic reticulum-associated degradation (ERAD) complex, interacted with and ubiquitinated Acly, thereby reducing its protein level. Hrd1 suppressed the acetyl-CoA level and inhibited lipogenesis through an Acly-dependent pathway. The expression of hepatic Hrd1 was negatively associated with NAFLD, whereas overexpression of Hrd1 ameliorated hepatic steatosis and enhanced insulin sensitivity, both in db/db mice and in separated mouse primary hepatocytes. CONCLUSIONS: Our results suggest that Acly, a master enzyme that regulates lipogenesis, is degraded by Hrd1 through ubiquitin modification. The activation of Hrd1 in hepatocytes might therefore represent a strategic approach for NAFLD therapy.