Role of Flavohemoglobins in the Development and Aflatoxin Biosynthesis of <i>Aspergillus flavus</i>

Aspergillus flavus is notorious for contaminating food with its secondary metabolite—highly carcinogenic aflatoxins. In this study, we found that exogenous nitric oxide (NO) donor could influence aflatoxin production in A. flavus. Flavohemoglobins (FHbs) are vital functional units in maintaining nitric oxide (NO) homeostasis and are crucial for normal cell function. To investigate whether endogenous NO changes affect aflatoxin biosynthesis, two FHbs, FHbA and FHbB, were identified in this study. FHbA was confirmed as the main protein to maintain NO homeostasis, as its absence led to a significant increase in intracellular NO levels and heightened sensitivity to SNP stress. Dramatically, FHbA deletion retarded aflatoxin production. In addition, FHbA played important roles in mycelial growth, conidial germination, and sclerotial development, and response to oxidative stress and high-temperature stress. Although FHbB did not significantly impact the cellular NO level, it was also involved in sclerotial development, aflatoxin synthesis, and stress response. Our findings provide a new perspective for studying the regulatory mechanism of the development and secondary mechanism in A. flavus

Real-time traffic signal optimization model based on average delay time per person

Real-time traffic signal control is very important for relieving urban traffic congestion. Many existing traffic control models were formulated using optimization approach, with the objective functions of minimizing vehicle delay time. To improve people’s trip efficiency, this article aims to minimize delay time per person. Based on the time-varying traffic flow data at intersections, the article first fits curves of accumulative arrival and departure vehicles, as well as the corresponding functions. Moreover, this article transfers vehicle delay time to personal delay time using average passenger load of cars and buses, employs such time as the objective function, and proposes a signal timing optimization model for intersections to achieve real-time signal parameters, including cycle length and green time. This research further implements a case study based on practical data collected at an intersection in Beijing, China. The average delay time per person and queue length are employed as evaluation indices to show the performances of the model. The results show that the proposed methodology is capable of improving traffic efficiency and is very effective for real-world applications

Health Effects of Peptides Extracted from Deer Antler

Deer antler is widely used as a nutraceutical in Asian countries. In the past decades, deer antler peptides (DAPs) have received considerable attention because of their various biological properties such as antioxidant, anti-inflammatory, anti-bone damage, anti-neurological disease, anti-tumor and immunomodulatory properties. This review describes the production methods of DAPs and the recent progress of research on DAPs, focusing on the physiological functions and their regulatory mechanisms

Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation

The mechanistic target of the rapamycin (mTOR) pathway, which participates in the regulation of cellular growth and metabolism, is aberrantly regulated in various cancer types. The mTOR complex 2 (mTORC2), which consists of the core components mTOR, Rictor, mSin1, and mLST8, primarily responds to growth signals. However, the coordination between mTORC2 assembly and activity remains poorly understood. Keap1, a major sensor of oxidative stress in cells, functions as a substrate adaptor for Cullin 3-RING E3 ubiquitin ligase (CRL3) to promote proteasomal degradation of NF-E2-related factor 2 (NRF2), which is a transcription factor that protects cells against oxidative and electrophilic stress. In the present study, we demonstrate that Keap1 binds to mLST8 via a conserved ETGE motif. The CRL3Keap1 ubiquitin ligase complex promotes non-degradative ubiquitination of mLST8, thus reducing mTORC2 complex integrity and mTORC2-AKT activation. However, this effect can be prevented by oxidative/electrophilic stresses and growth factor signaling-induced reactive oxygen species (ROS) burst. Cancer-derived Keap1 or mLST8 mutations disrupt the Keap1-mLST8 interaction and allow mLST8 to evade Keap1-mediated ubiquitination, thereby enhancing mTORC2-AKT activation and promoting cell malignancy and remodeling cell metabolism. Our findings provide new insights into the molecular mechanisms of Keap1/mLST8 mutation-driven tumorigenesis by promoting mTORC2-AKT activation, which is independent of the canonical NRF2 pathway

SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF

Abstract Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway

Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex

Abstract Signal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor