Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells.

BACKGROUND: Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy. METHODS: We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo. RESULTS: Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery. CONCLUSIONS: Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.

Unraveling the molecular mechanism of collagen flexibility during physiological warmup using molecular dynamics simulation and machine learning.

Physiological warmup plays an important role in reducing the injury risk in different sports. In response to the associated temperature increase, the muscle and tendon soften and become easily stretched. In this study, we focused on type I collagen, the main component of the Achilles tendon, to unveil the molecular mechanism of collagen flexibility upon slight heating and to develop a model to predict the strain of collagen sequences. We used molecular dynamics approaches to simulate the molecular structures and mechanical behavior of the gap and overlap regions in type I collagen at 307 K, 310 K, and 313 K. The results showed that the molecular model in the overlap region is more sensitive to temperature increases. Upon increasing the temperature by 3 degrees Celsius, the end-to-end distance and Young's modulus of the overlap region decreased by 5% and 29.4%, respectively. The overlap region became more flexible than the gap region at higher temperatures. GAP-GPA and GNK-GSK triplets are critical for providing molecular flexibility upon heating. A machine learning model developed from the molecular dynamics simulation results showed good performance in predicting the strain of collagen sequences at a physiological warmup temperature. The strain-predictive model could be applied to future collagen designs to obtain desirable temperature-dependent mechanical properties.

Rapid Shifts of Peak Flowering Phenology in 12 Species under the Effects of Extreme Climate Events in Macao.

Plant phenology is sensitive to climate change; the timing of flowering has served as a visible indicator of plant phenology in numerous studies. The present study used phenological records from a manual monitoring program to characterize the flowering phenology of 12 species in Guia Hill, Macao. The mean peak flowering dates (PFDs) of these species ranged from March to September, 41.7% of which occurred in May. The earliest or latest PFDs of nine species occurred in 2013, a year with extremely heavy rain events in early spring. In addition, we found that, in the 5-year period, the monthly mean temperature or monthly precipitation in two periods, specifically 1) during November to December of the previous year and 2) during 0-2 months before the PFDs of each species, were significantly correlated with the PFD of eight species. The result showed that, even though complex species-specific responses to the characteristics of climate widely exist, most species in the present study responded to shifts in climate shifts in these two periods. In addition, some species were extraordinarily sensitive to extreme climate events. Precipitation was more effective in altering flowering date than temperature, especially among the late-flowering species in Guia Hill, Macao.