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BACKGROUND: The manipulation of ferroptosis in cancer cells is a possible therapeutic technique that has been investigated for use in the treatment of cancer. Consequently, ferroptosis-inducing medications have recently received increased interest in cancer therapy. In this research, we assessed the anticancer efficacy of 14ß-hydroxy- 3ß-(ß-D-Glucopyranosyloxy)-5α-bufa-20,22-dienolide (HTB50-2), a natural product derived from the plant Helleborus thibetanus Franch, in Triple-Negative Breast Cancer (TNBC). Moreover, we also studied its potential mechanisms. METHODS: The biological effects of HTB50-2 in a series of breast cancer cell lines were analyzed using sulforhodamine B (SRB) and other methods. The migration ability was analyzed using three methods: wound healing assay, transwell assay, and Western blot. Meanwhile, the potential therapeutic value of HTB50-2 was evaluated in BALB/c mice by orthotopic transplantation. Transcriptome sequencing was conducted to explore the FOS-like antigen 2 (FOSL2) gene, and its role in ferroptosis was verified by Western blot and immunohistochemistry. The association of FOSL2 and ferroptosis-related genes was analyzed using NetworkAnalyst databases, and a TF-Gene interaction network was constructed. RESULTS: Ferroptosis was found to be induced in TNBC cells by HTB50-2. Furthermore, HTB50-2 inhibited tumor development by inducing ferroptosis in TNBC in vivo. Mechanistically, we demonstrated that a transcription factor FOSL2 mediated ferroptosis by HTB50-2. Additionally, it was found that Forkhead box C1 (FOXC1) was regulated by FOSL2 and correlated with ferroptosis. CONCLUSION: Our data suggest that HTB50-2 exerts its anti-cancer properties by ferroptosis via FOSL2/FOXC1 signaling pathway. Hence, HTB50-2 has an important application potential in the treatment of TNBC.

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Previous works on the flight dynamic stability of insects have focused on relatively large insects. Here, the longitudinal flight dynamic stability of two hovering miniature insects was computed. With the stability properties of the miniature insects from the present work and those of large insects from previous works, we studied the effects of insect size on the stability properties in the full range of insect sizes. The following results were obtained. Although the insects considered have a 30 000-fold difference in mass, their modal structure of flight stability is the same: an unstable oscillatory mode, a stable fast subsidence mode, and a stable slow subsidence mode; because of the unstable mode, the flight is unstable. An approximate analytical expression on the growth rate of the unstable mode as a function of insect mass (m) was derived. It shows that the time to double the initial values of disturbances (t_{d}) is proportional to the 0.17 power of the insect mass (m). That is, as m becomes smaller, t_{d} decreases (i.e., the instability becomes faster). This means that miniature insects need a faster nervous system to control the instability than larger insects. For example, the response time (represented by t_{d}) of a miniature insect, the gall midge (m≈0.05mg), needs to be faster by about 7 times than that of a larger insect, the hawk moth (m≈1600mg).

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Winged insects vary greatly in size, from tiny wasps (0.015 mg) to large moths (1.6 g). Previous studies on the power requirements of insect flight focused on relatively large insects; those of miniature insects remain relatively unknown. In this study the power requirements of a series of miniature insects were calculated, and changes with size across a range of insect sizes were investigated. Aerodynamic power was computed by numerically solving the Navier-Stokes equation, and inertial power was computed analytically. Comparison analysis was then conducted on the power requirements of miniature and large insects. Despite a 100,000-fold weight difference, the required power per unit insect mass, referred to as mass-specific power, was approximately equal for all the insects examined. This finding is explained as follows. Power is approximately proportional to the product of the wing speed and the wing drag per unit weight (i.e., "drag-to-lift ratio"). When insect size decreased, wing speed decreased (due to reduced wing-length), while wing drag increased (due to increased air-viscosity), resulting in an approximately unchanged mass-specific power. For large or small insects, flight power is derived from the same type of muscles (striated). Assuming that the mean power per unit muscle mass is the same under the same type of muscle, the above size/specific-power relation indicates that the ratio of flight-muscle mass to insect mass is the same for different sized insects.

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To investigate the way in which very small insects compensate for unilateral wing damage, we measured the wing kinematics of a very small insect, a phorid fly (Megaselia scalaris), with 16.7% wing area loss in the outer part of the left wing and a normal counterpart, and we computed the aerodynamic forces and power expenditures of the phorid flies. Our major findings are the following. The phorid fly compensates for unilateral wing damage by increasing the stroke amplitude and the deviation angle of the damaged wing (the large deviation angle gives the wing a deep U-shaped wing path), unlike the medium and large insects studied previously, which compensate for the unilateral wing damage mainly by increasing the stroke amplitude of the damaged wing. The increased stroke amplitude and the deep U-shaped wing path give the damaged wing a larger wing velocity during its flapping motion and a rapid downward acceleration in the beginning of the upstroke, which enable the damaged wing to generate the required vertical force for weight support. However, the larger wing velocity of the damaged wing also generates larger horizontal and side forces, increasing the resultant aerodynamic force of the damaged wing. Due to the larger aerodynamic force and the smaller wing area, the wing loading of the damaged wing is 25% larger than that of the wings of the normal phorid fly; this may greatly shorten the life of the damaged wing. Furthermore, because the damaged wing has much larger angular velocity and produces larger aerodynamic moment compared with the intact wing of the damaged phorid fly, the aerodynamic power consumed by the damaged wing is 38% larger than that by the intact wing, i.e., the energy distribution between the damaged and intact wings is highly asymmetrical; this may greatly increase the muscle wastage of the damaged side.

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Miniature insects fly at very low Reynolds number (Re); low Re means large viscous effect. If flapping as larger insects, sufficient vertical force cannot be produced. We measure the wing kinematics for miniature-insect species of different sizes and compute the aerodynamic forces. The planar upstroke commonly used by larger insects changes to a U-shaped upstroke, which becomes deeper as size or Re decreases. For relatively large miniature insects, the U-shaped upstroke produces a larger vertical force than a planar upstroke by having a larger wing velocity and, for very small ones, the deep U-shaped upstroke produces a large transient drag directed upwards, providing the required vertical force.

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