A dual recognition-based strategy employing Ni-modified metal-organic framework for in situ screening of SIRT1 inhibitors from Chinese herbs.

Sirtuin1 (SIRT1), an NAD+-dependent histone deacetylase, plays a crucial role in regulating molecular signaling pathways. Recently, inhibition of SIRT1 rather than its activation shows the therapeutic potential for central nervous system disorder, however, the discovered SIRT1 inhibitors remains limited. In this work, a dual recognition-based strategy was developed to screen SIRT1 inhibitors from natural resources in situ. This approach utilized a Ni-modified metal-organic framework (Ni@Tyr@UiO-66-NH2) along with cell lysate containing an engineered His-tagged SIRT1 protein, eliminating the need for purified proteins, pure compounds, and protein immobilization. The high-performance Ni@Tyr@UiO-66-NH2 was synthesized by modifying the surface of UiO-66-NH2 with Ni2+ ions to specifically capture His-tagged SIRT1 while persevering its enzyme activity. By employing dual recognition, in which Ni@Tyr@UiO-66-NH2 recognized SIRT1 and SIRT1 recognized its ligands, the process of identifying SIRT1 inhibitors from complex matrix was vastly streamlined. The developed method allowed the efficient discovery of 16 natural SIRT1 inhibitors from Chinese herbs. Among them, 6 compounds were fully characterized, and suffruticosol A was found to have an excellent IC50 value of 0.95 ±â€¯0.12 µM. Overall, an innovative dual recognition-based strategy was proposed to efficiently identify SIRT1 inhibitors in this study, offering scientific clues for the development of drugs targeting CNS disorders.

Physalin H ameliorates LPS-induced acute lung injury via KEAP1/NRF2 axis.

Physalin H (PH), a withanolide isolated from Physalisangulata L. has been reported to have anti-inflammatory effect. However, its impact on acute lung injury (ALI) remains unexplored. In this study, we observed that PH significantly alleviated inflammation in LPS-stimulated macrophages by suppressing the release of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and down-regulating the expression of the inflammation-related genes. RNA sequencing analysis revealed a significant up-regulation of the NRF2 pathway by PH. Further investigation elucidated that PH attenuated the ubiquitination of NRF2 by impeding the interaction between NRF2 and KEAP1, thereby facilitating NRF2 nuclear translocation and up-regulating the expression of target genes. Consequently, it regulated redox system and exerted anti-inflammatory effect. Consistently, PH also significantly alleviated pathological damage and inflammation in LPS-induced ALI mice model, which could be reversed by administration of an NRF2 inhibitor. Collectively, these results suggest that PH ameliorates ALI by activating the KEAP1/NRF2 pathway. These findings provide a foundation for further development of pH as a new anti-inflammatory agent for ALI therapy.

New indolequinazoline alkaloids from the fruits of Tetradium ruticarpum.

In this research, five new indolequinazoline alkaloids (1-5), along with six known indolequinazoline alkaloids (6-11) were obtained from the fruits of Tetradium ruticarpum. Their structures were elucidated through comprehensive spectroscopic data of 1D and 2D NMR, HRESIMS and ECD spectra. Additionally, all isolates were assayed for their SIRT1 inhibitory activities in vitro and compounds 2, 7, 10 and 11 exhibited activities with IC50 values ranged from 43.16 to 118.35 µM.

Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors.

The coexistence of ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of glutathione peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3'-oxime (IO) (CDK inhibitor). Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC50 = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC50 = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant cancer therapy.

Intense and Superflat White Laser with 700-nm 3-dB Bandwidth and 1-mJ Pulse Energy Enabling Single-Shot Subpicosecond Pulse Laser Spectroscopy.

An optical spectrometer is a basic spectral instrument that probes microscopic physical and chemical properties of macroscopic objects but generally suffers from difficulty in broadband time-resolved measurement. In this work, we report the creation of ultrabroadband white-light laser with a 3-dB bandwidth covering 385 to 1,080 nm, pulse energy of 1.07 mJ, and pulse duration of several hundred femtoseconds by passing 3-mJ pulse energy, 50-fs pulse duration Ti:Sapphire pulse laser through a cascaded fused silica plate and chirped periodically poled lithium niobate crystal. We utilize this unprecedented superflat, ultrabroadband, and intense femtosecond laser light source to build a single-shot (i.e., single-pulse) subpicosecond pulse laser ultraviolet-visible-near-infrared spectrometer and successfully measure various atomic and molecular absorption spectra. The single-shot ultrafast spectrometer may open up a frontier to monitor simultaneously the ultrafast dynamics of multiple physical and chemical processes in various microscopic systems.

Intense ultraviolet-visible-infrared full-spectrum laser.

A high-brightness ultrabroadband supercontinuum white laser is desirable for various fields of modern science. Here, we present an intense ultraviolet-visible-infrared full-spectrum femtosecond laser source (with 300-5000 nm 25 dB bandwidth) with 0.54 mJ per pulse. The laser is obtained by sending a 3.9 µm, 3.3 mJ mid-infrared pump pulse into a cascaded architecture of gas-filled hollow-core fiber, a bare lithium niobate crystal plate, and a specially designed chirped periodically poled lithium niobate crystal, under the synergic action of second and third order nonlinearities such as high harmonic generation and self-phase modulation. This full-spectrum femtosecond laser source can provide a revolutionary tool for optical spectroscopy and find potential applications in physics, chemistry, biology, material science, industrial processing, and environment monitoring.

Intense Two-Octave Ultraviolet-Visible-Infrared Supercontinuum Laser via High-Efficiency One-Octave Second-Harmonic Generation.

Intense ultrabroadband laser source of high pulse energy has attracted more and more attention in physics, chemistry, biology, material science, and other disciplines. We report design and realization of a chirped periodically poled lithium niobate nonlinear crystal that supports ultrabroadband second-harmonic generation covering 350-850 nm by implementing simultaneously up to 12 orders of quasiphase matching against ultrabroadband pump laser covering 700-1700 nm with an average high conversion efficiency of about 25.8%. We obtain a flat supercontinuum spectrum with a 10 dB bandwidth covering more than one octave (about 375-1200 nm) and 20 dB bandwidth covering more than two octaves (about 350-1500 nm) in the ultraviolet-visible-infrared regime and having intense energy as 0.17 mJ per pulse through synergic action of second-order and third-order nonlinearity under pump of 0.48 mJ per pulse Ti:sapphire femtosecond laser. This scheme would provide a promising method for the construction of supercontinuum laser source with extremely broad bandwidth, large pulse energy, and high peak power for a variety of basic science and high technology applications.

White Laser Realized via Synergic Second- and Third-Order Nonlinearities.

White laser with balanced performance of broad bandwidth, high average and peak power, large pulse energy, high spatial and temporal coherence, controllable spectrum profile, and overall chroma are highly desirable in various fields of modern science. Here, for the first time, we report an innovative scheme of harnessing the synergic action of both the second-order nonlinearity (2nd-NL) and the third-order nonlinearity (3rd-NL) in a single chirped periodically poled lithium niobate (CPPLN) nonlinear photonic crystal driven by a high-peak-power near-infrared (NIR) (central wavelength~1400 nm, energy~100 µJ per pulse) femtosecond pump laser to produce visible to near infrared (vis-NIR, 400-900 nm) supercontinuum white laser. The CPPLN involves a series of reciprocal-lattice bands that can be exploited to support quasiphase matching for simultaneous broadband second- and third-harmonic generations (SHG and THG) with considerable conversion efficiency. Due to the remarkable 3rd-NL which is due to the high energy density of the pump, SHG and THG laser pulses will induce significant spectral broadening in them and eventually generate bright vis-NIR white laser with high conversion efficiency up to 30%. Moreover, the spectral profile and overall chroma of output white laser can be widely modulated by adjusting the pump laser intensity, wavelength, and polarization. Our work indicates that one can deeply engineer the synergic and collective action of 2nd-NL and 3rd-NL in nonlinear crystals to accomplish high peak power, ultrabroadband vis-NIR white laser and hopefully realize the even greater but much more challenging dream of ultraviolet-visible-infrared full-spectrum laser.