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Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis
Vascular endothelial growth factors (VEGF), Vascular endothelial growth factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological and pathological angiogenesis. In the last 20 years, many anti-angiogenic drugs have been developed based on VEGF/VEGFR system to treat diverse cancers and retinopathies, and new drugs with improved properties continue to emerge at a fast rate. They consist of different molecular structures and characteristics, which enable them to inhibit the interaction of VEGF/VEGFR, to inhibit the activity of VEGFR tyrosine kinase (TK), or to inhibit VEGFR downstream signaling. In this paper, we reviewed the development of marketed anti-angiogenic drugs involved in the VEGF/VEGFR axis, as well as some important drug candidates in clinical trials. We discuss their mode of action, their clinical benefits, and the current challenges that will need to be addressed by the next-generation of anti-angiogenic drugs. We focus on the molecular structures and characteristics of each drug, including those approved only in China.
Journal Article
Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
Chemotherapy drugs can cause pyroptotic cell death by activating caspase-3 to cleave gasdermin E, potentially contributing to their toxicity and adverse effects.
Chemotherapy-induced cell death
The negative side effects of chemotherapy are well documented but the mechanisms behind them are not always known. Feng Shao and colleagues show that chemotherapy drug treatment of gasdermin-E-expressing tumour cells results in a caspase-3-dependent switch from apoptotic to pyroptotic cell death. The majority of human tumours tested appeared to have lost expression of gasdermin E, whereas normal tissues express it. This observation has potential implications for the treatment of gasdermin-E-expressing tumours, and for chemotherapy-induced tissue damage.
Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide
1
,
2
,
3
. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity
4
,
5
,
6
,
7
,
8
,
9
. GSDMD belongs to a gasdermin family that shares the pore-forming domain
4
,
6
,
10
. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5)
11
, can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs.
Gsdme
−/−
(also known as
Dfna5
−/−
) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.
Journal Article
Of ants and dinosaurs
\"In a sunlit clearing in central Gondwana, on an otherwise ordinary day in the late Cretaceous, the seeds of Earth's first and greatest civilization were sown in the grisly aftermath of a Tyrannosaurus' lunch.Throughout the universe, intelligence is a rare and fragile commodity - a fleeting glimmer in the long night of cosmic history. That Earth should harbour not just one but two intelligent species at the same time, defies the odds. That these species, so unalike - and yet so complementary - should forge an alliance that kindled a civilization defies logic. But time is endless and everything comes to pass eventually...The alliance between ants and dinosaurs, was of course, based on dentistry. Yet from such humble beginnings came writing, mathematics, computers, fusion, antimatter and even space travel - a veritable Age of Wonder! But such magnificent industry comes at a price - a price paid first by Earth's biosphere, and then by all those dependent on it. And yet the Dinosaurs refused to heed the Ants' warning of impending ecological collapse, leaving the Ant Federation facing a single dilemma: destroy the dinosaurs, destroy a civilization... or perish alongside them?\"--Publisher.
Pore-forming activity and structural autoinhibition of the gasdermin family
Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and artificially transformed bacteria. Gasdermin-N moved to the plasma membrane during pyroptosis. Purified gasdermin-N efficiently lysed phosphoinositide/cardiolipin-containing liposomes and formed pores on membranes made of artificial or natural phospholipid mixtures. Most gasdermin pores had an inner diameter of 10–14 nm and contained 16 symmetric protomers. The crystal structure of GSDMA3 showed an autoinhibited two-domain architecture that is conserved in the gasdermin family. Structure-guided mutagenesis demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.
The N-terminal domains of gasdermin proteins cause pyroptotic cell death by oligomerizing to form membrane pores.
Mechanism of gasdermin-induced cell death
Pyroptosis, an inflammatory form of programmed cell death that is part of the innate immune response, is triggered by caspase-mediated cleavage of the inflammasome protein gasdermin D. This study examines the underlying molecular mechanism for gasdermin functioning in pyroptosis. Jingjin Ding
et al
. show that the N-terminal domains of gasdermins D, A and A3 are cytotoxic because they disrupt cell membranes in both mammalian cells and artificially transformed bacteria through the formation of membrane pores. The pores are mostly about 10–14 nm in diameter, with 16 symmetric protomers. Elsewhere in this issue of
Nature
, Judy Lieberman and colleagues present evidence that caspase 11 cleavage of gasdermin D, previously shown to mediate pyroptosis, induces oligomerization of the N-terminal domain and pore formation.
Journal Article
Mechanical properties and energy evolution law of marble under the coupled effects of chemical corrosion and dry-wet cycles
The main factors affecting the safety of underground structures are groundwater chemical corrosion and water level fluctuations. To investigate the mechanical properties of marble and the energy evolution pattern during the failure process under the coupled effects of chemical corrosion and dry-wet cycling, samples were subjected to 5, 10 and 20 cycles of dry-wet ageing in chemical solutions with pH values of 4, 7 and 10, respectively, followed by mechanical property testing. The energy evolution pattern during the failure process of the specimens was also studied. It was found that there is a strong correlation between number of dry-wet cycles and pH value of chemical solution. Chemical corrosion at the early stage of dry-wet cycling has the greatest effect on the deterioration of the rock. As the number of dry-wet cycles increases, the degree of corrosion in acidic solutions is most evident, with the uniaxial compressive strength and elastic modulus decreasing by 27.88% and 33.52% respectively, followed by alkaline solutions, and the degree of corrosion in neutral solutions is the lowest. In addition, dry-wet cycling and chemical corrosion lead to an increase in the internal pores of the rock samples and a decrease in the energy storage capacity. Nevertheless, the proportion of energy loss increases with the number of dry and wet cycles, with the proportion of energy loss in acidic media increasing from 35.61% to 41.63%, indicating that the plastic deformability of marble increases under the action of chemical corrosion and dry and wet cycles. The research results have certain guiding significance for the design, construction and maintenance reinforcement of underground structures under the conditions of chemical corrosion and dry-wet cycling.
Journal Article
World-class universities : towards a global common good and seeking national and institutional contributions
In the era marked by globalization and its profound impacts on individuals, societies, states and markets, world-class universities need to position themselves in the forefront of seeking conceptual and practical solutions to daunting challenges by paying greater attention to their roles in serving local society and contributing to global common goods. Based on the findings of the Seventh International Conference on World-Class Universities, World-Class Universities: Towards a Global Common Good and Seeking National and Institutional Contributions provides updated insights and debates on how world-class universities will contribute to the global common good and balance their global, national and local roles in doing so.
Book
Clinical outcomes after surgical treatment of severe congenital spinal deformity in skeletally mature patients: A minimum two-year follow-up study
Background
Severe congenital spinal deformity is a rare but challenging condition. This study aimed to investigate the clinical outcomes following posterior surgical correction of severe congenital spinal deformities.
Methods
Consecutive patients who underwent surgery for severe congenital spinal deformities between September 1, 2010 and August 31, 2022 were retrospectively included. Standardized data were collected, including baseline demographic characteristics, intraoperative variables, and postoperative outcomes. Scoliosis Research Society-22 revised (SRS-22r) scores and radiographic parameters were evaluated preoperatively and at least 2 years postoperatively. Additionally, SRS-22r scores were compared between patients with and without complications, and potential risk factors for surgical complications were analyzed.
Results
Fifty-seven patients (25 males and 32 females) were included. The mean patient age was 21.9 ± 10.6 years (range: 14–49 years), and the mean follow-up period was 10.2 ± 4.2 years (range: 2–12 years). The preoperative coronal and sagittal Cobb angle was 70.0° ± 34.7° and 96.5° ± 21.2°, respectively. After a follow-up period of at least 2 years, the average correction rates were 60.5% ± 20.4% for the coronal plane and 67.5 ± 16.5% for the sagittal plane. Forty-four complications occurred in 21 (36.8%) patients. Clinically, patients with complications reported significantly lower postoperative SRS-22r satisfaction scores (3.9 ± 0.8 vs. 4.3 ± 0.6,
p
= 0.034) than those without complications at least 2 years postoperatively. Risk factors for major complications included kyphotic deformity, greater sagittal curve magnitude, higher sagittal and total deformity angular ratios (DARs), and increased fusion levels. Stratified analyses showed that total DAR (T-DAR) > 27 was associated with a higher incidence of neurological complications (44.4 vs. 9.5%,
p
= 0.015).
Conclusions
Sustained spinal correction and favorable patient-reported outcomes for at least 2 years postoperatively were obtained in skeletally mature patients with severe congenital spinal deformities. However, the patients showed high rates of complications that were significantly associated with kyphotic deformity, larger sagittal curve magnitude, higher DAR values, and increased fusion levels.
Journal Article