Ferroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis‐inducing agents have great potential as new antitumor candidates. Here, we report a IrIII complex (Ir1) ...containing a ferrocene‐modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton‐like reaction, produce hydroxyl radicals, induce lipid peroxidation, down‐regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis‐inducing capabilities for effective cancer immunotherapy.
Ferroptosis‐inducing agents have potential as antitumor candidates. A ferrocene‐modified IrIII complex with Fenton‐like catalytic activity is used to disturb the cellular redox balance, which leads to lipid peroxidation and ferroptosis of cancer cells. Ferroptosis induced by the IrIII complex causes immunogenic cell death (ICD) of cancer cell in vitro, which enhances cancer immune response in vivo.
Activation of the cyclic GMP‐AMP synthase‐stimulator of the interferon gene (cGAS‐STING) pathway is a potent anticancer immunotherapeutic strategy, and the induction of pyroptosis is a feasible way ...to stimulate the anticancer immune responses. Herein, two PtII complexes (Pt1 and Pt2) were designed as photoactivators of the cGAS‐STING pathway. In response to light irradiation, Pt1 and Pt2 could damage mitochondrial/nuclear DNA and the nuclear envelope to activate the cGAS‐STING pathway, and concurrently induce pyroptosis in cancer cells, which evoked an intense anticancer immune response in vitro and in vivo. Overall, we present the first photoactivator of the cGAS‐STING pathway, which may provide an innovative design strategy for anticancer immunotherapy.
The first small molecule that can activate cGAS‐STING in a photocontrollable way is reported. Upon irradiation, Pt1 and Pt2 can damage mitochondrial DNA, the nuclear envelope and nuclear DNA sequentially, which effectively releases DNA into cytoplasm to activate the cGAS‐STING pathway both in vitro and in vivo.
Photoimmunotherapy is attractive for cancer treatment due to its spatial controllability and sustained responses. This work presents a ferrocene‐containing Ir(III) photosensitizer (IrFc1) that can ...bind with transferrin and be transported into triple‐negative breast cancer (TNBC) cells via a transferrin receptor‐mediated pathway. When the ferrocene in IrFc1 is oxidized by reactive oxygen species, its capability to photosensitize both type I (electron transfer) and type II (energy transfer) pathways is activated through a self‐amplifying process. Upon irradiation, IrFc1 induces the generation of lipid oxidation to cause ferroptosis in TNBC cells, which promotes immunogenic cell death (ICD) under both normoxia and hypoxia. In vivo, IrFc1 treatment elicits a CD8+ T‐cell response, which activates ICD in TNBC resulting in enhanced anticancer immunity. In summary, this work reports a small molecule‐based photosensitizer with enhanced cancer immunotherapeutic properties by eliciting ferroptosis through a self‐amplifying process.
A Ir(III)‐based photosensitizer with self‐amplifying properties is reported in this work. IrFc1 can cause lipid oxidation leading to ferroptosis in transferrin receptor overexpressing cancer cells, which envokes intense anticaner immnuoenhancement both in vitro and in vivo.
Blood–brain barrier (BBB) dysfunction has been implicated in Alzheimer's disease (AD) and is closely linked to the release of proinflammatory cytokines in brain capillary endothelial cells. We have ...previously reported that lychee seed polyphenols (LSP) exerted anti‐neuroinflammatory effect. In this study, we aimed to explore the protective effect of LSP on BBB integrity. The monolayer permeability of bEnd.3 cells, and the mRNA level and protein expression of tight junction proteins (TJs), including Claudin 5, Occludin, and ZO‐1, were examined. In addition, the inhibition of Aβ(25–35)‐induced NLRP3 inflammasome activation, and the autophagy induced by LSP were investigated by detecting the expression of NLRP3, caspase‐1, ASC, LC3, AMPK, mTOR, and ULK1. Furthermore, the cognitive function and the expression of TJs, NLRP3, caspase‐1, IL‐1β, and p62 were determined in APP/PS1 mice. The results showed that LSP significantly decreased the monolayer permeability and inhibited the NLRP3 inflammasome in Aβ(25–35)‐induced bEnd3 cells. In addition, LSP induced autophagy via the AMPK/mTOR/ULK1 pathway in bEnd.3 cells, and improved the spatial learning and memory function, increased the TJs expression, and inhibited the expression of NLRP3, caspase‐1, IL‐1β, and p62 in APP/PS1 mice. Therefore, LSP protects BBB integrity in AD through inhibiting Aβ(25–35)‐induced NLRP3 inflammasome activation via the AMPK/mTOR/ULK1‐mediated autophagy.
Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on ...epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain–Barré syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivatives for SAR analysis. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 μM and displayed EC50 values of 1.52 μM and 1.91 μM against DENV and ZIKV infections of human neuronal BE(2)C cells, respectively. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.
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•A herb-based formula delivers positive clinical outcomes on COVID-19 patients.•The formula inhibits SARS-CoV-2 pathogenesis in anti-viral & -inflammatory assays.•Real-world-evidence ...offers insights to inform drug development.•Bed-to-bench approach shortens the time required for finding effective therapeutics.
COVID-19 is a global pandemic, with over 50 million confirmed cases and 1.2 million deaths as of November 11, 2020. No therapies or vaccines so far are recommended to treat or prevent the new coronavirus. A novel traditional Chinese medicine formula, Taiwan Chingguan Yihau (NRICM101), has been administered to patients with COVID-19 in Taiwan since April 2020. Its clinical outcomes and pharmacology have been evaluated. Among 33 patients with confirmed COVID-19 admitted in two medical centers, those (n = 12) who were older, sicker, with more co-existing conditions and showing no improvement after 21 days of hospitalization were given NRICM101. They achieved 3 consecutive negative results within a median of 9 days and reported no adverse events. Pharmacological assays demonstrated the effects of the formula in inhibiting the spike protein/ACE2 interaction, 3CL protease activity, viral plaque formation, and production of cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. This bedside-to-bench study suggests that NRICM101 may disrupt disease progression through its antiviral and anti-inflammatory properties, offering promise as a multi-target agent for the prevention and treatment of COVID-19.
The COVID-19 pandemic continues to pose a significant worldwide threat to human health, as emerging SARS-CoV-2 Omicron variants exhibit resistance to therapeutic antibodies and the ability to evade ...vaccination-induced antibodies. Here, we aimed to identify human antibodies (hAbs) from convalescent patients that are potent and broadly neutralizing toward Omicron sublineages.
Using a single B-cell cloning approach, we isolated BA.5 specific human antibodies. We further examined the neutralizing activities of the most promising neutralizing hAbs toward different variants of concern (VOCs) with pseudotyped virus.
Sixteen hAbs showed strong neutralizing activities against Omicron BA.5 with low IC
values (IC
< 20 ng/mL). Among four of the most promising neutralizing hAbs (RBD-hAb-B22, -B23, -B25 and -B34), RBD-hAb-B22 exhibited the most potent and broad neutralization profiles across Omicron subvariant pseudoviruses, with low IC
values (7.7-41.6 ng/mL) and a low PRNT
value (3.8 ng/mL) in plaque assays with authentic BA.5. It also showed potent therapeutic effects in BA.5-infected K18-hACE2 mice.
Thus, our efficient screening of BA.5-specific neutralizing hAbs from breakthrough infectious convalescent donors successfully yielded hAbs with potent therapeutic potential against multiple SARS-CoV-2 variants.
Background
Few studies assessed myocardial inflammation using Cardiovascular Magnetic Resonance Imaging in Kawasaki disease (KD) patients.
Purpose
To quantify myocardial edema in KD patients using T2 ...mapping and explore the independent predictors of T2 values.
Study Type
Prospective.
Subjects
Ninety KD patients including 40 in acute phase (26 males, 65.0%) and 50 in chronic phase (34 males, 68.0%). Thirty‐one healthy volunteers (21 males, 70.0%).
Field Strength/Sequence
3.0 T T2‐weighted Turbo Spin Echo‐Short Time of Inversion Recovery sequence, True fast imaging with steady precession flash sequence and fast low‐angle shot 3D spoiled gradient echo sequence.
Assessment
T2 values were compared among KD groups and controls.
Statistical Test
Student's t test and Fisher's exact test; One‐way analysis of variance; Pearson correlation analysis; Receiver operating curve analysis; Multivariable linear regression.
Results
Global T2 value of KD patients in acute phase was the highest, followed by those of chronic‐phase patients and controls (38.83 ± 2.41 msec vs. 37.55 ± 2.28 msec vs. 36.05 ± 1.64 msec). Regional T2 values showed a same trend. There were no significant differences in global and regional T2 values between KD patients with and without coronary artery (CA) dilation, no matter in acute or chronic phase (all KD patients: P = 0.51, 0.51, 0.53, 0.72; acute KD: P = 0.61, 0.37, 0.33, 0.83; chronic KD: P = 0.65, 0.79, 0.62, 0.79). No significant difference was observed in global T2 values between KD patients with Z score > 5.0 and 2.0 < Z score ≤ 5.0 (P = 0.65). Multivariate analysis demonstrated that stage of disease (β = −0.123) and heart rate (β = 0.280) were independently associated with global T2 values.
Data Conclusion
The degree of myocardial edema was more severe in acute‐phase than in chronic‐phase KD patients. Myocardial edema persists in patients regardless of the existence or degree of CA dilation.
Evidence Level
2
Technical Efficacy
Stage 2
The risks attributed to drug-herb interactions, even when known, are often ignored or underestimated, especially for those involving anti-clotting drugs and Chinese medicines. The aim of this study ...was to structurally search and evaluate the existing evidence-based data associated with potential drug interactions between anticoagulant/antiplatelet drugs and Chinese herbal medicines (CHMs) and evaluate the documented mechanisms, consequences, and/or severity of interactions.
Information related to anticoagulant/antiplatelet drug-CHM interactions was retrieved from eight interaction-based textbooks, four web resources and available primary biomedical literature. The primary literature searches were conducted in English and/or Chinese from January 2000 through December 2011 using the secondary databases (e.g., PubMed, Airiti Library, China Journal full-text database). The search terms included the corresponding medical subject headings and key words. Herbs or natural products not used as a single entity CHM or in Chinese Medicinal Prescriptions were excluded from further review. The corresponding mechanisms and severity ratings of interactions were retrieved using MicroMedex®, Lexicomp® and Natural Medicines Comprehensive Database®. Finally, we found 90 single entity CHMs contributed to 306 documented drug-CHM interactions. A total of 194 (63.4%) interactions were verified for its evidence describing possible mechanisms and severity. Of them, 155 interactions (79.9%) were attributable to pharmacodynamic interactions, and almost all were rated as moderate to severe interactions. The major consequences of these interactions were increased bleeding risks due to the additive anticoagulant or antiplatelet effects of the CHMs, specifically danshen, dong quai, ginger, ginkgo, licorice, and turmeric.
Conventional anticoagulants and antiplatelet drugs were documented to have harmful interactions with some commonly used single entity CHMs. For those patients who are taking conventional anti-clotting medications with CHMs for cardiovascular or cerebrovascular diseases, the potential risks of increased bleeding due to drug-CHM interactions should not be ignored.
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