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Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tamarixetin, a natural dietary flavone, exhibits remarkable potential for the treatment of ischemic stroke. The present article aimed to explore the impact of tamarixetin on ischemic stroke and elucidate the underlying mechanisms. Effects of tamarixetin on ischemic stroke were evaluated in rats using the middle cerebral artery occlusion and reperfusion (MCAO/R) model, by assessing the neurological deficit scores, brain water content, brain infraction, and neuronal damage. The levels of proinflammatory cytokines, NLRP3 inflammasome activation, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were measured in MCAO/R rats and lipopolysaccharide-stimulated cells. Tamarixetin administration improved the neurological dysfunction and neuronal loss in MCAO/R rats. In addition, tamarixetin reduced microglial hyperactivation and proinflammatory cytokines expression in vivo and in vitro. Tamarixetin attenuated NF-κB p65 phosphorylation and promoter activity, reduced NLRP3 expression and caspase-1 cleavage, and downregulated IL-1β and IL-18 secretions to suppress NLRP3 inflammasome activation. The levels of superoxide anion, hydrogen peroxide, and ROS were also suppressed by tamarixetin. The downregulation of NADP + and NADPH levels, and gp91phox expression indicated the ameliorative effects of tamarixetin on NADPH oxidase activation. In the gp91phox knockdown cells treated with lipopolysaccharide, the effects of tamarixetin on NADPH oxidase activation, ROS generation, and NLRP3 inflammasome activation were diminished. Moreover, tamarixetin protects neurons against microglial hyperactivation in vitro. Our findings support the potential of tamarixetin as a therapeutic agent for ischemic stroke, and its mechanism of action involves the inhibition of NADPH oxidase-NLRP3 inflammasome signaling., (© 2024 John Wiley & Sons, Ltd.)

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance., (© 2024. The Author(s).)

Background: Ischemic stroke (IS) is characterized as a detrimental cerebrovascular disease with high mortality and disability. Ferroptosis is a novel mechanism involved in neuronal death. There is a close connection between IS and ferroptosis, and inhibiting ferroptosis may provide an effective strategy for treating IS. Our previous investigations have discovered that kellerin, the active compound of Ferula sinkiangensis K. M. Shen, possesses the capability to shield against cerebral ischemia injury., Purpose: Our objective is to clarify the relationship between the neuroprotective properties of kellerin against IS and its ability to modulate ferroptosis, and investigate the underlying regulatory pathway., Study Design: We investigated the impact and mechanism of kellerin in C57BL/6 mice underwent middle cerebral artery occlusion/reperfusion (MCAO/R) as well as SH-SY5Y cells exposed to oxygen-glucose deprivation/ re-oxygenation (OGD/R)., Methods: The roles of kellerin on neurological severity, cerebral infarction and edema were investigated in vivo. The regulatory impacts of kellerin on ferroptosis, mitochondrial damage and Akt/Nrf2 pathway were explored. Molecular docking combined with drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) were performed to analyze the potential target proteins for kellerin., Results: Kellerin protected against IS and inhibited ferroptosis in vivo. Meanwhile, kellerin improved the neuronal damage caused by OGD/R and suppressed ferroptosis by inhibiting the production of mitochondrial ROS in vitro. Further we found that kellerin directly interacted with Akt and enhanced its phosphorylation, leading to the increase of Nrf2 nuclear translocation and its downstream antioxidant genes expression. Moreover, kellerin's inhibitory effect on ferroptosis and mitochondrial ROS release was eliminated by inhibiting Akt/Nrf2 pathway., Conclusions: Our study firstly demonstrates that the neuroprotective properties of kellerin against IS are related to suppressing ferroptosis through inhibiting the production of mitochondrial ROS, in which its modulation on Akt-mediated transcriptional activation of Nrf2 plays an important role. This finding shed light on the potential mechanism that kellerin exerts therapeutic effects in IS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Sepsis is considered as a severe illness due to its high mortality. Sepsis can cause septic encephalopathy, thus leading to brain injury, behavioral and cognitive dysfunction. Pyroptosis is a type of regulated cell death (RCD) and takes a crucial part in occurrence and development of sepsis. Americanin B (AMEB) is a lignan compounds, which is extracted from Vernicia fordii. In our previous study, AMEB could inhibit microglial activation in inflammatory cell model. However, the function of AMEB in septic encephalopathy mice is uncertain. It would be worthwhile to ascertain the role and mechanism of AMEB in sepsis., Purpose: Current study designs to certify the relationship between pyroptosis and septic encephalopathy, and investigate whether AMEB can restrain NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and restrict pyroptosis by targeting NLRP3 in septic mice model., Study Design: C57BL/6 mice were utilized to perform sepsis model in vivo experiments. BV-2 cell lines were used for in vitro experiments., Methods: In vivo sepsis model was established by lipopolysaccharide (LPS) intraperitoneal injection in male C57BL/6 J mice and in vitro model was exposed by LPS plus ATP in BV-2 cells. The survival rate was monitored on the corresponding days. NLRP3, apoptosis associated Speck-like protein (ASC), caspase-1, GasderminD (GSDMD), interleukin-1β (IL-1β) and interleukin-18 (IL-18) level were detected by western blotting and immunofluorescence analysis. Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) experiments, RNAi transfection and quantitative real-time PCR were applied to confirm the potential target of AMEB., Results: The results suggested that AMEB could rise survival percentage and lighten brain injury in LPS-induced sepsis mice. In addition, AMEB could inhibit pyroptosis and the activiation of NLRP3 inflammasome. The inhibiting function of AMEB on the activiation of NLRP3 inflammasome is weakened following si-NLRP3 transfection. Moreover, AMEB exerted anti-pyroptosis effect via targeting NLRP3 protein., Conclusions: Our findings first indicate NLRP3 is an effective druggable target for septic encephalopathy related brain injury, and also provide a candidate-AMEB for the treatment of septic encephalopathy. These emerging findings on AMEB in models of sepsis suggest an innovative approach that may be beneficial in the prevention of septic encephalopathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Among adults, stroke is the main causes of mortality and permanent disability. Neuroinflammation is one of the main causes of stoke-mediated neuronal death. Our previous study revealed that (E)-5-(2-(Quinolin-4-yl) vinyl) benzene-1, 3-diol (RV01), a quinolinyl analog of resveratrol, inhibits microglia-induced neuroinflammation and safeguards neurons from inflammatory harm. The preventive role of RV01 in ischemic stroke and its underlying cellular mechanisms and molecular targets remain poorly understood., Purpose: To investigate whether RV01 alleviates ischemia-reperfusion (I/R) injury by inhibiting microglia-mediated neuroinflammation and determine the potential molecular mechanisms and targets by which RV01 inhibits the I/R-mediated microglia activation., Methods: Rat middle cerebral artery occlusion and reperfusion (MCAO/R) and BV-2 or primary microglial cells oxygen-glucose deprivation and reperfusion (OGD/R) models were established. The neurological behavior scores, 2, 3, 5-triphenyl tetrazolium chloride staining and immunofluorescence were used to detect the neuroprotective effect of RV01 in the MCAO/R rats. In addition, the mRNA expression levels of IL-6, TNF-α, and IL-1β were detected to reveal the antineuroinflammatory effect of RV01. Moreover, a western blot assay was performed to explore the protein expression changes in NF-κB-mediated neuroinflammation. Finally, we identified TLR4 as an RV01 target through molecular docking, drug sensitivity target stability analysis, cellular thermal shift analysis, and surface plasmon resonance techniques., Results: RV01 reduced the infarct volume and neurological deficits, increased the rotarod duration, and decreased the number of rightward deflections in the MCAO/R rats. RV01 inhibited the NF-κB signaling pathway in vitro and in vivo, as demonstrated by the reduction in the transcription factor p65-mediated expression of several inflammatory factors including IL-6, TNF-α, and IL-1β. Further studies showed that its protective effect was associated with targeting the TLR4 protein. Notably, the anti-inflammatory effect of RV01 was markedly reinforced by the TLR4 knockdown, but inhibited by the overexpression of TLR4. Results revealed that the conditioned medium derived from the RV01-treated BV-2 cells significantly decreased the OGD/R-mediated neuronal damage., Conclusion: Our results are the first to reveal the protective effects of RV01 on cerebral ischemia, depending on its inhibitory effect on the NF-κB pathway by targeting TLR4. RV01 could be a potential protective agent in ischemic stroke treatment., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, author- ship, and/or publication of this article., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Ethnopharmacological Relevance: Jinhua Qinggan granules (JHQG), the traditional Chinese formula come into the market in 2016, has been proved clinically effective against coronavirus disease. Acute lung injury (ALI) is a major complication of respiratory infection such as coronavirus and influenza virus, with a high clinical fatality rate. Macrophage activation-induced inflammatory response plays a crucial role in the pathogenesis of ALI. However, the participation of inflammatory response in the efficacy of JHQG and its material basis against ALI is still unknown., Aim of the Study: The research aims to investigate the inflammatory response-involved efficacy of JHQG on ALI, explore the "ingredient-target-pathway" mechanisms, and searching for key material basis of JHQG by integrated network pharmacology and experimental validation-based approach., Materials and Methods: Lipopolysaccharide (LPS)-induced ALI mice was established to assess the protective impact of JHQG. Network pharmacology was utilized to identify potential targets of JHQG and investigate its action mechanisms related to inflammatory response in treating ALI. The therapeutic effect and mechanism of the primary active ingredient in JHQG was verified through high performance liquid chromatography (HPLC) and a combination of wet experiments., Results: JHQG remarkably alleviated lung damage in mice model via suppressing macrophage activation, and inhibiting pro-inflammatory mediator level, p-ERK and p-STAT3 expression, TLR4/NF-κB activation. Network pharmacology combined with HPLC found luteolin is the main effective component of JHQG, and it could interact with TLR4/MD2 complex, further exerting the anti-inflammatory property and the protective role against ALI., Conclusions: In summary, our finding clarified the underlying mechanisms and material basis of JHQG therapy for ALI by integrated network pharmacology and experimental validation-based strategy., Competing Interests: Declaration of competing interest We certify that all authors have seen and approved the final version of the manuscript being submitted (entitled “Integrated network pharmacology and experimental validation-based approach to reveal the underlying mechanisms and key material basis of Jinhua Qinggan granules against acute lung injury”). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Ischemic stroke (IS) is considered as a serious cerebral vascular disease. Ferroptosis is a novel type of regulated cell death (RCD), that closely related to the occurrence and progress of IS. Loureirin C, a type of dihydrochalcone compound derived from the Chinese Dragon's blood (CDB). The effective components extracted from CDB have shown neuroprotective effects in ischemia reperfusion models. However, the role of Loureirin C in mice after IS is not well understood. Thus, it is worth to identify the effect and mechanism of Loureirin C on IS., Purpose: The present research aims to prove the existence of ferroptosis in IS and explore whether Loureirin C can inhibit ferroptosis by regulating nuclear factor E2 related factor 2 (Nrf2) pathway in mice and exert neuroprotective effects on IS models., Methods: Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established to evaluate the occurrence of ferroptosis and the potential Loureirin C brain-protective effect in vivo. The analysis of free iron, glutamate content, reactive oxygen species (ROS) and lipid peroxidation levels, along with transmission electron microscope (TEM) was applied to prove the existence of ferroptosis. The function of Loureirin C on Nrf2 nuclear translocation was verified by immunofluorescence staining. In vitro, primary neurons and SH-SY5Y cells were processed with Loureirin C after oxygen and glucose deprivation-reperfusion (OGD/R). ELISA kits, western blotting, co-immunoprecipitation (Co-IP) analysis, immunofluorescence, and quantitative real-time PCR were devoted to proving the neuroprotective effects of Loureirin C on IS via regulating ferroptosis and Nrf2 pathways., Results: The results showed that Loureirin C not only dramatically alleviated brain injury and inhibited neurons ferroptosis in mice after MCAO/R, but also dose-dependently reduce ROS accumulation in ferroptosis after OGD/R. Further, Loureirin C inhibits ferroptosis by activating Nrf2 pathway, and promoting nuclear translocation of Nrf2. Besides, Loureirin C increases heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione peroxidase 4 (GPX4) content after IS. Intriguingly, the anti-ferroptosis effect of Loureirin C is weakened by Nrf2 knockdown., Conclusion: Our discoveries first revealed that the inhibitory action of Loureirin C on ferroptosis may greatly depend on its adjusting effect on the Nrf2 pathway, suggesting that Loureirin C could act as a novel anti-ferroptosis candidate and play a therapeutic role in IS. These novel discoveries on the role of Loureirin C on IS models reveal an innovative method that may contribute to neuroprotection for the prevention of IS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Cognitive impairment is the main clinical feature following stroke, and microglia-mediated inflammatory response is a major contributor to it. Coreopsis tinctoria Nutt., an edible chrysanthemum, is commonly used as a functional ingredient in healthcare beverages and food. Okanin, the main active ingredient of Coreopsis tinctoria Nutt. flower, inhibits microglial activation. However, the role of okanin in cognitive impairment following ischemic stroke is still unknown. In this study, we investigated the effect of okanin on ischemic stroke and its underlying mechanism both in vivo and in vitro . Okanin was found to attenuate cognitive impairment in bilateral common carotid artery occlusion (BCCAO) mice, inhibit neuronal loss and microglial activation, decrease NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and increase miR-7 expression. Okanin suppressed NLRP3 inflammasome activation in oxygen-glucose deprivation (OGD) and lipopolysaccharide (LPS)-stimulated microglia by increasing miR-7 expression and inhibited microglia-induced neuronal injury. This study provides new insights into the role of okanin in ischemic stroke and shows that the miR-7/NLRP3 axis plays an important role in mediating the beneficial effects of okanin on cerebral ischemia. These findings suggest that okanin has great potential as a functional food for stroke recovery.

Ethnopharmacological Relevance: Aconiti Lateralis Radix Praeparata (Chinese name: Fuzi), the root of Aconitum carmichaelii Debx., is a representative medicine for restoring yang and rescuing patient from collapse. However, less studies had been reported on the reproductive toxicity and genotoxicity of Fuzi. According to the principle of reducing toxicity and preserving efficiency, only processed products of Fuzi are commonly applied in clinic, including Baifupian, Heishunpian and Danfupian. However, whether processing could alleviate the reproductive toxicity and genotoxicity of Fuzi had not been revealed., Aim of the Study: To assess the effect and possible mechanism of Fuzi and its processed products on reproductive toxicity and genotoxicity in male mice., Materials and Methods: Aqueous extracts of Fuzi and its processed products (Baifupian, Heishunpian and Danfupian, 5.85 g/kg) were administrated by gavage once daily for fourteen consecutive days. The reproductive toxicity was evaluated by testis weight, testis ratio, testis histopathology, sperm count, sperm viability rate and sperm deformity rate. The genotoxicity was evaluated by comet assay and micronucleus test in sperm, peripheral blood cell and bone marrow cell. Possible mechanisms of attenuating toxicity by processing were analyzed by detecting the level of testosterone, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and catalase (CAT)., Results: Fuzi significantly caused different degrees of reproductive toxicity and genotoxicity, specifically reducing the weight and testicular coefficient of testis, causing obvious pathological changes in testicular tissue, reducing sperm count and sperm viability rate, increasing sperm deformity rate and DNA damage in sperm/peripheral blood cells/bone marrow cells. Moreover, Fuzi decreased the level of testosterone, SOD, GSH and CAT, while increased the level of MDA in serum. Notably, the reproductive toxicity and genotoxicity induced by the processed products, especially Heishunpian and Danfupian, were significantly lowered compared to Fuzi. Processing could increase the level of testosterone, SOD, GSH, CAT and decrease the level of MDA compared to Fuzi., Conclusion: Fuzi and its processed products had reproductive toxicity and genotoxicity, but the toxicity of processed products was significantly weakened compared to Fuzi. The protective mechanism of processing to reduce the toxicity of Fuzi might be related to increasing the level of testosterone and decreasing oxidative stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Long-chain non-coding RNA (lncRNA) is closely related to many biological activities. Since its sequence structure is similar to that of messenger RNA (mRNA), it is difficult to distinguish between the two based only on sequence biometrics. Therefore, it is particularly important to construct a model that can effectively identify lncRNA and mRNA., Results: First, the difference in the k-mer frequency distribution between lncRNA and mRNA sequences is considered in this paper, and they are transformed into the k-mer frequency matrix. Moreover, k-mers with more species are screened by relative entropy. The classification model of the lncRNA and mRNA sequences is then proposed by inputting the k-mer frequency matrix and training the convolutional neural network. Finally, the optimal k-mer combination of the classification model is determined and compared with other machine learning methods in humans, mice and chickens. The results indicate that the proposed model has the highest classification accuracy. Furthermore, the recognition ability of this model is verified to a single sequence., Conclusion: We established a classification model for lncRNA and mRNA based on k-mers and the convolutional neural network. The classification accuracy of the model with 1-mers, 2-mers and 3-mers was the highest, with an accuracy of 0.9872 in humans, 0.8797 in mice and 0.9963 in chickens, which is better than those of the random forest, logistic regression, decision tree and support vector machine.

In this work, we proposed an optically transparent double-layer frequency-selective surface (FSS) based on interlaced multiring metallic mesh. By changing the large metal area of a conventional double-layer FSS into triangular-orthogonal distributed basic rings and nested rotated subrings, we achieved an FSS with high optical transmittance and low normalized high-order diffraction intensity while maintaining a flat passband and steep transition band. The results showed that our fabricated FSS had a normalized visible transmittance of 90.31%, stable filtering passband of ∼33.9  GHz, 3 dB bandwidth of 13.4 GHz, and uniform diffraction distribution, which are favorable characteristics for optically transparent FSS applications.

We report a nested multi-ring array metallic mesh (NMA-MM) that shows a highly uniform diffraction pattern theoretically and experimentally. Then a high-performance transparent electromagnetic interference (EMI) shielding structure is constituted by the double-layer interlaced NMA-MMs separated by transparent quartz-glass substrate. Experimental results show that double-layer interlaced NMA-MM structure exhibits a shielding effectiveness (SE) of over 27 dB in the Ku-band, with a maximal SE of 37 dB at 12 GHz, normalized optical transmittance of 90%, and minimal image quality degradation due to the interlaced arrangement. It thus shows great potential for practical applications in transparent EMI shielding devices.

An optically transparent frequency selective surface (FSS) based on a nested ring metallic mesh is proposed, whose diffraction distribution is uniform and normalized higher-order diffraction intensity is lower than that of an existing transparent FSS based on metallic meshes. Compared with non-meshed FSSs, the proposed FSS has a remarkably higher optical transmittance, lower -3 dB bandwidth, and higher maximum transmittance in the microwave band. Experimental results indicate that the FSS sample achieved a normalized visible transmittance of 94.84%, uniform diffraction distribution, and stable filtering passband around 31.00 GHz simultaneously, which are attractive properties for transparent FSS applications.

The validity of real and complex equivalent refractive index models (ERIMs) is verified for a shielding effectiveness evaluation of high-transmittance double-layer metallic meshes. Theoretical and experimental studies show that the real ERIM is invalid for thin substrates and inaccurate for thick substrates for double-layer meshes, although it has long been used successfully for single-layer meshes. However, the complex ERIM shows more reasonable results not only for double-layer but also for single-layer meshes, and the evaluation accuracy is further improved by modifying the equivalent reactance coefficient using least-squares fitting. Therefore, the modified complex ERIM is applicable in most conditions.