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Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. Methods: We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. Results: Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. Conclusions: BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers. Highlights: 1. BA is a potent wild-type EGFR inhibitor. 2. BA enhances the anticancer efficacy of erlotinib/gefitinib in NSCLC patients with wild-type EGFR. 3. The combination of BA and gefitinib/osimertinib synergistically blocks EGFR and inhibits the PI3K-AKT-mTOR signaling pathway, leading to autophagic cell death and cell cycle arrest. 4. This combination strategy targets wild-type EGFR in NSCLC and induces autophagy and tumor suppression in vivo. BA, an EGFR inhibitor, sensitizes EGFR-TKIs' activity, indicating that BA plus EGFR-TKIs may be a potential therapeutic strategy to overcome the primary resistance of wild-type EGFR NSCLC. [ABSTRACT FROM AUTHOR]

Phytoalexins play a crucial role in plant immunity. However, the mechanism of how phytoalexin is primed by beneficial microorganisms against broad‐spectrum pathogens remains elusive. This study showed that Bacillus cereus AR156 could trigger ISR against broad‐spectrum disease. RNA‐sequencing and camalexin content assays showed that AR156‐triggered ISR can prime the accumulation of camalexin synthesis and secretion‐related genes. Moreover, it was found that AR156‐triggered ISR elevates camalexin accumulation by increasing the expression of camalexin synthesis genes upon pathogen infection. We observed that the priming of camalexin accumulation by AR156 was abolished in cyp71a13 and pad3 mutants. Further investigations reveal that in the wrky33 mutant, the ability of AR156 to prime camalexin accumulation is abolished, and the mediated ISR against the three pathogens is significantly compromised. Furthermore, PEN3 and PDR12, acting as camalexin transporters, participate in AR156‐induced ISR against broad‐spectrum pathogens differently. In addition, salicylic acid and JA/ET signalling pathways participate in AR156‐primed camalexin synthesis to resist pathogens in different forms depending on the pathogen. In summary, B. cereus AR156 triggers ISR against Botrytis cinerea, Pst DC3000 and Phytophthora capsici by priming camalexin synthesis. Our study provides deeper insights into the significant role of camalexin for AR156‐induced ISR against broad‐spectrum pathogens. Summary statement: Beneficial rhizobacterium AR156 triggered ISR by enhancing camalexin accumulation in Arabidopsis, with WRKY33 acting as a positive regulator. PEN3 and PDR12 are involved in AR156‐induced ISR. Salicylic acid and JA/ET signalling pathways participate in AR156‐primed camalexin synthesis to resist various pathogens. [ABSTRACT FROM AUTHOR]

Clinacanthus nutans (Burm. f.) Lindau, a traditional herb renowned for its anti-tumor, antioxidant, and anti-inflammatory properties, has garnered considerable attention. Although its hepatoprotective effects have been described, there is still limited knowledge of its treatment of acute liver injury (ALI), and its mechanisms remain unclear. To assess the efficacy of Clinacanthus nutans in ALI and to identify the most effective fractions and their underlying mechanism of action. Bioinformatics was employed to explore the underlying anti-hepatic injury mechanisms and active compounds of Clinacanthus nutans. The binding ability of schaftoside, a potential active ingredient in Clinacanthus nutans , to the core target nuclear factor E2-related factor 2 (Nrf2) was further determined by molecular docking. The role of schaftoside in improving histological abnormalities in the liver was observed by H&E and Masson's staining in an ALI model induced by CCl 4. Serum and liver biochemical parameters were measured using AST, ALT and hydroxyproline kits. An Fe2+ kit, transmission electron microscopy, western blotting, RT-qPCR, and DCFH-DA were used to measure whether schaftoside reduces ferroptosis-induced ALI. Subsequently, specific siRNA knockdown of Nrf2 in AML12 cells was performed to further elucidate the mechanism by which schaftoside attenuates ferroptosis-induced ALI. Bioinformatics analysis and molecular docking showed that schaftoside is the principal compound from Clinacanthus nutans. Schaftoside was shown to diminish oxidative stress levels, attenuate liver fibrosis, and forestall ferroptosis. Deeper investigations revealed that schaftoside amplified Nrf2 expression and triggered the Nrf2/GPX4 pathway, thereby reversing mitochondrial aberrations triggered by lipid peroxidation, GPX4 depletion, and ferroptosis. The lead compound schaftoside counters ferroptosis through the Nrf2/GPX4 axis, providing insights into a novel molecular mechanism for treating ALI, thereby presenting an innovative therapeutic strategy for ferroptosis-induced ALI. [Display omitted] • Network pharmacology studies have demonstrated the hepatoprotective effects of schaftoside in Clinacanthus nutans. • Ferroptosis is responsible for CCl 4 -induced acute liver injury. • Schaftoside alleviates CCl 4 -induced ferroptosis in acute liver injury. • Schaftoside inhibits ferroptosis via the Nrf2-GPX4 pathway to protect against acute liver injury. [ABSTRACT FROM AUTHOR]

Diabetic patients often experience delayed wound healing due to impaired functioning of human umbilical vein endothelial cells (HUVECs) under high glucose (HG) conditions. This is because HG conditions trigger uncontrolled lipid peroxidation, leading to iron‐dependent ferroptosis, which is caused by glucolipotoxicity. However, natural flavonoid compound Orientin (Ori) possesses anti‐inflammatory bioactive properties and is a promising treatment for a range of diseases. The current study aimed to investigate the function and mechanism of Ori in HG‐mediated ferroptosis. A diabetic wound model was established in mice by intraperitoneal injection of streptozotocin (STZ), and HUVECs were cultured under HG to create an in vitro diabetic environment. The results demonstrated that Ori inhibited HG‐mediated ferroptosis, reducing levels of malondialdehyde (MDA), lipid peroxidation, and mitochondrial reactive oxygen species (mtROS), while increasing decreased levels of malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species, as well as increased levels of glutathione (GSH). Ori treatment also improved the wound expression of glutathione peroxidase 4 (GPX4) and angiogenesis markers, reversing the delayed wound healing caused by diabetes mellitus (DM). Additional investigations into the mechanism revealed that Ori may stimulate the nuclear factor‐erythroid 2‐related factor 2 (Nrf2)/GPX4 signaling pathway. Silencing Nrf2 in HG‐cultured HUVECs negated the beneficial impact mediated by Ori. By stimulating the Nrf2/GPX4 signaling pathway, Ori may expedite diabetic wound healing by decreasing ferroptosis. [ABSTRACT FROM AUTHOR]

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) serve as transcriptional co-activators that dynamically shuttle between the cytoplasm and nucleus, resulting in either the suppression or enhancement of their downstream gene expression. Recent emerging evidence demonstrates that YAP/TAZ is strongly implicated in the pathophysiological processes that contribute to cardiovascular diseases (CVDs). In the cardiovascular system, YAP/TAZ is involved in the orchestration of a range of biological processes such as oxidative stress, inflammation, proliferation, and autophagy. Furthermore, YAP/TAZ has been revealed to be closely associated with the initiation and development of various cardiovascular diseases, including atherosclerosis, pulmonary hypertension, myocardial fibrosis, cardiac hypertrophy, and cardiomyopathy. In this review, we delve into recent studies surrounding YAP and TAZ, along with delineating their roles in contributing to the pathogenesis of CVDs with a link to various physiological processes in the cardiovascular system. Additionally, we highlight the current potential drugs targeting YAP/TAZ for CVDs therapy and discuss their challenges for translational application. Overall, this review may offer novel insights for understanding and treating cardiovascular disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

• Activation of sigma-1 receptor ameliorates sepsis-induced myocardial injury. • Activation of sigma-1 receptor attenuates mitochondrial oxidative stress and reduces apoptosis. • Sigma-1 receptor has cardioprotective effects against oxidative stress through the Nrf2/HO1 signaling pathway. Sepsis is a condition that triggers the release of large amounts of reactive oxygen species and inflammatory factors in the body, leading to myocardial injury and cardiovascular dysfunction — an important contributor to the high mortality rate associated with sepsis. Although it has been demonstrated that the sigma-1 receptor (S1R) is essential for preventing oxidative stress, its effectiveness in treating sepsis is yet unknown. This study aimed to investigate the role and mechanisms of S1R activation in sepsis-induced myocardial injury. A model of sepsis-induced myocardial injury was constructed by performing cecum ligation and puncture(CLP) surgery on rats. Flv or BD1047 were intraperitoneally injected into rats for one consecutive week before performing CLP, and then intraperitoneally injected into the rats again 1 h after the surgery.The effects of Flv and BD1047 were detected by HE staining, immunofluorescence staining, IHC staining, echocardiography measurements,TUNEL, oxidative stress detection, TEM, flow cytometry and western blot. We further validated the mechanism in vitro using neonatal rat cardiomyocites and H9C2 cells. S1R protein level was reduced in the hearts of septic rats, whereas administration of Flv, an S1R activator, ameliorated myocardial injury, mitochondrial oxidative stress, and pathological manifestations of sepsis. On the other hand, administration of the S1R inhibitor BD1047 exacerbated the mitochondrial oxidative stress, and apoptosis, as well as symptoms and pathological manifestations of sepsis. In addition, we found that up-regulation of S1R activated the Nrf2/HO1 signaling pathway and promoted nuclear translocation of Nrf2, which activated downstream proteins to generate antioxidant factors, such as HO1, in turn alleviating oxidative stress and countering myocardial damage. By scavenging ROS accumulation and reducing mitochondrial oxidative stress via the Nrf2/HO1 signaling pathway, activation of S1R improves cardiac function, mitigates death of cardiomyocytes, and attenuates sepsis-induced myocardial injury. [ABSTRACT FROM AUTHOR]