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Anti‐cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin‐I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin‐I, which can self‐assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin‐I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin‐I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K‐AKT‐mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin‐I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin‐I can provide new insights into the mechanism of ACPs, and Lycosin‐I, which is characterized by high potency and specificity, can be a promising lead for the development of anti‐leukemia drugs. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation contributes to the progression of isoproterenol (ISO)‐induced heart failure (HF). Caspase‐associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO‐driven cardiac remodelling is little explored. Methods: This study utilized Card9−/− mice and reconstituted C57BL/6 mice with either Card9−/− or Otud1−/− marrow‐derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK‐293T cells. Results: Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deletion inhibited ISO‐driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO‐induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33‐linked ubiquitin from CARD9 to promote the assembly of the CARD9‐BCL10‐MALT1 (CBM) complex, without affecting CARD9 stability. The ISO‐activated CBM complex results in NF‐κB activation and macrophage‐based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid‐specific OTUD1 deletion also attenuated ISO‐induced murine cardiac inflammation and remodelling. Conclusions: These results suggested that the OTUD1‐CARD9 axis is a new pro‐inflammatory signal in ISO‐challenged macrophages and targeting this axis has a protective effect against ISO‐induced HF. Key points: Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration.Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deficiency protected mice from ISO‐induced inflammatory heart remodeling.ISO promoted the assembly of CBM complex and then activated NF‐κB signaling in macrophages through OTUD1‐mediated deubiquitinating modification.OTUD1 deletion in myeloid cells protected hearts from ISO‐induced injuries in mice. [ABSTRACT FROM AUTHOR]

Background and Purpose: The NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is activated in many inflammatory conditions. So far, no low MW compounds inhibiting NLRP3 have entered clinical use. Identification of naturally occurring NLRP3 inhibitors may be beneficial to the design and development of compounds targeting NLRP3. Alantolactone is a phytochemical from a traditional Chinese medicinal plant with anti‐inflammatory activity, but its precise target remains unclear. Experimental Approach: A bank of phytochemicals was screened for inhibitors of NLRP3‐driven production of IL‐1β in cultures of bone‐marrow‐derived macrophages from female C57BL/6 mice. Models of gouty arthritis and acute lung injury in male C57BL/6J mice were used to determine the in vivo effects of the most potent compound. Key Results: Among the 150 compounds screened in vitro, alantolactone exhibited the highest inhibitory activity against LPS + ATP‐induced production of IL‐1β in macrophages, suppressing IL‐1β secretion, caspase‐1 activation and pyroptosis. Alantolactone directly bound to the NACHT domain of NLRP3 to inhibit activation and assembly of NLRP3 inflammasomes. Molecular simulation analysis suggested that Arg335 in NLRP3 was a critical residue for alantolactone binding, leading to suppression of NLRP3–NEK7 interaction. In vivo studies confirmed significant alleviation by alantolactone of two NLRP3‐driven inflammatory conditions, acute lung injury and gouty arthritis. Conclusion and Implications: The phytochemical alantolactone inhibited activity of NLRP3 inflammasomes by directly targeting the NACHT domain of NLRP3. Alantolactone shows great potential in the treatment of NLRP3‐driven diseases and could lead to the development of novel NLRP3 inhibitors. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin‐like kinase 1 (DCLK1), a microtubule‐associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified upregulated DCLK1 in macrophages in atherosclerotic lesions of ApoE−/− mice fed an HFD and determined that macrophage‐specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL‐induced inflammation via NF‐κB signaling pathway in primary macrophages. Coimmunoprecipitation followed by LC–MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF‐κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF‐κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis. Syopsis: Macrophage DCLK1 promotes inflammatory atherosclerosis by directly binding to IKKβ and activating IKKβ/NF‐κB signal. DCLK1 is a new regulator of IKKβ and a potential therapeutic target for atherosclerosis. Macrophage‐specific deletion or pharmacological inhibition of DCLK1 attenuates inflammatory atherosclerosis in mice.Blockage of DCLK1 alleviates oxLDL‐induced inflammation by inhibiting NF‐κB activation in macrophages.DCLK1 directly binds to IKKβ to induce IKKβ phosphorylation at S177/181, resulting in NF‐κB activation. [ABSTRACT FROM AUTHOR]

Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. Here, we investigate the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)‐induced vascular remodeling. We detect upregulated OTUD1 in the vascular endothelium of Ang II‐challenged mice and show that OTUD1 deletion attenuates vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravates these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 is identified as a substrate of OTUD1 using co‐immunoprecipitation followed by LC–MS/MS. We find that OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48‐ and K63‐linked deubiquitination. OTUD1‐mediated SMAD3 activation regulates transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reverses OTUD1‐promoted vascular remodeling. Our findings demonstrate that endothelial OTUD1 promotes Ang II‐induced vascular remodeling by deubiquitinating SMAD3. We identify SMAD3 as a target of OTUD1 and propose OTUD1 as a potential therapeutic target for diseases related to vascular remodeling. Synopsis: OTUD1 stabilizes SMAD3 and facilitates its activation by K48‐ and K63‐linked deubiquitination to regulate vascular EndMT and remodeling in mouse endothelial cells. OTUD1 deletion attenuates vascular remodeling, collagen deposition, and EndMT in angiotensin II‐challenged mice.OTUD1 stabilizes SMAD3 and facilitates its activation by K48‐ and K63‐linked deubiquitination.Endothelial OTUD1‐mediated SMAD3 activation regulates transcription of genes involved in vascular EndMT and remodeling. [ABSTRACT FROM AUTHOR]

Obesity‐induced cardiomyopathy (OIC) is an increasingly serious global disease caused by obesity. Chronic inflammation greatly contributes to the pathogenesis of OIC. This study aimed to explore the role and mechanism of tabersonine (Tab), a natural alkaloid with antiinflammatory activity, in the treatment of OIC. High fat diet (HFD)‐induced obese mice were administered with Tab. The results showed that Tab significantly inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of body weight and hyperlipidemia, in HFD‐induced obese mice. H9c2 cells and primary cardiomyocytes stimulated by palmitic acid (PA) were used to explore the molecular mechanism and target of Tab. We examined the effect of Tab on key proteins involved in HFD/PA‐induced inflammatory signaling pathway and found that Tab significantly inhibits TAK1 phosphorylation in cardiomyocytes. We further detected the direct interaction between Tab and TAK1 at the cellular, animal, and molecular levels. We found that Tab directly binds to TAK1 to inhibit TAK1 phosphorylation, which then blocks TAK1‐TAB2 interaction and then NF‐κB pro‐inflammatory pathway in cultured cardiomyocytes. Our results indicate that Tab is a potential agent for the treatment of OIC, and TAK1 is an effective therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Chronic inflammation plays an important role in hypertensive heart failure. Suppressing angiotensin II (Ang II)‐induced cardiac inflammation may contribute to the treatment of hypertension‐associated heart failure. Sclareol, a natural product initially isolated from the leaves and flowers of Salvia sclarea, possesses antiinflammatory and immune‐regulation activity in various systems. However, its effect on Ang II‐induced cardiac remodeling remains unknown. In this study, we have explored the potential effects of sclareol on Ang II‐induced heart failure. In vivo experiments were conducted in mice with Ang II‐pump infusion for 28 days. Sclareol administration at 5 mg·kg−1·d−1 significantly reduced the expression of myocardial injury markers. Sclareol also exerts protective effects against Ang II‐induced cardiac dysfunction in mice which is associated with alleviated cardiac inflammation and fibrosis. Transcriptome analysis revealed that inhibition of the Ang II‐activated mitogen‐activated protein kinase (MAPK) pathway contributed to the protective effect of sclareol. Sclareol inhibits Ang II‐activated MAPKs pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Blockage of MAPKs in cardiomyocytes abolished the antiinflammatory effects of sclareol. In conclusion, we show that sclareol protects hearts against Ang II‐induced injuries through inhibiting MAPK‐mediated inflammation, indicating the potential use of sclareol in the prevention of hypertensive heart failure. [ABSTRACT FROM AUTHOR]

Diabetes manifests as chronic inflammation and leads to the development diabetic cardiomyopathy (DCM). Targeting key proteins in inflammatory signaling may provide new therapy for DCM. In this study, the authors explore the pharmacological effects and mechanisms of Schisandrin B (Sch B), a natural compound with anti‐inflammatory activity against DCM. It is shown that Sch B prevents high‐level glucose (HG)‐induced hypertrophic and fibrotic responses in cultured cardiomyocytes. RNA sequencing and inflammatory qPCR microarray show that Sch B mainly affects myeloid differentiation primary response 88 (MyD88)‐dependent inflammatory gene expression in HG‐challenged cardiomyocytes. Further studies indicate that Sch B directly binds to and inhibits MyD88 activation, but does not alter MyD88‐independent Toll‐like receptor signaling in vivo and in vitro. Inhibiting or silencing MyD88 is associated with reduced levels of HG‐induced inflammatory cytokines and myocardial injuries in vitro. Treatment of type 1 and type 2 diabetic mice with Sch B protects heart function, reduces myocardial injuries, and decreases secretion of inflammatory cytokines. Cardiomyocyte‐specific MyD88 knockout also protects mice against cardiac inflammation and injury in type 1 diabetic mice. In conclusion, these studies show that cardiomyocyte MyD88 plays an apathogenetic role in DCM and Sch B specifically targets MyD88 to reduce inflammatory DCM. [ABSTRACT FROM AUTHOR]

Background: Non‐alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. Methods: Wild‐type, Md2−/− and bone marrow reconstitution mice fed with high‐fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA‐seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies. Results: Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD‐mediated suppression of AMP‐activated protein kinase (AMPK). This preservation of AMPK in Md2‐deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2‐increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. Conclusion: Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1‐AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non‐inflammatory function of MD2 and evidence for the important role of MD2 in NALFD. [ABSTRACT FROM AUTHOR]

Intramuscular fat (IMF) and subcutaneous fat (SCF) are important traits affecting the economics of the pork industry, in which less SCF and more IMF content is desirable. However, the mechanisms that regulate IMF and SCF content are not clear yet. In this study, we demonstrate that KLF3 (Krüppel‐like factor 3) was negatively correlated with IMF content in the longissimus dorsi muscle of Erhualian pigs. In addition, the expression level of KLF3 was significantly higher in IMF than SCF. Overexpression and knockdown experiments revealed that KLF3 could suppress adipocyte differentiation in vitro by downregulating adipogenic markers, including PPARG, C/EBPA, and FABP4. Luciferase activity analysis proved that miR‐32‐5p was able to suppress KLF3. Notably, miR‐32‐5p level was negatively correlated to KLF3 mRNA level in both IMF and SCF tissues. The same relationship was proved in samples with different IMF content. Further studies showed that miR‐32‐5p could promote adipocyte differentiation via inhibiting KLF3. Our results suggest that the miR‐32‐5p‐KLF3 pathway is involved in the regulation of differential fat deposition of IMF and SCF tissues. [ABSTRACT FROM AUTHOR]

Previous studies suggest that specific binding to the complex consisting of fibroblast growth factor receptor‐1 (FGFR1) and the coreceptor beta‐Klotho (KLB) is the premise for human FGF19 and FGF21 activating the downstream signaling cascades, and regulating the metabolic homeostasis. However, it was found that human FGF21 loses its ability to bind to FGFR1–KLB after iodination with Na125I and chloramine T, whereas human FGF19 retained its affinity for FGFR1–KLB even after iodination. The molecular mechanisms underlying these differences remained elusive. In this study, we first demonstrated that an intramolecular disulfide bond was formed between cysteine‐102 and cysteine‐121 in FGF21, implying that the oxidation of the cysteine to cysteic acid, which may interfere with the active conformation of FGF21, did not occur during the iodination procedures, and thus ruled out the possibility of the two conserved cysteine residues mediating the loss of FGF21 binding affinity to FGFR1–KLB upon iodination. Site‐directed mutagenesis and molecular modeling were further applied to determine the residue(s) responsible for the loss of FGFR1–KLB affinity. The results showed that mutation of a single tyrosine‐207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1–KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1–KLB, but decreased the receptor binding ability of the iodinated protein, suggesting that tyrosine‐207 is the crucial amino acid responsible for the loss of specifying FGFR1–KLB affinity of the iodinated FGF21. Human fibroblast growth factor‐21 (FGF21) but not FGF19 lost its ability to bind to FGF receptor‐1 and coreceptor beta‐Klotho (FGFR1–KLB) after iodination with Na125I and chloramine T. Our results suggesting that tyrosine‐207 in FGF21 is the crucial amino acid responsible for the loss of specifying FGFR1–KLB affinity of the iodinated FGF21. [ABSTRACT FROM AUTHOR]

Metal-organic frameworks (MOFs) have potentially useful applications and an intriguing variety of architectures and topologies. Two homochiral coordination polymers have been synthesized by the hydrothermal method, namely poly[(μ- N-benzyl-L-phenylalaninato-κ4 O, O′: O, N)(μ-formato-κ2 O: O′)zinc(II)], [Zn(C16H16NO2)(HCOO)] n, (1), and poly[(μ- N-benzyl-L-leucinato-κ4 O, O′: O, N)(μ-formato-κ2 O: O′)zinc(II)], [Zn(C13H18NO2)(HCOO)] n, (2), and studied by single-crystal X-ray diffraction, elemental analyses, IR spectroscopy and fluorescence spectroscopy. Compounds (1) and (2) each have a two-dimensional layer structure, with the benzyl or isobutyl groups of the ligands directed towards the interlayer interface. Photoluminescence investigations show that both (1) and (2) display a strong emission in the blue region. [ABSTRACT FROM AUTHOR]

Two homochiral coordination polymers based on a chiral reduced Schiff base ligand, namely poly[(μ5-4-{[(N R,1 S)-(1-carboxylato-2-phenylethyl)amino]methyl}benzoato)zinc(II)], [Zn(C17H15NO4)] n, (1), and poly[(μ5-4-{[(N R,1 S)-(1-carboxylato-2-phenylethyl)amino]methyl}benzoato)cobalt(II)], [Co(C17H15NO4)] n, (2), have been obtained by hydrothermal methods and studied by single-crystal X-ray diffraction, elemental analyses, powder X-ray diffraction, thermogravimetric analysis, IR spectroscopy and fluorescence spectroscopy. Compounds (1) and (2) are isostructural and crystallize in the P212121 space group. Both display a three-dimensional network structure with a one-dimensional channel, with the benzyl group of the ligand directed towards the channel. An investigation of photoluminescence properties shows that compound (1) displays a strong emission in the purple region. [ABSTRACT FROM AUTHOR]