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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]

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]

Chinese herbal formula JiaWeiSiNiSan (JWSNS) has been widely used to prevent stress-induced neuropsychiatric ailments in clinics and proven to have therapeutic anti-stress effects on rats. However, the mechanism remains unclear. Based on the proteomics of cerebrospinal fluid (CSF), this study explores the possible mechanism and target proteins of JiaWeiSiNiSan raising stress resilience and preventing stress damage. A 6-week Chronic Unpredictable Mild Stress (CUMS) model was applied on adult Wistar male rats to observe the effects of JWSNS on improving mental stress resilience. Tandem Mass Tag (TMT) proteomics and bioinformatics analysis were used to screen and analyze differentially expressed proteins (DEPs) in CSF. Parallel Reaction Monitoring (PRM) was used to validate target DEPs. Significantly decreased sucrose preference, locomotion activity level and accuracy of T-maze, as well as increased immobility time, were observed in CUMS rats compared to CON rats while JWSNS improved above depression-like behaviours. The quantitative proteomics and bioinformatics analysis showed that JWSNS decreased the expression of Rps4x, HSP90AA1, Rps12, Uba1, Rsp14, Tuba1b in CUMS rats CSF (p < 0.05, FDR < 0.5). Immunofluorescence results showed that the number of BrdU/DCX positive cells (p < 0.01) and the relative number of neurons (p < 0.01) in the hippocampus dentate gyrus (DG) of the JSWNS group significantly increased, compared with the CUMS group. JWSNS could increase mental stress resilience and prevent stress damage by regulating proteins in CSF. This study provides a scientific basis for further study on Chinese formulas preventing mental illness. [ABSTRACT FROM AUTHOR]

There is a strong epidemiological link between obesity, a growing worldwide concern, and kidney disease. Emerging evidence indicates that the pathogenic basis of obesity-related kidney disease may be attributed to Toll-like receptor 4 (TLR4) of the innate immune system. We hypothesized that renal epithelial cell injury in response to oxidized low-density lipoprotein (oxLDL) requires myeloid differentiation factor 2 (MD2), a co-receptor of TLR4. Moreover, we also hypothesized that renal dysfunction is MD2-dependent in the high-fat diet (HFD) mouse model. Results indicated that the MD2 selective inhibitor (L6H21) abrogated the oxLDL-induced formation of MD2-TLR4 dimerization in the renal proximal tubular epithelial cell line NRK-52E. Further, MD2 blockade in NRK-52E cells using siRNA target sequences or L6H21 prevented oxLDL-induced cell injury as indicated by expression of profibrotic molecules, autophagic activity and apoptosis. Similarly, TLR4 knockdown in NRK-52E cells using siRNA target sequences prevented oxLDL-induced cell injury. In the HFD mouse model, MD2 knockout protected against development of kidney dysfunction and renal tissue injury, corroborating the observations observed in NRK-52E cells. Thus, the oxLDL-induced renal tubular epithelial cell profibrotic responses, autophagy and apoptosis were dependent on MD2, as were the renal dysfunction and tissue impairment in HFD mice. These are new findings indicating that the MD2-TLR4 immune signaling complex is a critical pathogenic factor in the development of kidney disease related to obesity or metabolic syndrome. [ABSTRACT FROM AUTHOR]

Abstract Development of atherosclerosis involves chronic and sustained inflammation and oxidative stress. Recent studies have linked atherosclerosis to the innate immune system. Genetic deficiency in myeloid differentiation primary-response protein 88 (MyD88) protects against the development and progression of atherosclerosis. However, it is unknown if pharmacological inhibition of MyD88 is able to be a therapeutic strategy for this disease. In this study, we evaluated the effect of a newly synthesized small-molecule inhibitor of MyD88, LM9, in an ApoE−/− mouse model of atherosclerosis. Our results showed that the major source of MyD88 in atherosclerotic lesions is infiltrated macrophage. Treatment of HFD-fed ApoE−/− mice with LM9 significantly attenuated the pathogenesis of atherosclerosis, accompanied with reduced vascular inflammatory responses and oxidative stress. These effects were achieved without changes to serum lipid levels. We further showed that LM9 inhibited oxidized-lipoprotein induced foam cell formation through suppression of MyD88 and inflammatory pathway in macrophages. Additionally, either LM9 treatment or MyD88 knockdown prevented ox-LDL-induced oxidative stress in macrophages. This study highlights the translational role of MyD88 as a therapeutic target and identifies the MyD88 inhibitor LM9 as a new candidate for the treatment of atherosclerosis. Graphic abstract Unlabelled Image Highlights • MyD88 signaling is involved in the pathology of atherosclerosis. • MyD88 inhibitor LM9 suppressed ox-LDL induced inflammation and oxidative stress in macrophages. • MyD88 inhibition inhibited ox-LDL induced CD36 expression and foam cell formation. • Pharmacological inhibition of MyD88 by LM9 attenuated experimental atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes. A multitude of factors are involved in the pathogenesis of DCM including chronic inflammation and oxidative stress. We have recently shown that compound LF10 prevents inflammatory responses in an animal model of lung injury. In the present study, we explored the protective effects and mechanism of LF10 against DCM using a mouse model of streptozotocin-induced diabetes and high glucose (HG)-challenged cultured cardiomyocytes. We show that LF10 suppressed diabetes-induced cardiomyocyte hypertrophy and fibrosis, which was accompanied by preservation of cardiac function in mice. Mechanistically, LF10 prevented increases in the levels of pro-inflammatory molecules and oxidative stress under in vitro and in vivo diabetic conditions. Moreover, LF10 restored HG-downregulated sirtuin 1 (SIRT1) in cardiomyocytes and prevented HG-induced activation of MAPKs. Using specific small-molecule regulators, we found that SIRT1 was an upstream signal of MAPKs. In conclusion, LF10 inhibited ROS and MAPKs-mediated inflammation by restoring SIRT1, and prevented development of DCM. LF10 targeted both oxidative stress and inflammation, two tightly interconnected pathogenic pathways, which makes LF10 a highly advantageous therapeutic drug potential. Highlights • LF10 suppressed diabetes-induced cardiomyocyte hypertrophy and fibrosis. • LF10 prevented increases of pro-inflammatory molecules and oxidative stress. • LF10 induced blockade of ROS and MAPKs-mediated inflammation by restoring SIRT1. • LF10 could be a highly advantageous therapeutic drug potential. [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]

A conceptual design of extractive distillation for the separation of cyclopentane and neohexane mixtures using a mixture of N , N -dimethyl formamide (DMF) and ionic liquid (IL) as entrainer is developed. [PCNMIM][ClO 4 ] was found to be the most promising solvent through the COSMO-RS calculations. Quantum chemistry calculations were then carried out to further understand the separation ability of the solvent. The vapor–liquid equilibrium (VLE) experimental results showed that the relative volatility of neohexane to cyclopentane is enhanced using the N , N -dimethyl formamide (DMF) + [PCNMIM][ClO 4 ] mixed solvents when compared to the benchmark solvent DMF. The interaction parameters of non-random two-liquid (NRTL) model were correlated using the measured experimental VLE data. For comparison, two extractive distillation processes, using mixed solvents and pure DMF, were simulated in Aspen Plus. The results showed that the mixed solvents exhibit a better separation performance than DMF. The process using mixed solvents can reduce the total annual cost by 21.49% compared with that using DMF. [ABSTRACT FROM AUTHOR]

[Display omitted] • NLRP3-mediated pyroptosis was highly involved in the development of acute tubular necrosis. • Tan IIA-derived compound 15a activated mitophagy and reduced mtROS to suppress NLRP3-mediated pyroptosis in macrophages. • Tan IIA-derived compound 15a attenuated acute tubular necrosis by inhibiting NLRP3 inflammasome activation in macrophages. Acute tubular necrosis (ATN) is a common type of acute renal failure. Recent studies have shown that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in macrophages plays a crucial role in the progression of ATN. Previously, we synthesized an anti-inflammatory compound 15a based on Tanshinone IIA (Tan IIA). In the present study, we found that compound 15a exhibited a greater inhibitory effect on NLRP3-mediated pyroptosis than Tan IIA in vitro. C57BL/6 and NLRP3-knockout (NLRP3-KO) mice were intraperitoneally injected with LPS or folic acid (FA) to develop ATN. In vitro, bone marrow-derived macrophages (BMDMs) were treated with LPS for 3 h and then treated with ATP for 0.5 h. We explored the mechanism by which compound 15a inhibited NLRP3 inflammasome in BMDMs as well as its renal protective effect against ATN in mice. We found that compound 15a exhibited a protective effect on mitochondria and reduced the production of mitochondrial reactive oxygen species (mtROS). Moreover, we revealed that compound 15a remarkably reduced the production of mtROS by promoting mitophagy, which resulted in the inhibition of NLRP3 inflammasome to alleviates ATN in mice. In summary, compound 15a inhibited NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate ATN. Our results identified compound 15a as a promising candidate for the treatment of NLRP3-driven ATN. [ABSTRACT FROM AUTHOR]

A synthetic approach to poly(arylene ether ketones) grafted with super-acidic perfluoroalkyl-sulfonic-acids is reported. A series of iodo-containing poly(arylene ether ketone)s derived from a 4-iodophenylated hydroquinone monomer were synthesized by aromatic nucleophilic substitution (SNAr). The iodo-containing polymers were functionalized via the Ullmann reaction to give poly(arylene ether ketone)s grafted with perfluoroalkyl-sulfonic-acid. The perfluoroalkyl-sulfonic-acid functionalized aromatic polymers were investigated as proton exchange membranes (PEM). The membranes had good overall properties of thermal-oxidative stability, mechanical strength, methanol permeability and proton conductivity. A membrane with IEC ~ 1.37 meq g − 1 had a proton conductivity of 0.088 S cm − 1 at 100 °C, which was higher than many sulfonated hydrocarbon PEMs with similar IEC values. [ABSTRACT FROM AUTHOR]

Ss. [Display omitted] Hyperglycemia-associated inflammation contributes to diabetic cardiomyopathy. Myeloid differentiation primary-response protein 88 (MyD88) is an adapter protein of many Toll-like receptors (TLRs) and is recruited to TLRs to initiate inflammatory response in endotoxin-activated innate immunity. However, the role of MyD88 in diabetic cardiomyopathy is unknown. We examined the role and mechanism of MyD88 in inflammatory heart injuries in diabetes and identified MyD88 as a potential target for the treatment of diabetic cardiomyopathy. In this study, we first found that MyD88 expression was increased in cardiomyocytes of diabetic mouse hearts. In cultured cardiomyocytes, MyD88 inhibition either by siRNA or by small-molecular inhibitor LM8 markedly blocked TLR4-MyD88 complex formation, reduced pro-inflammatory mitogen-activated protein kinases/nuclear factor-κB (MAPKs/NF-κB) cascade activation and decreased pro-inflammatory cytokine expression under high glucose condition. Moreover, pharmacologic inhibition of MyD88 by LM8 showed significantly anti-inflammatory, anti-hypertrophic and anti-fibrotic effects in the hearts of both type 1 and type 2 diabetic mice. These beneficial effects of MyD88 inhibition were correlated to the reduced activation of TLR4-MyD88-MAPKs/NF-κB signaling pathways in the hearts. Taken together, MyD88 in cardiomyocytes mediates diabetes-induced cardiac inflammatory injuries and pharmacological inhibition of MyD88 shows significantly cardioprotective effects, indicating MyD88 as a potential therapeutic target for diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

[Display omitted] • MyD88 in tubular epithelial cell mediates AngII-induced inflammation and fibrosis. • MyD88 inhibition attenuates AngII-induced renal inflammation, dysfunction in mice. • MyD88 is a potential target for treating hypertension-associated kidney disease. Kidney damage is a frequent event in the course of hypertension. Recent researches highlighted a critical role of non-hemodynamic activities of angiotensin II (Ang II) in hypertension-associated kidney fibrosis and inflammation. These activities are mediated through toll-like receptors (TLRs) but the mechanisms by which Ang II links TLRs to downstream inflammatory and fibrogenic responses is not fully known. In this study, we investigated the role of TLR adapter protein called myeloid differentiation primary-response protein-88 (MyD88) as the potential link. C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop nephropathy. Mice were treated with small-molecule MyD88 inhibitor LM8. In vitro , MyD88 was blocked using siRNA or LM8 in Ang II-challenged renal tubular epithelial cells. We show that MyD88 is mainly located in tubular epithelial cells and Ang II increases the interaction between TLR4 and MyD88. This interaction activates MAPKs and nuclear factor-κB (NF-κB), leading to increased production of inflammatory and fibrogenic factors. Inhibition of MyD88 by siRNA or selective inhibitor LM8 supresses MyD88-TLR4 interaction, NF-κB activation, and elaboration of inflammatory cytokines and fibrosis-associated factors. These protective actions resulted in decreased renal pathological changes and preserved renal function in LM8-treated hypertensive mice, without affecting hypertension. These results demonstrate that Ang II induces inflammation and fibrosis in renal tubular epithelial cells through MyD88 and present MyD88 as a potential point of intervention for hypertension-associated kidney disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • CMNT had significant anti-hypoglycemic effects in diabetes mice and patients with type 2 diabetes. • CMNT promoted insulin secretion, increased β-cell proliferation and attenuated macrophage infiltration of pancreatic islets in diabetes mice. • Altered gut microbiota composition by CMNT are correlated with improvement in β-cell function in diabetes mice. • The clinical benefits of CMNT were correlated with alteration of gut microbiota composition in patients with type 2 diabetes. Medicine food homologous (MFH) plants and wholegrains have gained increasing attention for prevention and treatment of type 2 diabetes (T2D). Substantial evidence supports the effectiveness of intermittent energy restriction (IER) in T2D management. However, there are few studies that report intermittent use of a low-calorie pre-prepared food including MFH plants and wholegrains in T2D. The aim of this study was to investigate the effects of Chinese Medical Nutrition Therapy (CMNT), a MFH plants and wholegrains diet accompanied by IER, on glycemic control and potential mechanism. Ten-week-old diabetic db/db mice were randomly divided into CMNT group (feeding low-calorie mouse CMNT diet in day 1–4 and ad libitum regular chow for up to 7 days per cycle) and control group (ad libitum access to regular chow). The results showed that CMNT reduced fasting blood glucose, improved glucose tolerance with higher insulin secretion, attenuated macrophage infiltration, promoted β-cell proliferation of pancreatic islets, and increased diabetes-improving microbiota (Bacteroides , Rikenellaceae_RC9_gut_group and Coprococcus_1) in db/db mice. Additionally, we performed a pilot study evaluating CMNT in thirty-nine T2D patients without obesity. Participants with T2D randomly assigned to two groups: CMNT group (receiving a consecutive 5-day low-calorie human CMNT diet with 10 days of habitual eating per cycle for 90 days) and control group (continuing on a normal diet). We observed an improvement in glycemic control in CMNT group with significant reduction in HbA1c, fasting glucose, 2 h postprandial blood glucose but control group were not affected. After CMNT intervention, the abundance of the phylum Bacteroidetes , and genus Bacteroides , Parabacteroides and Roseburia were significantly higher than baseline in T2D patient, which were closely associated with glycemic control. These findings suggested that CMNT is a promising nutritional intervention approach in diabetes management. [ABSTRACT FROM AUTHOR]

Activation of the innate immune system through toll-like receptors (TLRs) has been repeatedly demonstrated in non-alcoholic fatty liver disease (NAFLD) and several TLRs have been shown to contribute. Myeloid differentiation primary response 88 (MyD88) is as an adapter protein for the activation of TLRs and bridges TLRs to NF-κB-mediated inflammation in macrophages. However, whether myeloid cell MyD88 contributes to NAFLD are largely unknown. To test this approach, we generated macrophage-specific MyD88 knockout mice and show that these mice are protected against high-fat diet (HFD)-induced hepatic injury, lipid accumulation, and fibrosis. These protective effects were associated with reduced macrophage numbers in liver tissues and surpassed inflammatory responses. In cultured macrophages, saturated fatty acid palmitate utilizes MyD88 to activate NF-κB and induce inflammatory and fibrogenic factors. In hepatocytes, these factors may cause lipid accumulation and a further elaboration of inflammatory cytokines. In hepatic stellate cells, macrophage-derived factors, especially TGF-β, cause activation and hepatic fibrosis. We further show that pharmacological inhibition of MyD88 is also able to reduce NAFLD injury in HFD-fed mice. Therefore, our study has provided empirical evidence that macrophage MyD88 participates in HFD-induced NAFLD and could be targeted to prevent the development and progression of NAFLD/NASH. • The levels of MyD88 is increased in liver tissues from patients and mice with NAFLD. • MyD88 is mainly overexpressed in macrophages cells during the NAFLD process. • MyD88 regulates macrophage-derived cytokines to disrupt the lipid metabolism in hepatocytes. • MyD88-driven macrophage factors promoted the activation and proliferation of HSCs. • MyD88 could be a therapeutic target for the treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Heart failure is a fairly common outcome of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertensive heart failure via inducing cardiac inflammation. Drugs that disrupt Ang II-induced cardiac inflammation may have clinical utility in the treatment of hypertensive heart failure. A naturally occurring compound, corynoline, exhibit anti-inflammatory activities in other systems. C57BL/6 mice were injected with Ang II via a micro-osmotic pump for four weeks to develop hypertensive heart failure. The mice were treated with corynoline by gavage for two weeks. RNA-sequencing analysis was performed to explore the potential mechanism of corynoline. We found that corynoline could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. RNA-sequencing analysis indicates that the PPARα pathway is involved Ang II-induced cardiac fibrosis and cardiac remodeling. Corynoline reversed Ang II-induced PPARα inhibition both in vitro and in vivo. We further found that corynoline increases the interaction between PPARα and P65 to inhibit the NF-κB pro-inflammatory pathway in H9c2 cells. Our studies show that corynoline relieves Ang II-induced hypertensive heart failure by increasing the interaction between PPARα and P65 to inhibit the NF-κB pathway. [Display omitted] • Hypertensive heart failure remains a health challenge worldwide, associated with high rates of hospitalization, morbidity, and mortality especially in the elderly. Recently, it has been shown that Corynoline has anti-inflammatory effects in mastitis, rheumatoid arthritis, liver injury and acute lung injury. • However, there remains an unknown on the molecular mechanism of Corynoline in inhibiting inflammation. • This is the first time to show that Corynoline alleviates Ang II-induced cardiac inflammation and remodeling by increasing PPARα and inhibiting the NF-κB pathway both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. Basic fibroblast growth factor (bFGF) is up-regulated in NSCLC patients and plays an important role in tumor growth. In this paper, we attempt to evaluate the therapeutic potential of bFGF binding peptide (named as P7) using as a potent bFGF antagonist via exploration of its anti-proliferation effect on NSCLC cells. Our experiments showed that P7 peptide inhibited bFGF-stimulated proliferation of NSCLC cell lines including A549, H1299, and H460. The inhibitory mechanism of P7 involved cell cycle arrest at the G0/G1phase caused by suppression of cyclin D1, blockage of the activation of Erk1/2, P38, Akt, and inhibition of bFGF internalization. Strategies using bFGF antagonist peptides with potent anti-proliferation property may have therapeutic potential in NSCLC. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. Basic fibroblast growth factor (bFGF) is up-regulated in NSCLC patients and plays an important role in tumor growth and angiogenesis. Therefore, it is regarded as a potential therapeutic target of NSCLC. We have previously obtained a high-affinity bFGF antagonist peptide (named P7) with the potential of suppressing angiogenesis stimulated by bFGF from the phage display random heptapeptide library. Herein, we further revealed the underlying anti-angiogenic mechanisms of P7 peptides in human NSCLC cells. P7 not only inhibited the expressions of angiogenesis related factors including VEGF, MMP-2 and MMP-9 at both transcriptional and translational levels, but also induced significant changes in the expressions of proteins related to tumor growth and progress. Our results suggested that P7 peptides with potent anti-angiogenic activity may have therapeutic potential in NSCLC. [ABSTRACT FROM AUTHOR]

Highlights: [•] An FGF8b gN helix derived peptide (8b-13) inhibits proliferation of prostate cancer cells. [•] 8b-13 arrests the cell cycle at the G0/G1 phase, and down-regulated the expression of cyclinD1. [•] 8b-13 reduces the activation of Erk1/2, P38, and Akt cascades [•] 8b-13 alters the expression of certain proteins involved in the regulation of proliferation. [•] Our findings suggest that 8b-13 may exert an antitumor effect in cancers with high FGF8b levels. [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]

Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1. Taken together, our results how that hyperglycemia activates CDK9-MAPK-AP1 axis in kidneys to induce inflammation and fibrosis, leading to renal dysfunction. Our findings also suggest that CDK9 may serve as a potential therapeutic target for DN. [Display omitted] • Hyperglycemia causes phosphorylation of CDK9, leading to activation of MAPK-AP1 pathway. • CDK9 inhibitor suppresses diabetes-induced inflammation and improves renal function in vivo. • CDK9 may potentially be the therapeutic target for the treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Kaempferia rhizome is a famous traditional herbal medical in tropical and subtropical areas. Kaempferol (KPF) is one of the main bioactive compounds in Kaempferia rhizome, with anti-oxidant/anti-inflammatory effects demonstrated in various disease models, including cancers, obesity and diabetes. Inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). TRAF6 functions as a signal transducer in toll-like receptor 4 and NF-κB pro-inflammatory signaling pathway. We aimed at investigate whether KPF is able to mitigate inflammatory responses by regulating TRAF6 in DN. C57BL/6 mice were injected with streptozotocin to induce type 1 DN. NRK-52E, a tubular epithelial cell line, was used for in vitro analysis. TRAF6 was knockdown using siRNA in vitro and AAV2/2-shRNA in vivo. The anti-DN and inflammatory effects of KPF or knockdown of TRAF6 were evaluated by investigating renal filtration index, pathological changes of kidney tissue. Proinflammatory cytokine levels were detected using ELISA. NF-κB pathway and protein levels of related pathways were detected through Western blot. KPF significantly reduced renal inflammation, fibrosis, and kidney dysfunction in diabetic mice. These effects were associated with a downregulation of TRAF6 in diabetic mouse kidneys, indicating the potential role of TRAF6. Knockdown of TRAF6 in mice through AAV2-shTRAF6 confirmed the importance of TRAF6 in DN. In vitro , treatment of KPF in NRK-52E cells attenuated high glucose (HG)-induced inflammatory and fibrogenic responses, associated with downregulated TRAF6 expression. The conclusion was further confirmed in NRK-52E cells by knocking down the expression and by overexpression of TRAF6. Our findings provide direct evidence that TRAF6 mediates diabetes-induced inflammation leading to renal dysfunction. We also show that KPF is a potential therapeutic agent to reduce inflammatory responses in DN. Also, TRAF6 may represent an interesting target to combat DN. Image 1 [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II)-induced vascular inflammation and injury entails endothelial to mesenchymal transition (EndMT). Recent studies have shown that Ang II engages toll-like receptor 4 (TLR4) in the vasculature to mediate adverse effects. Here, we aimed to investigate whether myeloid differentiation protein 2 (MD2), an extracellular molecule indispensable for TLR4 activation, mediates Ang II-induced vascular injury and EndMT. We utilized MD2 knockout mice and wildtype mice treated with a specific MD2 inhibitor to decipher its role in aortas of Ang II-challenged mice. To confirm our results and to provide mechanistic insights, we exposed cultured endothelial cells to Ang II, with or without MD2 silencing. We show that Ang II causes deleterious remodeling and EndMT in aortas of mice within two weeks. These Ang II effects were largely absent in MD2 knockout mice and in wildtype mice treated with a MD2 inhibitor. MD2 silencing in cultured endothelial cells confirmed the essential role of MD2 in Ang II-induced inflammatory factor induction, and EndMT-associated phenotypic change. We also found that Ang II-MD2-EndMT axis involves the activation of nuclear factor-κB. Our studies highlight an essential role of MD2 in Ang II-induced vascular inflammation and EndMT contributing to vascular injury. These results also imply that MD2 may be targeted to dampen inflammatory cardiovascular and EndMT-associated diseases. • MD2 deficiency alleviates Ang II-induced inflammation and EndMT in aortas in vivo. • Ang II-MD2-NF-κB axis induces the activation of vascular EndMT. • MD2 is a potential therapeutic target for vascular remodeling-related diseases. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) represents a common pathological state brought about by diabetes mellitus (DM). Patchouli alcohol (PatA) is known for its diverse advantageous effects, notably its anti-inflammatory properties and protective role against metabolic disorders. Despite this, the influence of PatA on DCM remains relatively unexplored. To explore the effect of PatA on diabetes-induced cardiac injury and dysfunction in mice, streptozotocin (STZ) was used to mimic type 1 diabetes in mice. Serological markers and echocardiography show that PatA treatment protects the heart against cardiomyopathy by controlling myocardial fibrosis but not by reducing hyperglycemia in diabetic mice. Discovery Studio 2017 software was used to perform reverse target screening of PatA, and we found that JAK2 may be a potential target of PatA. RNA-seq analysis of heart tissues revealed that PatA activity in the myocardium was primarily associated with the inflammatory fibrosis through the Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of the transcription 3 (STAT3) pathway. In vitro, we also found that PatA alleviates high glucose (HG) + palmitic acid (PA)-induced fibrotic and inflammatory responses via inhibiting the JAK2/STAT3 signaling pathway in H9C2 cells. Our findings illustrate that PatA mitigates the effects of HG + PA- or STZ-induced cardiomyopathy by acting on the JAK2/STAT3 signaling pathway. These insights indicate that PatA could potentially serve as a therapeutic agent for DCM treatment. [ABSTRACT FROM AUTHOR]

Prolonged stimulation of β-adrenergic receptor (β-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction (MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2 interacts with Calcium–calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2 overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2 in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential as a therapeutic target for combating the disease. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. All have been checked [ABSTRACT FROM AUTHOR]

Macrophage activation has been shown to play an essential role in renal fibrosis and dysfunction in hypertensive chronic kidney disease. Dectin-1 is a pattern recognition receptor that is also involved in chronic noninfectious diseases through immune activation. However, the role of Dectin-1 in Ang II-induced renal failure is still unknown. In this study, we found that Dectin-1 expression on CD68 + macrophages was significantly elevated in the kidney after Ang II infusion. We assessed the effect of Dectin-1 on hypertensive renal injury using Dectin-1-deficient mice infused by Angiotensin II (Ang II) at 1000 ng/kg/min for 4 weeks. Ang II-induced renal dysfunction, interstitial fibrosis, and immune activation were significantly attenuated in Dectin-1-deficient mice. A Dectin-1 neutralizing antibody and Syk inhibitor (R406) were used to examine the effect and mechanism of Dectin-1/Syk signaling axle on cytokine secretion and renal fibrosis in culturing cells. Blocking Dectin-1 or inhibiting Syk significantly reduced the expression and secretion of chemokines in RAW264.7 macrophages. The in vitro data showed that the increase in TGF-β1 in macrophages enhanced the binding of P65 and its target promotor via the Ang II-induced Dectin-1/Syk pathway. Secreted TGF-β1 caused renal fibrosis in kidney cells through Smad3 activation. Thus, macrophage Dectin-1 may be involved in the activation of neutrophil migration and TGF-β1 secretion, thereby promoting kidney fibrosis and dysfunction. [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]

In this paper, the dynamic process from period-doubling bifurcations to chaos is observed by changing the driving period of a modified Pohl’s torsion pendulum that formally exhibits periodical dynamics. A data acquisition system with a CCD camera connected to a computer and corresponding image processing software is designed to exhibit the dynamics of the modified pendulum automatically by recording the oscillating angle of the copper rotating wheel. As a result, abundant chaotic sequence diagrams and phase diagrams can be clearly seen in real time. In our experiment, we come up with a simple method simply by adding a fine iron bar with a matching nut on a Pohl’s torsion pendulum to improve the existing apparatus. As a result, the experiment itself is feasible—it is easy, cheap, and convenient to carry out—which allows undergraduate students to observe and to understand the unpredictability of deterministic mechanical systems and at the same time stimulates their interest in nonlinear dynamics and related experiments. [ABSTRACT FROM AUTHOR]

Heme, as an essential component of hemoproteins, is a prosthetic co-factor found in many cells, which is essential for physiologically vital oxygen transport. However, extracellular or circulatory heme is cytotoxic and triggers inflammation. Although the proinflammatory role of heme has been reported to be associated with Toll-like receptor 4 (TLR4) signaling, the exact mechanism remains unknown. Here, we show that heme promotes TLR4 signaling and inflammation via directly physically interacting with TLR4 and its adaptor protein myeloid differentiation protein 2 (MD2). Genetic loss of MD2 ameliorates heme-induced inflammation and inflammatory cytokine production in the spleen of MD2 knockout (MD2-/-) mice. Using mouse macrophage RAW 264.7 cell line, we show that heme induces TLR4 dimerization and MD2/TLR4/MyD88 activation by physically interacting with TLR4 and MD2 in vitro. Genetic loss of MD2 inhibits heme-induced inflammation and MAPK/NF-κB pathway in mouse primary macrophages extracted from MD2-/- mice. Furthermore, pharmacological inhibition of MD2 by L6H9 ameliorates heme-induced inflammation in macrophages. These findings demonstrate that heme causes inflammation by directly binding to MD2/TLR4 complex, leading to activation of TLR4/MAPK/NF-κB signaling pathway and production of downstream effectors of inflammation. [Display omitted] • Heme induces inflammatory response via directly binding to both of TLR4 and MD2. • Deletion of MD2 normalizes heme-induced systemic inflammation in mice. • Inhibition of MD2 attenuates heme-induced inflammation in macrophages. • MD2 could be a target for the therapy of high circulatory heme related diseases. [ABSTRACT FROM AUTHOR]

• The MyD88-dependent signaling cascade induced by Ang II was the predominant pro-inflammatory pathway in driving myocardial remodeling. • Sch B, isolated from Schisandra chinensis , selectively blocks Ang II-induced MyD88 but not TRIF recruitment in cardiomyocytes. • Sch B reduces the inflammatory and fibrosis responses in vitro and in vivo. • Sch B effectively inhibits the activation of MyD88-dependent signaling, thereby preventing Ang II-induced myocardial inflammation and remodeling. Cardiac tissue remodeling is characterized by altered heart tissue architecture and dysfunction, leading to heart failure. Sustained activation of the renin-angiotensin-aldosterone system (RAAS) greatly promotes the development of myocardial remodeling. Angiotensin II (Ang II), which is the major component of RAAS, can directly lead to cardiac remodeling by inducing an inflammatory response. Schisandrin B (Sch B), the active component extracted from the fruit of Schisandra chinensis (Turcz.) Baill has been shown to exhibit anti-inflammatory activity through its ability to target TLR4 and its adaptor protein, MyD88. In this study, we explored whether Sch B alleviates Ang II-induced myocardial inflammation and remodeling via targeting MyD88. Sch B significantly suppressed Ang II-induced inflammation as well as increased the expression of several genes of tissue remodeling (β-Mhc, Tgfb, Anp, α-Ska) both in vivo and in vitro. These protective effects of Sch B were due to the inhibition of recruitment of MyD88 to TLR2 and TLR4, suppressing the Ang II-induced NF-κB activation and reducing the following inflammatory responses. Moreover, the knockdown of Myd88 in cardiomyocytes abrogated the Ang II-induced increases in the production of inflammatory cytokines and expression of remodeling genes. These findings provide new evidence that the mechanism of Sch B protection was attributed to selective inhibition of MyD88 signaling. This finding could pave the way for novel therapeutic strategies for myocardial inflammatory diseases. [ABSTRACT FROM AUTHOR]

: The ovarian tumor (OTU) family consists of deubiquitinating enzymes thought to play a crucial role in immunity. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) pose substantial clinical challenges due to severe respiratory complications and high mortality resulting from uncontrolled inflammation. Despite this, no study has explored the potential link between the OTU family and ALI/ARDS. Using publicly available high-throughput data, 14 OTUs were screened in a simulating bacteria- or LPS-induced ALI model. Subsequently, gene knockout mice and transcriptome sequencing were employed to explore the roles and mechanisms of the selected OTUs in ALI. Our screen identified OTUD1 in the OTU family as a deubiquitinase highly related to ALI. In the LPS-induced ALI model, deficiency of OTUD1 significantly ameliorated pulmonary edema, reduced permeability damage, and decreased lung immunocyte infiltration. Furthermore, RNA-seq analysis revealed that OTUD1 deficiency inhibited key pathways, including the IFN-γ/STAT1 and TNF-α/NF-κB axes, ultimately mitigating the severity of immune responses in ALI. In summary, our study highlights OTUD1 as a critical immunomodulatory factor in acute inflammation. These findings suggest that targeting OTUD1 could hold promise for the development of novel treatments against ALI/ARDS. [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]

Purpose: The objectives of this study were to investigate the incidences of hepatitis B virus (HBV) reactivation and hepatitis in gastrointestinal cancer patients with positive hepatitis B surface antigen (HBsAg) after chemotherapy and assess the effect of antiviral therapy on preventing HBV reactivation and hepatitis. Methods: The medical records of gastric or colorectal cancer patients with positive HBsAg undergoing chemotherapy in West China Hospital were reviewed from January 2009 to August 2014. Results: One hundred and fifty-six patients were included. Seventy-six patients had no records of the baseline HBV DNA copy (bHDC) and received no antiviral therapy. Of 80 patients with known bHDCs, 39 patients received antiviral therapy. The incidence of HBV reactivation was 14.6 % in the non-antiviral group with known bHDCs ( n = 41), compared with 0 % in the antiviral group ( P = 0.039). Compared with 12.8 % in the antiviral group ( P = 0.034), 29.9 % of patients suffered from hepatitis in the total non-antiviral group ( n = 117). More patients with moderate/severe hepatitis were seen in the non-antiviral group ( P = 0.027). Non-antiviral therapy was the only risk factor for hepatitis in multivariate analysis (HR 3.195, 95 % CI 1.117-10.989; P = 0.043). Conclusions: HBV reactivation and hepatitis occurred in a significant proportion of gastrointestinal cancer patients with positive HBsAg who received chemotherapy. Antiviral therapy could reduce the incidences of HBV reactivation and hepatitis. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is one of the major causes of death among diabetic patients. Although studies have shown that curcumin analog C66 can remarkably relieve diabetes-associated cardiovascular and kidney complications, the role of SJ-12, SJ-12, a novel curcumin analog, in diabetic cardiomyopathy and its molecular targets are unknown. 7-week-old male C57BL/6 mice were intraperitoneally injected with single streptozotocin (STZ) (160 mg/kg) to develop diabetic cardiomyopathy (DCM). The diabetic mice were then treated with SJ-12 via gavage for two months. Body weight, fast blood glucose, cardiac utrasonography, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers were assessed. The potential target of SJ-12 was evaluated via RNA-sequencing analysis. The O-GlcNAcylation levels of SP1 were detected via immunoprecipitation. SJ-12 effectively suppressed myocardial hypertrophy and fibrosis, thereby preventing heart dysfunction in mice with STZ-induced heart failure. RNA-sequencing analysis revealed that SJ-12 exerted its therapeutic effects through the modulation of the calcium signaling pathway. Furthermore, SJ-12 reduced the O-GlcNAcylation levels of SP1 by inhibiting O-linked N -acetylglucosamine transferase (OGT). Also, SJ-12 stabilized Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a), a crucial regulator of calcium homeostasis, thus reducing hypertrophy and fibrosis in mouse hearts and cultured cardiomyocytes. However, the anti-fibrotic effects of SJ-12 were not detected in SERCA2a or OGT-silenced cardiomyocytes, indicating that SJ-12 can prevent DCM by targeting OGT-dependent O-GlcNAcylation of SP1.These findings indicate that SJ-12 can exert cardioprotective effects in STZ-induced mice by reducing the O-GlcNAcylation levels of SP1, thus stabilizing SERCA2a and reducing myocardial fibrosis and hypertrophy. Therefore, SJ-12 can be used for the treatment of diabetic cardiomyopathy. [Display omitted] • Compound SJ-12 alleviates cardiac dysfunction, hypertrophy, and fibrosis in DCM. • SJ-12 increases the level of SERCA2a, a crucial regulator of calcium homeostasis, thus playing a protective role in DCM. • Mechanistically, the cardiac protection effect of SJ-12 was targeting OGT-regulated O-GlcNAc-Sp1/SERCA2a axis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Active compound a24 is an effective DCLK1 inhibitor. • Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation via inhibiting DCLK1-mediated IKKβ phosphorylation. • Compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase involved in neurogenesis and human cancer. Recent studies have revealed a novel functional role for DCLK1 in inflammatory signaling, thus positioning it as a novel target kinase for respiratory inflammatory disease treatment. In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1. Bio-layer interferometry binding screening and kinase assays of the NVP-TAE684 derivatives led to the discovery of an effective DCLK1 inhibitor (a24), with an IC 50 of 179.7 nM. Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages with higher potency than the lead compound. Mechanistically, compound a24 inhibited LPS-induced inflammation by inhibiting DCLK1-mediated IKKβ phosphorylation. Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases. [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]

Constrained reinforcement learning (CRL), also termed as safe reinforcement learning, is a promising technique enabling the deployment of RL agent in real-world systems. In this paper, we propose a successive convex approximation based off-policy optimization (SCAOPO) algorithm to solve the general CRL problem, which is formulated as a constrained Markov decision process (CMDP) in context of the average cost. The SCAOPO is based on solving a sequence of convex objective/feasibility optimization problems obtained by replacing the objective and constraint functions in the original problem with convex surrogate functions. The proposed SCAOPO enables reuse of experiences from previous updates, thereby significantly reducing implementation cost when deployed in real-world engineering systems that need to online learn the environment. In spite of the time-varying state distribution and the stochastic bias incurred by off-policy learning, the SCAOPO with a feasible initial point can still provably converge to a Karush-Kuhn-Tucker (KKT) point of the original problem almost surely. [ABSTRACT FROM AUTHOR]

Sea perch iridovirus (SPIV) infection causes severe disease of fish and has led to economic loss of the sea perch Lateolabrax japonicus aquaculture industry. In this study, severe pathological damage of SPIV-infected sea perch was observed; the relationship of SPIV infection, gut microbial community structure, and gut transcripts of sea perch were explored. SPIV infection could inhibit normal immune function of the gut. The expression levels of immune genes such as MHC I, MHC II, TCR, BCR, and IgM were down-regulated during SPIV infection. Intestinal immunosuppression breaks the balance between mucosal immunity and gut microbes. Opportunistic pathogens such as Lawsonella , Corynebacterium , and Achromobacter expanded substantially following SPIV infection. The abundance of potential probiotics in aquatic animals such as Romboutsia declined following SPIV infection. Intestinal microbial lipopolysaccharide biosynthesis and bacterial secretion related functions increased in SPIV infection and correlated with the expression of intestinal lipopolysaccharide binding protein (LBP), TLR5, IL-1β and other genes. These results suggest that gut microbes can stimulate the innate immune system and trigger an acute inflammatory response through LPS. In conclusion, we analyzed the interaction between SPIV infection and gut microbes and provided a basis for further studies on the mechanism of SPIV pathogenesis and treatment. • The animal model of SPIV-infected sea perch was constructed. • SPIV induced immune response of the gut was evaluated. • Interaction between SPIV infection and gut microbes in sea perch was explored. [ABSTRACT FROM AUTHOR]

Heart failure represents a major cause of death worldwide. Recent research has emphasized the potential role of protein ubiquitination/deubiquitination protein modification in cardiac pathology. Here, we investigate the role of the ovarian tumor deubiquitinase 1 (OTUD1) in isoprenaline (ISO)- and myocardial infarction (MI)-induced heart failure and its molecular mechanism. OTUD1 protein levels were raised markedly in murine cardiomyocytes after MI and ISO treatment. OTUD1 deficiency attenuated myocardial hypertrophy and cardiac dysfunction induced by ISO infusion or MI operation. In vitro, OTUD1 knockdown in neonatal rat ventricular myocytes (NRVMs) attenuated ISO-induced injuries, while OTUD1 overexpression aggravated the pathological changes. Mechanistically, LC-MS/MS and Co-IP studies showed that OTUD1 bound directly to the GAF1 and PDEase domains of PDE5A. OTUD1 was found to reverse K48 ubiquitin chain in PDE5A through cysteine at position 320 of OTUD1, preventing its proteasomal degradation. PDE5A could inactivates the cGMP-PKG-SERCA2a signaling axis which dysregulate the calcium handling in cardiomyocytes, and leading to the cardiomyocyte injuries. In conclusion, OTUD1 promotes heart failure by deubiquitinating and stabilizing PDE5A in cardiomyocytes. These findings have identified PDE5A as a new target of OTUD1 and emphasize the potential of OTUD1 as a target for treating heart failure. [Display omitted] • OTUD1 is upregulated in ISO- and MI-induced heart failure mice. • OTUD1 directly interacts with and deubiquitinates PDE5A to increase its stability, resulting in the cardiomyocyte injuries. • ISO- and MI-induced heart failure is markedly decreased in OTUD1-deficient mice compared to wide-type mice. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a pathophysiological condition triggered by diabetes mellitus and can lead to heart failure. Doublecortin-like kinase protein 1 (DCLK1) is a multifunctional protein kinase involved in the regulation of cell proliferation, differentiation, survival, and migration. Current studies on DCLK1 mainly focus on cancer development; however, its role in non-tumor diseases such as DCM is yet to be deciphered. Our analysis revealed that DCLK1 was upregulated in cardiomyocytes of streptozotocin (STZ)-induced type 1 diabetic mouse, suggesting a correlation between DCLK1 and DCM progression. It was further demonstrated that either cardiomyocyte-specific DCLK1 knockout or pharmacological DCLK1 inhibitor DCLK1-IN-1 significantly alleviated cardiac hypertrophy and fibrosis in STZ-induced diabetic mice. RNA-seq analysis of heart tissues revealed that DCLK1 regulated the nuclear factor kappa B (NF-κB)-mediated inflammatory response in DCM. In vitro , DCLK1 activated NF-κB and the inflammatory response by inducing the IKKβ phosphorylation in high-concentration glucose (HG)-challenged cardiomyocytes. DCLK1-IN-1 also prevented HG-induced IKKβ/NF-κB activation and inflammatory injuries in cardiomyocytes. In conclusion, this study highlights the novel role of cardiomyocyte DCLK1 in regulating IKKβ/NF-κB, which aggravates inflammation to promote the pathogenesis of DCM. DCLK1 may serve as a new target for DCM treatment. [Display omitted] • DCLK1 is upregulated in the heart tissues of STZ-induced diabetic mice. • Either DCLK1 deletion in cardiomyocytes or pharmacological inhibition of DCLK1 attenuated DCM in diabetic mice. • DCLK1 regulates NF-κB pathway to aggravate inflammation in cardiomyocytes. • DCLK1 could be a novel therapeutic target for the treatment of inflammatory DCM. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH), a subtype of nonalcoholic fatty liver disease (NAFLD), is the leading cause of liver-related morbidity worldwide. Caspase recruitment domain family member 9 (CARD9), a myeloid cell-specific signaling protein, belongs to the CARD protein family. However, its role in NASH is unknown. Therefore, this study aimed to investigate the role of CARD9 in the development of NASH. NASH models were established using CARD9-knockout and wild-type mice. They were either fed a methionine/choline deficient (MCD) diet for 6 weeks or a high-fat high-cholesterol (HFHC) diet for 16 weeks. Liver fibrosis model was also developed using CCl 4. CARD9 deficiency accelerated steatohepatitis development in MCD or HFHC diet-fed mice, accompanied by an upregulation of fibrosis, adipogenesis, and proinflammatory genes. CARD9 deficiency was found to exacerbate CCl 4 -induced liver fibrosis. In vitro studies demonstrated that CARD9 deficiency induced the expression of S100a8/a9 through Toll-like receptor in Kupffer cells treated with palmitate. This led to an increased expression of proinflammatory, fibrosis, and lipid metabolism-related genes in NASH progression. These results highlight the role of CARD9 in the development of NASH and provide new insights into the therapeutic strategies for NASH. • CARD9−/− accelerated steatohepatitis development in different mouse NASH model. • CARD9−/− exacerbated CCl 4 -induced liver fibrosis in vivo. • CARD9−/− induced the expression of S100a8/a9 that activated TLR in Kupffer cells. • Targeting CARD9 could be a therapeutic strategy for the treatment of NASH. [ABSTRACT FROM AUTHOR]

Enhanced levels of angiotensin-2 (Ang-II) causes hypertensive heart failure (HHF) through non-hemodynamical and hemodynamical alterations. 20(S)-ginsenoside Rh2 (20(S)-Rh2) is a natural ginseng compound with numerous cardiovascular benefits. This investigation elucidates the influence of 20(S)-Rh2 on Ang-II-induced heart failure and cardiac alterations. Ang-II was administered in C57BL/6 mice for 4 weeks to induce HHF. In the last 2 weeks of treatment, 20(S)-Rh2 was orally administered in mice to assess the potential 20(S)-Rh2 mechanism. Subsequently, RNA sequencing was carried out. It was indicated that 20(S)-Rh2 suppresses myocardial fibrosis, hypertrophy, and inflammation, thereby inhibiting cardiac disruption in Ang-II-challenged mice without affecting blood pressure. According to the RNA sequencing data, this cardio-protective effect was linked with the (JNK)/AP 1 pathway. 20(S)-Rh2 alleviated heart tissue and cardiomyocytes inflammation by inhibiting the Ang-II-mediated JNK/AP-1 pathway. Within cardiomyocytes, JNK or AP-1 absence abolished the anti-inflammatory effects of 20(S)-Rh2. This study investigation indicated that 20(S)-Rh2 prevents cardiovascular dysfunction induced by Ang-II induced by decreasing JNK-regulated inflammatory responses, providing evidence for its use as an efficient regimen for HHF. [Display omitted] [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is one of the severe complications of diabetes mellitus-related microvascular lesions, which remains the leading cause of end-stage kidney disease. The genesis and development of DKD is closely related to inflammation. Myeloid differentiation 2 (MD2) mediates hyperlyciemia-induced renal inflammation and DKD development and is considered as a potential therapeutic target of DKD. Here, we identified a new small-molecule MD2 inhibitor, JM-9. In vitro , JM-9 suppressed high glucose (HG) and palmitic acid (PA)-induced inflammation in MPMs, accompanied by inhibition of MD2 activation and the downstream TLR4/MyD88-MAPKs/NFκB pro-inflammatory signaling pathway. Macrophage-derived factors increased the fibrotic and inflammatory responses in renal tubular epithelial cells, which were inhibited by treating macrophages with JM-9. Then, we investigated the therapeutic effects against DKD in streptozotocin-induced type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mouse models. Treatment with JM-9 prevented renal inflammation, fibrosis, and dysfunction by targeting MD2 in both T1DM and T2DM models. Our results show that JM-9, a new small-molecule MD2 inhibitor, protects against DKD by targeting MD2 and inhibiting MD2-mediated inflammation. In summary, JM-9 is a potential therapeutic agent for DKD. [Display omitted] • We designed a new small-molecule MD2 inhibitor, JM-9, which derived from curcumin. • JM-9 attenuates renal injury, inflammation and fibrosis both in T1DM and T2DM. • JM-9 inhibites MD2 activation and downstream pathway in diabetic nephropathy. • JM-9 is expected to be a therapeutic candidate for diabetic nephropathy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Chronic inflammation contributes to the development of DCM, • A novel MyD88 inhibitor, c17, has been shown to exhibit anti-inflammatory effect. • Compound c17 improved heart dysfunction, hypertrophy, and fibrosis in DCM. • The cardiac protection effect of c17 was mediated via suppressing the interaction of TLR4 and MyD88. • Compound c17 could be a potential candidate for DCM. Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and is associated with increased morbidity and mortality due to cardiac dysfunction. Chronic inflammation plays a significant role in the development of DCM, making it a promising target for novel pharmacological strategies. Our previous study has synthesized a novel compound, c17, which exhibited strong anti-inflammatory activity by specifically targeting to myeloid differentiation primary response 88 (MyD88). In this study, we evaluated the therapeutic effect of c17 in DCM. The small molecular selective MyD88 inhibitor, c17, was used to evaluate the effect of MyD88 on DCM in both high concentration of glucose- and palmitic acid-stimulated macrophages and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice. The treatment of c17 in T1DM mice resulted in improved heart function and reduced cardiac hypertrophy, inflammation and fibrogenesis. RNA sequencing analysis of the heart tissues revealed that c17 effectively suppressed the inflammatory response by regulating the MyD88-dependent pathway. Co-immunoprecipitation experiments further confirmed that c17 disrupted the interaction between MyD88 and Toll-like receptor 4 (TLR4), consequently inhibiting downstream NF-κB activation. In vitro studies demonstrated that c17 exhibited similar anti-inflammatory activity by targeting MyD88 in macrophages, which are the primary regulators of cardiac inflammation. Furthermore, conditioned medium derived from c17-treated macrophages showed reduced capacity to induce hypertrophy, pro-fibrotic reactions, and secondary inflammation in cardiomyocytes. In conclusion, the small-molecule MyD88 inhibitor, c17, effectively combated the inflammatory DCM, therefore could be a potential candidate for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Abstract Myeloid differentiation primary response protein 88 (MyD88), an essential adapter protein used by toll-like receptors (TLR), is a promising target molecule for the treatment of respiratory inflammatory diseases. Previous studies explored the activities of novel 2-amino-4-phenylthiazole analogue (6) in inflammation-induced cancer, and identified the analogue as an inhibitor of MyD88 toll/interleukin-1 receptor (TIR) homology domain dimerization. Here, we describe the synthesis of 47 new analogues by modifying different sites on this lead compound and assessed their anti-inflammatory activities in lipopolysaccharide-induced mouse primary peritoneal macrophages (MPMs). The most promising compound, 15d , was found to effectively interact with MyD88 protein and prevented formation of the MyD88 homodimeric complex. Furthermore, 15d showed in vivo anti-inflammatory activity in LPS-caused model of acute lung injury. This work provides new candidates as MyD88 inhibitors to combat inflammation diseases. Graphical abstract Image 1 Highlights • Forty-seven 2-amino-4-phenylthiazole analogues as MyD88 inhibitors were synthesized and evaluated for anti-inflammatory activity. • Active compound, 15d, was found to interact with MyD88 and inhibits its homodimerization. • 15d exhibited remarkable anti-inflammatory activities in LPS induced macrophages and acute lung injury mouse model. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the primary cause of mortality in patients with diabetes and obesity. Hyperglycemia and hyperlipidemia in diabetes alters cardiac function, which is associated with broader cellular processes such as aberrant inflammatory signaling. Recent studies have shown that a pattern recognition receptor called Dectin-1, expressed on macrophages, mediates pro-inflammatory responses in innate immunity. In the present study, we examined the role of Dectin-1 in the pathogenesis of diabetic cardiomyopathy. We observed increased Dectin-1 expression in heart tissues of diabetic mice and localized the source to macrophages. We then investigated the cardiac function in Dectin-1-deficient mice with STZ-induced type 1 diabetes and high-fat-diet-induced type 2 diabetes. Our results show that Dectin-1 deficient mice are protected against diabetes-induced cardiac dysfunction, cardiomyocyte hypertrophy, tissue fibrosis, and inflammation. Mechanistically, our studies show that Dectin-1 is important for cell activation and induction of inflammatory cytokines in high-concentration glucose and palmitate acid (HG + PA)-challenged macrophages. Deficiency of Dectin-1 generate fewer paracrine inflammatory factors capable of causing cardiomyocyte hypertrophy and fibrotic responses in cardiac fibroblasts. In conclusion, this study provides evidence that Dectin-1 mediates diabetes-induced cardiomyopathy through regulating inflammation. Dectin-1 may be a potential target to combat diabetic cardiomyopathy. [Display omitted] • Dectin-1 is upregulated in cardiac tissue of diabetic mice. • Dectin-1 aggravates diabetic cardiomyopathy via regulating Syk/NF-κB activation and cardiac inflammatory response. • Dectin-1-mediated cytokines in macrophages promote hypertrophy in cardiomyocytes and fibrosis in cardiac fibroblasts. • Targeting Dectin-1 may offer new promises in diabetes-induced cardiac injuries. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ginsenoside Rg5 (Rg5) occurs naturally in ginseng, which has shown various benefits for cardiovascular diseases. Increased level of Angiotensin II (Ang II) contributes to hypertensive heart failure via -hemodynamic and non-hemodynamic actions. Ginsenoside Rg5 (Rg5) occurs naturally in ginseng, which has shown various benefits for cardiovascular diseases. This study evaluated Rg5′s effects on Ang II-caused cardiac remodeling and heart failure. C57BL/6 mice developed hypertensive cardiac failure after four weeks of Ang II infusion. The mice were administered Rg5 via oral gavage for the last two weeks to investigate the potential mechanism of Rg5. RNA sequencing of heart tissues was performed for mechanistic studies. It was discovered that Rg5 inhibited cardiac inflammation, myocardial fibrosis, and hypertrophy, and prevented cardiac malfunction in mice challenged with Ang II, without altering blood pressure. RNA sequencing showed that Rg5′s cardioprotective effect involves the JNK/AP-1 signaling pathway. Rg5 diminished inflammation in mice hearts and cultured cardiomyocytes by blocking Ang II-activated JNK/AP-1 pathway. In the absence of JNK or AP-1 in cardiomyocytes, the anti-inflammatory effects of Rg5 were nullified. The study found that Rg5 preserved the hearts of Ang II-induced mice by reducing JNK-mediated inflammatory responses, suggesting that Rg5 is an effective therapy for hypertensive heart failure. [ABSTRACT FROM AUTHOR]

We focus on a dual-functional multi-input-multi-output (MIMO) radar-communication (RadCom) system, where a single transmitter with multiple antennas communicates with downlink cellular users and detects radar targets simultaneously. Several design criteria are considered for minimizing the downlink multiuser interference. First, we consider both omnidirectional and directional beampattern design problems, where the closed-form globally optimal solutions are obtained. Based on the derived waveforms, we further consider weighted optimizations targeting a flexible tradeoff between radar and communications performance and introduce low-complexity algorithms. Moreover, to address the more practical constant modulus waveform design problem, we propose a branch-and-bound algorithm that obtains a globally optimal solution, and derive its worst-case complexity as function of the maximum iteration number. Finally, we assess the effectiveness of the proposed waveform design approaches via numerical results. [ABSTRACT FROM AUTHOR]

• TET significantly alleviates AS via inhibiting STING pathway in both vitro and vivo. • TET attenuates immune cell infiltration, inflammatory response and aortic fibrosis in AS. • TET may serve as a potential therapeutic drug for AS. Atherosclerosis (AS) is a chronic inflammatory disease. Recent studies have showed that stimulator of interferon genes (STING), an important protein in innate immunity, mediates pro-inflammatory activation of macrophages in the development of AS. Tetrandrine (TET) is a natural bisbenzylisoquinoline alkaloid isolated from Stepania tetrandra and possesses anti-inflammatory activities, with unknown effects and mechanisms in AS. In this study, we explored the anti-atherosclerotic effects of TET and investigated the underlying mechanisms. Mouse primary peritoneal macrophages (MPMs) are challenged with cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) or oxidized LDL (oxLDL). We found that pretreatment with TET dose-dependently inhibited cGAMP- or oxLDL-induced STING/ TANK-binding kinase 1 (TBK1) signaling, then suppressing nuclear factor kappa-B (NF-κB) activation and pro-inflammatory factor expression in MPMs. ApoE-/- mice were fed a high-fat diet (HFD) to develop an atherosclerotic phenotype. Administration of TET at 20 mg/kg/day significantly reduced HFD-induced atherosclerotic plaques, accompanied with decreased macrophage infiltration, inflammatory cytokine production, fibrosis, and STING/TBK1 activation in aortic plaque lesions. In summary, we demonstrate that TET inhibits STING/TBK1/NF-κB signaling pathway to reduce inflammation in oxLDL-challenged macrophages and alleviate atherosclerosis in HFD-fed ApoE-/- mice. These findings proved that TET could be a potential therapeutic candidate for the treatment of atherosclerosis-related diseases. [ABSTRACT FROM AUTHOR]