Chronic inflammation is a pivotal event in the pathogenesis of cardiovascular diseases, including atherosclerosis, restenosis, and coronary artery disease. The efficacy of current treatment or ...preventive strategies for such inflammation is still inadequate. Thus, new anti-inflammatory strategies are needed. In this study, based on molecular docking and structural analysis, a potential peptide KCF18 with amphiphilic properties (positively charged and hydrophobic residues) derived from the receptors of proinflammatory cytokines was designed to inhibit cytokine-induced inflammatory response. Simulations suggested that KCF18 could bind to cytokines simultaneously, and electrostatic interactions were dominant. Surface plasmon resonance detection showed that KCF18 bound to both tumor necrosis factor-α (TNF-α) and interleukin-6, which is consistent with MM/PBSA binding free energy calculations. The cell experiments showed that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors, suppressed TNF-α mRNA expression and monocyte binding and transmigration, and alleviated the infiltration of white blood cells in a peritonitis mouse model. The designed peptide KCF18 could remarkably diminish the risk of vascular inflammation by decreasing plasma cytokines release and by directly acting on the vascular endothelium. This study demonstrated that a combination of structure-based in silico design calculations, together with experimental measurements can be used to develop potential anti-inflammatory agents.
Interleukin (IL)-8 plays a vital role in regulating inflammation and breast cancer formation by activating CXCR1/2. We previously designed an antagonist peptide, (RF16), to inhibits the activation of ...downstream signaling pathways by competing with IL-8 in binding to CXCR1/2, thereby inhibiting IL-8-induced chemoattractant monocyte binding. To evaluate the effect of the RF16 peptide on breast cancer progression, triple-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells were used to investigate whether RF16 can inhibit the IL-8-induced breast cancer metastasis. Using growth, proliferation, and invasiveness assays, the results revealed that RF16 reduced cell proliferation, migration, and invasiveness in MDA-MB-231 cells. The RF16 peptide also regulated the protein and mRNA expressions of epithelial–mesenchymal transition (EMT) markers in IL-8-stimulated MDA-MB-231 cells. It also inhibited downstream IL-8 signaling and the IL-8-induced inflammatory response via the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways. In the xenograft tumor mouse model, RF16 synergistically reinforces the antitumor efficacy of docetaxel by improving mouse survival and retarding tumor growth. Our results indicate that RF16 significantly inhibited IL-8-stimulated cell growth, migration, and invasion in MDA-MB-231 breast cancer cells by blocking the activation of p38 and AKT cascades. It indicated that the RF16 peptide may serve as a new supplementary drug for breast cancer.
Breast cancer (BC) is a frequently diagnosed cancer among women worldwide. Currently, BC can be divided into different subgroups according to the presence of the following hormone receptors: estrogen ...receptor, progesterone receptor, and human epidermal growth factor receptor 2. Each of these subgroups has different treatment strategies. However, the presence of new metastatic lesions and patient deterioration suggest resistance to a given treatment. Various lines of evidence had shown that cytokines are one of the important mediators of tumor growth, invasion, metastasis, and treatment resistance. Interleukin-10 (IL-10) is an immunoregulatory cytokine, and acts as a poor prognostic marker in many cancers. The anti-inflammatory IL-10 blocks certain effects of inflammatory cytokines. It also antagonizes the co-stimulatory molecules on the antigen-presenting cells. Here, we review the current knowledge on the function and molecular mechanism of IL-10, and recent findings on how IL-10 contributes to the progression of BC.
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Currently,
infections are predominantly treated with albendazole. However, the use of albendazole can provoke certain neurological symptoms as a result of the immune response triggered by the dead ...worms. Therefore, treatment usually involves co-administration of corticosteroids to limit the inflammatory reaction. Corticosteroids play a useful role in suppressing inflammation in the brain; however, long-term usage or high dosage may make it problematic.Schisandrin B, an active ingredient from
, has been shown to have anti-inflammatory effects on the brain. This study aimed to investigate the effects and potential of schisandrin B in combination with albendazole to treat
-induced meningoencephalitis. Here, we show that albendazole-schisandrin B co-treatment suppressed neuroinflammation in
-infected mice and increased the survival of the mice. Accordingly, albendazole-schisandrin B co-treatment significantly inhibited inflammasome activation, pyroptosis, and apoptosis. The sensorimotor functions of the mice were also repaired after albendazole-schisandrin B treatment. Immune response was shown to shift from Th2 to Th1, which reduces inflammation and enhances immunity against
. Collectively, our study showed that albendazole-schisandrin B co-therapy may be used as an encouraging treatment for
-induced meningoencephalitis.
Three novel naphthalimide‐based derivatives were synthesized and tested in vitro as anticancer agents. Our previous report of the C4‐benzazole 1,8‐naphthalimide derivatives showed good inhibition ...against murine melanoma. We aimed to synthesize more potent agents and found that compound 5 reported in this article behaved 5‐ to 10‐fold potency than our previous best results. The unique structure of compound 5 consisted of a naphthalimide framework in which C4 position was linked with an ethylenediamine group where the amino group was coupled with a 2‐piconic acid moiety. Compound 5 exhibited the most potent inhibitory activity toward human DNA topoisomerase II proteins with IC50 value (2.6 ± 0.1 μM) against murine B16F10 melanoma cells among the three target compounds synthesized in this study. In accordance with this finding, the results of molecular docking also revealed that compound 5 has the highest affinity with human DNA topoisomerase II among the selected compounds. Compound 5, therefore, has high potential for becoming a lead compound.
A potent anticancer agent was synthesized and evaluated its biological activity against murine melanoma.
The high incidence of Mycobacterium infection, notably multidrug-resistant M. tuberculosis infection, has become a significant public health concern worldwide. In this study, we isolate and analyze a ...mycobacteriophage, BTCU-1, and a foundational study was performed to evaluate the antimycobacterial activity of BTCU-1 and its cloned lytic endolysins. Using Mycobacterium smegmatis as host, a mycobacteriophage, BTCU-1, was isolated from soil in eastern Taiwan. The electron microscopy images revealed that BTCU-1 displayed morphology resembling the Siphoviridae family. In the genome of BTCU-1, two putative lytic genes, BTCU-1_ORF7 and BTCU-1_ORF8 (termed lysA and lysB, respectively), were identified, and further subcloned and expressed in Escherichia coli. When applied exogenously, both LysA and LysB were active against M. smegmatis tested. Scanning electron microscopy revealed that LysA and LysB caused a remarkable modification of the cell shape of M. smegmatis. Intracellular bactericidal activity assay showed that treatment of M. smegmatis-infected RAW 264.7 macrophages with LysA or LysB resulted in a significant reduction in the number of viable intracellular bacilli. These results indicate that the endolysins derived from BTCU-1 have antimycobacterial activity, and suggest that they are good candidates for therapeutic/disinfectant agents to control mycobacterial infections.
Human interleukin-10 (IL-10) is an immunosuppressive and anti-inflammatory cytokine, and its expression is upregulated in tumor tissues and serum samples of patients with various cancers. Because of ...its immunosuppressive nature, IL-10 has also been suggested to be a factor leading to tumor cells' evasion of immune surveillance and clearance by the host immune system. In this study, we refined a peptide with 20 amino acids, named NK20a, derived from the binding region of IL-10 on the basis of in silico analysis of the complex structure of IL-10 with IL-10Ra, the ligand binding subunit of the IL-10 receptor. The binding ability of the peptide was confirmed through in vitro biophysical biolayer interferometry and cellular experiments. The IL-10 inhibitory peptide exerted anticancer effects on lymphoma B cells and could abolish the suppression effect of IL-10 on macrophages. NK20a was also conjugated with gold nanoparticles to target the chemotherapeutic 5-fluorouracil (5-FU)-loaded nanoparticles to enhance the anticancer efficacy of 5-FU against the breast cancer cell line BT-474. Our study demonstrated that NK20a designed in silico with improved binding affinity to the IL-10 receptor can be used as a tool in developing anticancer strategies.
Human CD93, an epidermal growth factor (EGF)-like domain containing transmembrane protein, is predominantly expressed in the vascular endothelium. Studies have shown that AA4, the homolog of CD93 in ...mice, may mediate cell migration and angiogenesis in endothelial cells. Soluble CD93 has been detected in the plasma of healthy individuals. However, the role of soluble CD93 in the endothelium remains unclear. Recombinant soluble CD93 proteins with EGF-like domains (rCD93D123, with domains 1, 2, and 3; and rCD93D23, with domains 2 and 3) were generated to determine their functions in angiogenesis. We found that rCD93D23 was more potent than rCD93D123 in stimulating the proliferation and migration of human umbilical vein endothelial cells (HUVECs). Production of matrix-metalloproteinase 2 increased after the HUVECs were treated with rCD93D23. Further, in a tube formation assay, rCD93D23 induced cell differentiation of HUVECs through phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase and extracellular signal-regulated kinases-1/2 signaling. Moreover, rCD93D23 promoted blood vessel formation in a Matrigel-plug assay and an oxygen-induced retinopathy model in vivo. Our findings suggest that the soluble EGF-like domain containing CD93 protein is a novel angiogenic factor acting on the endothelium.
“Jinchuang ointment” is a traditional Chinese herbal medicine complex for treatment of incised wounds. For more than ten years, it has been used at China Medical University Hospital (Taichung, ...Taiwan) for the treatment of diabetic foot infections and decubitus ulcers. Three different cases are presented in this study. “Jinchuang” ointment is a mixture of natural product complexes from nine different components, making it difficult to analyze its exact chemical compositions. To further characterize the herbal ingredients used in this study, the contents of reference standards present in a subset of the ointment ingredients (dragon’s blood, catechu, frankincense, and myrrh) were determined by HPLC. Two in vitro cell based assay platforms, wound healing and tube formation, were used to examine the biological activity of this medicine. Our results show that this herbal medicine possesses strong activities including stimulation of angiogenesis, cell proliferation, and cell migration, which provide the scientific basis for its clinically observed curative effects on nonhealing diabetic wounds.
Chemokine CXCL8 is crucial for regulation of inflammatory and immune responses via activating its cognate receptor CXCR1. In this study, molecular docking and binding free energy calculations were ...combined to predict the initial binding event of CXCL8 to CXCR1 for peptide drug design. The simulations reveal that in the initial binding, the N-loop of CXCL8 interacts with the N-terminus of CXCR1, which is dominated by electrostatic interactions. The derived peptides from the binding region of CXCL8 are synthesized for further confirmation. Surface plasmon resonance analyses indicate that the CXCL8 derived peptide with 14 residues is able to bind to the receptor CXCR1 derived peptide with equilibrium KD of 252 μM while the peptide encompassing a CXCL8 K15A mutation hardly binds to CXCR1 derived peptide (KD = 1553 μM). The cell experiments show that the designed peptide inhibits CXCL8-induced and LPS-activated monocytes adhesion and transmigration. However, when the peptides were mutated on two lysine residues (K15 and K20), the inhibition effects were greatly reduced indicating these two amino acids are key residues for the initial binding of CXCL8 to CXCR1. This study demonstrates that in silico prediction based functional peptide design can be effective for developing anti-inflammation drugs.
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