Ethanol Extracts from the Aerial Parts of Inula japonica and Potentilla chinensis Alleviate Airway Inflammation in Mice That Inhaled Particulate Matter 10 and Diesel Particulate Matter.

Air pollution causes various airway diseases. However, many commonly used treatments can have high risks of side effects or are costly. To examine the anti-inflammatory properties of Inula japonica Thunb. and Potentilla chinensis Ser., a mouse model was generated via inhalation of both particulate matter 10 and diesel particulate matter, and 30% ethanol extracts of either I. japonica (IJ) or P. chinensis (PC) and a mixture of both ethanol extracts (IP) were orally administered to BALB/c mice for 12 days. IJ, PC, and IP inhibited immune cell numbers and their regulation in both the bronchoalveolar lavage fluid (BALF) and lungs. These agents suppressed the levels of interleukin (IL)-1α, IL-17, tumor necrosis factor (TNF)-α, C-X-C motif chemokine ligand (CXCL)-1, and CXCL-2 in BALF, and also inhibited F4/80 and IL-1 receptor-associated kinase (IRAK)-1 in lungs. They reduced the gene expression of TNF-α, CXCL-1, inducible NOS, COX-2, Mucin 5AC, and transient receptor potential cation channel subfamily V member 1 in lungs. These extracts also reduced histopathological changes and inflammatory progression, manifested as decreased cell infiltration, collagen deposition, and respiratory epithelial cell thickness. I. japonica and P. chinensis show potential for development as pharmaceuticals that suppress inflammatory progression and alleviate airway inflammation diseases caused by air pollutants.

3',4'-Dihydroxyflavone mitigates inflammatory responses by inhibiting LPS and TLR4/MD2 interaction.

BACKGROUND: We previously reported the potential inhibitory activity of 3',4'-dihydroxyflavone (DHF) on nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated macrophages. PURPOSE: We investigated the underlying molecular mechanisms of DHF in LPS-activated macrophages and evaluated its effect on LPS-induced septic shock in mice. METHODS: To explore the anti-inflammatory effect of DHF, nitrite, PGE2, and cytokines were measured in vitro and in vivo experiments. In addition, to verify the molecular signaling pathway, quantitative real time-PCR, luciferase assay, nuclear extraction, electrophoretic mobility shift assay, immunocytochemistry, immunoprecipitation, molecular docking analysis, and myeloid differentiation 2 (MD2)-LPS binding assay were conducted. RESULTS: DHF suppressed the LPS-induced expression of proinflammatory mediators through nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF3) inactivation pathways in RAW 264.7 macrophages. Importantly, molecular docking analysis and in vitro binding assays showed that DHF interacts with the hydrophobic pocket of MD2 and then interferes with the interaction between LPS and toll-like receptor 4 (TLR4). DHF inhibited LPS-induced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). Treatment of LPS-induced endotoxemia mice with DHF reduced the expression levels of pro-inflammatory mediators via the inactivation of NF-κB, AP-1, and signal transducer and activator of transcription 1 (STAT1) in the lung tissue, thus increasing the survival rate. CONCLUSION: Taken together, our data first time revealed the underlying mechanism of the DHF-dependent anti-inflammatory effect by preventing LPS from binding to the TLR4/MD2 complex. Therefore, DHF may be a possible anti-inflammatory agent for the treatment of LPS-mediated inflammatory diseases.

Protective effect of 7-hydroxyl-1-methylindole-3-acetonitrile on the intestinal mucosal damage response to inflammation in mice with DSS-induced colitis.

Ulcerative colitis (UC), a pathological condition of inflammatory bowel disease, is a chronic inflammatory disorder that involves an abnormal immune response and epithelial barrier dysfunction. Although we have previously reported the anti-inflammatory effects of 7-hydroxyl-1-methylindole-3-acetonitrile (7-HMIA), a synthesized analog of arvelexin on macrophages and paw edema, its anti-colitis effect and its mechanism are not known. In this study, colitis was induced in mice model by 4% (w/v) dextran sodium sulfate (DSS) solution in drinking water for 9 days. At the same time, from the first day of administering drinking water containing DSS, the animals were treated with 5-aminosalicylic acid (5-ASA), 75 mg/kg/day, orally) or 7-HMIA (10 or 20 mg/kg/day, intraperitoneally), depending on the experimental group, respectively. The studies were terminated on the tenth day of the experiment. Our data showed that 7-HMIA reduced the disease activity index and spleen/body weight (S/B) ratio, and improved the shortened colon length comparable to the effects of 5-ASA observed in the DSS-exposed mice. 7-HMIA, like 5-ASA, inhibited the histological damage, such as a thickened colonic muscle layer and shortened crypt length in the colon of the mice with DSS-induced colitis. 7-HMIA restored the tight junction-related proteins (occludin, claudin-1, and claudin-2) and epithelial-mesenchymal transition-mediated proteins (E-cadherin, N-cadherin, and vimentin) in the colon tissue of mice with DSS-induced colitis. Additionally, 7-HMIA (20 mg/kg/day) showed the inhibitory effects similar to that of 5-ASA on the myeloperoxidase activity, interleukin (IL)-6 production, and expression levels of inducible nitric oxide synthase (iNOS), and even showed greater inhibition of IL-1ß production in the DSS-induced mice. Furthermore, the DSS-induced activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) were effectively suppressed by 7-HMIA treatment like the effects of 5-ASA. Overall, our findings revealed that 7-HMIA decreased the severity of colitis by protecting the inflamed mucosal barrier by interfering with NF-κB and STAT3 activation.

Atherosclerosis by Virus Infection-A Short Review.

Atherosclerosis manifests by the thickening of artery walls and their narrowed channels through the accumulation of plaque. It is one of the most important indicators of cardiovascular disease. It can be caused by various factors, such as smoking, a high cholesterol diet, hypertension, hyperglycemia, and genetic factors. However, atherosclerosis can also develop due to infection. It has been reported that some bacteria and viruses can cause the development of atherosclerosis. Examples of these viruses are influenza viruses, herpes viruses, hepatitis viruses, or papillomaviruses, which are all prevalent and eminent globally for infecting the population worldwide. Moreover, many patients with coronavirus disease 2019 (COVID-19) showed symptoms of cardiovascular disease. In this review paper, the viruses linked to the development of atherosclerosis are introduced, and their viral characteristics, the mechanisms of the development of atherosclerosis, and the current vaccines and antiviral treatment methods are summarized.

Anti-Colitic Effect of an Exopolysaccharide Fraction from Pediococcus pentosaceus KFT-18 on Dextran Sulfate Sodium-Induced Colitis through Suppression of Inflammatory Mediators.

We previously reported the immunostimulatory effect of an exopolysaccharide fraction from Pediococcus pentosaceus KFT18 (PE-EPS), a lactic acid bacterium, in macrophages and primary splenocytes, as well as in cyclophosphamide-induced immunosuppressed mice. In this study, the anti-colitic activity of PE-EPS was investigated in a dextran sulfate sodium (DSS)-induced colitis animal model. PE-EPS relieved DSS-induced colitis symptoms, such as stool blood, decreased colon length, crypt disruption, and mucus layer edema. Regarding the molecular mechanism, PE-EPS reduced the enhanced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1) in the colon tissue of colitis-induced mice. Additionally, PE-EPS protected against DSS-induced phosphorylation of p65 and signal transducer and activator of transcription 1 (STAT1). These findings suggested that the exopolysaccharide fraction from Ped. pentosaceus KFT18 can be used to treat inflammatory bowel disease by alleviating colonic inflammation.

Mosloflavone-Resveratrol Hybrid TMS-HDMF-5z Exhibits Potent In Vitro and In Vivo Anti-Inflammatory Effects Through NF-κB, AP-1, and JAK/STAT Inactivation.

TMS-HDMF-5z is a hybrid of the natural products mosloflavone and resveratrol. It was discovered to show potent inhibitory effects against lipopolysaccharide (LPS)-induced production of inflammatory mediators in RAW 264.7 macrophages. However, its mechanism of action is unknown. Hence this study aimed to demonstrate and explore in vitro and in vivo anti-inflammatory effects of TMS-HDMF-5z and its mechanism of action employing RAW 264.7 macrophages and carrageenan-induced hind paw edema. This work revealed that TMS-HDMF-5z suppressed the LPS-induced inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein, mRNA, and promoter binding levels and tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6, and interferon-ß (IFN-ß) at the mRNA expression in RAW 264.7 macrophages. The results showed that TMS-HDMF-5z reduced the transcription and DNA binding activities of nuclear factor-κB (NF-κB) through inhibiting nuclear translocation of p65 and phosphorylation of κB inhibitor α (IκBα), IκB kinase (IKK), and TGF-ß activated kinase 1 (TAK1). Additionally, TMS-HDMF-5z attenuated the LPS-induced transcriptional and DNA binding activities of activator protein-1 (AP-1) by suppressing nuclear translocation of phosphorylated c-Fos, c-Jun, and activating transcription factor 2 (ATF2). TMS-HDMF-5z also reduced the LPS-induced phosphorylation of Janus kinase 1/2 (JAK1/2), signal transducers and activators of transcription 1/3 (STAT1/3), p38 mitogen-activated protein kinase (MAPK), and MAPK-activated protein kinase 2 (MK2). In rats, TMS-HDMF-5z alleviated carrageenan-induced hind paw edema through the suppressing iNOS and COX-2 via NF-κB, AP-1, and STAT1/3 inactivation. Collectively, the TMS-HDMF-5z-mediated inhibition of NF-κB, AP-1, and STAT1/3 offer an opportunity for the development of a potential treatment for inflammatory diseases.

DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity.

Specific antibody therapy, including mAbs and bispecific T cell engagers (BiTEs), are important new tools for cancer immunotherapy. However, these approaches are slow to develop and may be limited in their production, thus restricting the patients who can access these treatments. BiTEs exhibit a particularly short half-life and difficult production. The development of an approach allowing simplified development, delivery, and in vivo production would be an important advance. Here we describe the development of a designed synthetic DNA plasmid, which we optimized to permit high expression of an anti-HER2 antibody (HER2dMAb) and delivered it into animals through adaptive electroporation. HER2dMAb was efficiently expressed in vitro and in vivo, reaching levels of 50 µg/ml in mouse sera. Mechanistically, HER2dMAb blocked HER2 signaling and induced antibody-dependent cytotoxicity. HER2dMAb delayed tumor progression for HER2-expressing ovarian and breast cancer models. We next used the HER2dMAb single-chain variable fragment portion to engineer a DNA-encoded BiTE (DBiTE). This HER2DBiTE was expressed in vivo for approximately 4 months after a single administration. The HER2DBiTE was highly cytolytic and delayed cancer progression in mice. These studies illustrate an approach to generate DBiTEs in vivo, which represent promising immunotherapies for HER2+ tumors, including ovarian and potentially other cancers.

Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity.

The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET.