Jiedu Quyu Decoction mitigates monocrotaline-induced right-sided heart failure associated with pulmonary artery hypertension by inhibiting NLRP3 inflammasome in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Right-side heart failure could accelerate mortality in patients of pulmonary hypertension, Jiedu Quyu Decoction (JDQYF) was used to manage pulmonary hypertension, but its right-sided heart protective effect associated with pulmonary artery hypertension is still unclear. AIM OF THE STUDY: Here, we evaluated the therapeutic effect of JDQYF on monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension in Sprague-Dawley (SD) rats and investigated the potential mechanism of action. MATERIALS AND METHODS: The main chemical components of JDQYF were detected and analyzed using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. The effects of JDQYF were investigated using a rat model of monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension. We assessed the morphology of cardiac tissue using histopathology and the structure and function of the right heart using echocardiography. The biomarkers of heart failure, atrial natriuretic peptide and B-type natriuretic peptide, as well as serum pro-inflammatory markers, interleukin (IL)-1ß, and IL-18, were measured by enzyme-linked immunosorbent assay (ELISA). Furthermore, the mRNA and protein expression levels of NLRP3 (NOD-, LRR-, and pyrin domain-containing 3), capase-1, IL-1ß, and IL-18 in the right heart tissue were examined by real-time quantitative reverse transcription PCR and western blotting. RESULTS: JDQYF improved ventricular function, alleviated pathological lesions in the right cardiac tissue, reduced the expression levels of biomarkers of heart failure and serum pro-inflammatory factors (IL-1ß and IL-18), and downregulated the mRNA and protein expression levels of NLRP3, caspase-1, IL-1ß, and IL-18 in the right cardiac tissue. CONCLUSIONS: JDQYF possesses cardioprotective effect against right heart failure induced by pulmonary arterial hypertension, possibly owing to reduction of cardiac inflammation through the inhibition of NLRP3 inflammasome activation.

1-Tetracosanol isolated from the leaves of Eupatorium glandulosum, accelerates wound healing by expressing inflammatory cytokines and matrix metalloproteinase.

ETHNOPHARMACOLOGICAL RELEVANCE: The leave paste of the plant, Eupatorium glandulosum H. B & K, has been traditionally used to treat cuts and wounds by the tribal community of the Nilgiris district of Tamilnadu, India. AIM OF THE STUDY: The present study was carried out to investigate the wound healing potential of this plant extract and the compound, 1-Tetracosanol, isolated from the ethyl acetate fraction. MATERIALS AND METHODS: An in vitro study was designed to compare the viability, migration and apoptosis of the fresh methanolic extract fractions and 1-Tetracosanol using mouse fibroblast NIH3T3 cell lines and human keratinocytes HaCaT cell lines, respectively. 1-Tetracosanol was evaluated for its viability, migration, qPCR analysis, in silico, in vitro and in vivo. RESULTS: 1-Tetracosanol at the concentration of 800, 1600, 3200 µM has significant wound closure of 99% at 24 h. The compound when screened in silico against various wound healing markers, TNF-α, IL-12, IL-18, GM-CSF and MMP-9, revealed high binding energy of -5, 4.9 and -6.4 kcal/mol for TNF-α, IL-18 and MMP-9, respectively. Gene expression and the release of cytokines increased at an early stage of the wound repair. 1-Tetracosanol, at 2% gel showed 97.35 ± 2.06% wound closure at 21st day. CONCLUSION: 1-Tetracosanol is a good lead for drug development targeted towards wound healing activity and work in this direction is in progress.

Effects of hyperbaric oxygen on NLRP3 inflammasome activation in the brain after carbon monoxide poisoning.

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1ß and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air - i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by FluoroMyelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1ßß and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1ß and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

Reduction of expression of IL-18, IL-1ß genes in the articular joint by sumac fruit extract (Rhus coriaria L.).

BACKGROUND: Osteoarthritis is the most common malignant disease in the world. The disease is caused by changes in the metabolism, the structure and function of multiple joints, and joint tissues. Sumac is one of the indigenous plants of Iran and has traditionally been used as a spice in Iran. The aim of this study was to investigate the reduction of expression of IL-18, IL-1ß genes in the articular joint by sumac fruit extract (Rhus coriaria L.). METHODS: The alcoholic extract of sumac fruit (E.E.R.C.L) was prepared from the Genetic Reserve Center. Bleeding was used to provide synoviocyte cells from the joint and fluid of the anatomical metacarpal limb of the 8-month-old Holstein healthy calf without any signs of inflammation. Using cell-hemocytometer count, their viability was evaluated by trypan blue and after lipopolysaccharide (LPS) proliferation and injection to enhance the level of cytokines. After isolating the RNA and preparing the cDNA, RT-PCR and PCR were performed and then, using the real-time PCR method, the expression of the desired genes was investigated. RESULTS: In this study, after the expression of IL-18 cytokines, IL-1ß increased to 100%, and following the treatment with alcoholic extract, the reduction of expression of these cytokines was 33.61% and 29.01%, respectively. The results of anti-inflammatory effects showed that the alcoholic extract of sumac reduced the IL-1ß, IL-18 expression in LPS-stimulated cells. CONCLUSION: Sumac fruit extract can be an effective medication for reducing pain.

Shotgun proteomic analysis of porcine colostrum and mature milk.

The epitheliochorial nature of the porcine placenta prevents the transfer of maternal immunity. Therefore, ingestion of the colostrum immediately after birth is crucial for neonatal piglets to acquire passive immunity from the sow. We performed a shotgun proteomic analysis of porcine milk to reveal in detail the protein composition of porcine milk. On the basis of the Swiss-Prot database, 113 and 118 proteins were identified in the porcine colostrum and mature milk, respectively, and 50 of these proteins were common to both samples. Some immune-related proteins, including interleukin-18 (IL-18), were unique to the colostrum. The IL-18 concentration in the colostrum and mature milk of four sows was measured to validate the proteomic analysis, and IL-18 was only detected in the colostrum (191.0 ± 53.9 pg/mL) and not in mature milk. In addition, some proteins involved in primary defense, such as azurocidin, which has never been detected in any other mammal's milk, were also identified in the colostrum.

Targeting reactive oxygen species by edaravone inhalation in a rat hyperoxic lung injury model: role of inflammasome.

This study was undertaken to investigate the effect of edaravone inhalation on inflammasome activation in a rat hyperoxia-induced lung injury (HILI) model. Sprague Dawley rats (n = 61) were randomly assigned into three groups: Control group, HILI group and Edaravone (Eda) group. Rats in the Control group breathed room air, but those in the HILI group and Eda group were exposed to pure oxygen at 2.5 atmospheres absolute (atm abs) for six hours. Immediately after HILI, rats in the Eda group received inhalation of aerosol edaravone at 0.5 mg/ml for 30 minutes. Twenty-four hours later, rats were sacrificed. The bronchoalveolar lavage fluid (BALF) and lungs were obtained for detection of oxidative stress, IL-1beta, IL-18 and caspase-1; the lungs were collected for HE staining and TUNEL staining. The pathological features of the lungs of rats in the Eda group were significantly improved when compared with the HILI group, accompanied by reduction in apoptotic cells. In addition, in the Eda group, the malonyldialdehyde (MDA) was reduced and total antioxidant capacity (T-AOC) was increased significantly in the lung and BALF when compared with the HILI group (P < 0.05 for both). Moreover, the contents of IL-1beta, IL-18 and caspase-1 in the lung and BALF, downstream factors of inflammasome, were also dramatically lower in the Eda group than in the HILI group (P < 0.05 for all). These findings suggest that edaravone may inhibit inflammasome activation due to its anti-oxidative capacity exerting a protective effect on HILI.

The importance of interleukin 18, glutathione peroxidase, and selenium concentration changes in acute pancreatitis.

Cytokinemia and oxidative stress are important factors responsible for an inadequate immune response in the early course of acute pancreatitis (AP). The aim of the study was to evaluate the profiles of interleukin 18 (IL-18), glutathione peroxidase (GPx), and selenium concentrations in serum with respect to AP severity and to study the relationships between these parameters and recognized prognostic indicators of AP severity. Prospective clinical analyses were performed on 61 patients with mild and severe forms of AP and for 15 healthy volunteers. In both forms of AP severity, the IL-18 concentration in the serum was significantly higher than in healthy controls. In the severe form of AP, the IL-18 concentration was the highest and exceeded significantly the values recorded on the 1st, 2nd, 3rd, 5th, and 10th days of mild AP. A significantly lower GPx concentration in the serum was recorded in severe AP compared to the mild form and in the control group. There was a significantly lower selenium concentration in the severe form of AP. Significant correlations between GPx and selenium, between IL-18 and GPx, and between IL-18 and selenium were recorded. The ROC analysis shows a high prognostic accuracy of IL-18 and GPx concentrations in the determination of AP severity. IL-18 is released early in the course of AP and may be a key immunomodulator of the inflammatory response in the severe form of this disease. Low GPx and selenium concentrations in severe AP reflect the lower antioxidative ability in this form of AP. IL-18 and GPx may represent new indicators of AP severity.

Dietary soy phytoestrogens and ERalpha signalling modulate interferon gamma production in response to bacterial infection.

Diets rich in soy phytoestrogens have many potential health benefits but isoflavones such as genistein may suppress cell mediated immune function. The effect of dietary phytoestrogens on the host response to infection has not been extensively examined. Mice were fed a diet containing soy phytoestrogens and infected with Mycobacterium avium to establish a chronic infection and inflammatory response. As phytoestrogens may act through classical oestrogen receptors (ER), mice deficient in ERalpha signalling and wild type mice were evaluated for a panel of Type 1-associated cytokines (IFNgamma, IL-12 and IL-18) in the spleen. IFNgamma production in the spleen was increased approximately 4-fold in ERalpha-deficient mice fed a casein-based diet over wild type mice fed a casein-based diet (P < 0.05), suggesting a role for ERalpha in suppressing IFNgamma production. IL-18 levels in spleens of wild type mice were decreased compared to ERalpha-deficient mice on a casein diet. Splenic IL-12 and IL-18 levels were not affected in wild type and ERalpha-deficient mice on the phytoestrogen containing diets, with the exception that whole soy increased IL-12 levels in the tissues of ERalpha deficient mice. We conclude that ERalpha and dietary phytoestrogens can influence production of key regulatory cytokines in response to chronic bacterial infection.