Exploration of costunolide derivatives as potential anti-inflammatory agents for topical treatment of atopic dermatitis by inhibiting MAPK/NF-κB pathways.

Atopic dermatitis (AD) is a common inflammatory disease and it is very difficult to treat. In the present work, a series of costunolide derivatives have been prepared, and in vitro and in vivo anti-inflammatory activities have evaluated. The results showed that most derivatives displayed good inhibition of NO generation with low cytotoxicity, and 7d could inhibit the phosphorylation of P38, P65 NF-κB and IκB-α in LPS-induced RAW264.7 model. The in vivo researches showed that 7d could improve skin injury symptoms, decrease Th2-type cytokine levels, inhibit HIS levels, alleviate scratching and repaire the damaged skin barrier through the inhibition of phosphorylation of MAPK and NF-κB signaling pathways on MC903-induced AD model. Therefore, costunolide derivatives may be new potent anti-AD agents for further study.

Vasicine alleviates 2,4-dinitrochlorobenzene-induced atopic dermatitis and passive cutaneous anaphylaxis in BALB/c mice.

Atopic dermatitis (AD), a type of skin inflammation, is associated with immune response mediated by T-helper 2 (Th2) cells, and mast cells. Vasicine is an alkaloid isolated from Adhatoda vasica, a popular Ayurvedic herbal medicine used for treating inflammatory conditions. In the present study, the anti-AD effects of vasicine were evaluated on 2,4-dinitrochlorobenzene-induced AD-like skin lesions in BALB/c mice. The potential anti-allergic effects of vasicine were also assessed using the passive cutaneous anaphylaxis (PCA) test. The results showed that the oral administration of vasicine improved the severity of AD-like lesional skin by decreasing histopathological changes and restoring epidermal thickness. Vasicine also inhibited the infiltration of mast cells in the skin and reduced the levels of pro-Th2 and Th2 cytokines as well as immunoglobulin E in the serum. Finally, vasicine inhibited the expression of pro-Th2 and Th2 cytokines in skin tissues, indicating the therapeutic potential of vasicine for AD.

[Numerical Investigation of Particle Deposition in Human Nasal Cavity for Different Parameters of Spay Device].

Whether the drug is successfully transported to the focus area is the key to the treatment of the rhinitis disease. The efficiency of drug delivery is dependent on the design of nasal spray device. A three-dimensional model of nasal cavity was constructed from the head CT image data of a healthy human subject. The deposition of drug particles was simulated numerically by Computational Fluid Dynamics technique. The main variables of the study were the size and density of drug particles, the injecting speed of drugs etc. In conclusion, with the increase of particle intensity and injection speed, the deposition of particles in the affected area trends to increase after first slow decrease.

Vasicine attenuates atherosclerosis via lipid regulation, inflammation inhibition, and autophagy activation in ApoE-/- mice.

Atherosclerosis is marked with the accumulation of low-density lipoproteins and chronic inflammation. The anti-inflammatory therapies exert protective effects on atherosclerosis. Vasicine is a bioactive alkaloid with anti-inflammatory activity from a medicinal plant in Ayurveda and Unani. In this study, the effects of vasicine were evaluated on atherosclerosis in vivo and in vitro. The results showed that vasicine alleviated atherosclerotic lesions and regulated the lipid synthesis by reducing the levels of TC, TG, LDL-C and inhibiting the expresses of scavenger receptors (SR-A, CD36 and LOX-1) to inhibit foam cell formations. And vasicine decreased the levels of IL-1ß, IL-6, MCP-1, and TNF-α to modulate inflammatory response. Besides, vasicine downregulated MAPK and PI3K/AKT/mTOR pathway to activated autophagy, which inhibited the procession of atherosclerosis.

Association of carbon monoxide poisoning with cardiovascular disease risk: A systematic review and meta-analysis.

Objective: This study aims to provide an updated overview of the relationship between carbon monoxide poisoning (COP) and cardiovascular disease. Methods: A systematic literature search was conducted in PubMed, Embase, Cochrane, and Web of Science databases up to September 2023. The association between COP patients and cardiovascular adverse events was examined and summarized. The outcomes included arrhythmia, coronary heart disease, heart failure, myocardial infarction, major adverse cardiovascular events (MACE), carboxyhaemoglobin percent (COHB%), Pondus Hydrogenii (PH) electrocardiography (ECG) parameters. Results: Eight eligible articles, involving a total of 251,971 patients, were included for evidence synthesis. The analysis revealed a heightened incidence of MACE in patients with COP. Additionally, COP exhibited an impact on specific ECG parameters. The incidence of MACE after COP was found to be similar in Korean and Chinese populations, and there was no significant effect of gender or underlying diseases on MACE incidence following COP. The incidence of MACE after COP did not differ significantly in individuals aged 50 years and older. Conclusions: Considering the observed heterogeneity and potential biases in the selected studies, emergency physicians should be aware of the increased likelihood of cardiovascular events in patients diagnosed with COP.

Development of new dehydrocostuslactone derivatives for treatment of atopic dermatitis via inhibition of the NF-κB signaling pathway.

Atopic dermatitis (AD), a recurrent inflammatory systemic skin disease, is difficult to cure. In the present study, several ethylenediamine-derived dehydrocostuslactone (DHCL) derivatives were prepared to assess their in vitro and in vivo anti-inflammatory activities. The results indicated that DHCL derivatives inhibited NO generation with low cytotoxicity. In particular, compound 5d exhibited the best anti-inflammatory activity. Subsequent experiments revealed that 5d not only inhibited the LPS-induced inflammatory response in RAW264.7 cells via the MAPK-NF-κB signaling pathway inhibition but also significantly decreased Th2-type cytokine levels and inhibited the NF-κB signaling pathway activation in mice with MC903-induced AD. Therefore, DHCL derivatives may be considered as new agents for the treatment of AD.

Inhibitory effects of catalpol on DNCB-induced atopic dermatitis and IgE-mediated mast cells reaction.

Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease driven by immune dysregulation. Catalpol is an iridoids, possessing anti-inflammatory, antioxidant, and neuroprotective activities. It can be added to food as a dietary supplement. To evaluate the effects and mechanisms of catalpol on AD, both in vitro and in vivo studies were conducted. It was found that catalpol downregulated the phosphorylation of Lyn and Syk to inhibit various downstream pathways, including intracellular Ca2+ elevation, cytokines generation, and histamine release, which ultimately controlled mast cell (MCs) degranulation. The results showed that catalpol alleviated AD-like skin lesions and MC infiltration via regulation of pro-Th2 and Th2 cytokines in vivo. Furthermore, this compound reduced the levels of IgE in AD mice and improved allergic reactions in PCA mice. The results provided that catalpol was potentially developed as a dietary supplement to improve AD and other atopic diseases.

[3, 4- dinitro-furazan-based oxidation furazan acute and subchronic toxicity studies].

OBJECTIVE: To study the 3, 4- dinitro-furazan-based oxidation furazan (DNTF) of sub-acute toxicity and chronic toxicity, to determine the acute toxicity classification DNTF, the nature of toxic effects and major target organ for the development provide the basis for occupational exposure limits. METHODS: ( 1) Acute toxicity: The oral gavage method once infected, symptoms of poisoning of animals observed to calculate the LD50DNTF and 95% confidence limits. ( 2) sub-chronic experiment: selection of 96 healthy SD rats were randomly divided into four groups, doses of 25, 56.2, 125 mg/kg and the negative control group, Exposure for ninety days,five days a week, once a day, The rats were killed at end of Exposure, heart, liver, spleen, lung, kidney, brain,testis, uterus were taken to observe the pathological changes. RESULTS: ( 1) Acute oral toxicity test results indicate that DNTF rat oral LD50 greater than 5000 mg/kg, DNTF mice treated by oral LD50 4589 mg/kg, 95%confidence limit for the 4026-5230 mg/kg, Acute toxicity grade level is low toxicity compounds. (2) Sub-chronic toxicity experiment, the high-dose male rats, high, medium and low-dose group female rats weight gain than the negative control group, compared with the control group, the difference was statistically significant (P<0.05).125 mg/kg of serum alanine aminotransferase, aspartate aminotransferase was significantly higher. 125 mg/kg dose groups, liver, kidney, lung, testicular factor was significantly higher. Liver, kidney, lung histological examination showed obvious morphological changes. CONCLUSION: Acute toxicity grade DNTF low toxicity level compounds, target organ toxicity of liver, kidney and lung.

[Teratogenicity of 3, 4 two furazan-based oxidation furazan in rats].

OBJECTIVE: To study the teratogenicity of new high-energy compounds, 3, 4 two furazan-based oxidation furazan (DNTF) and the impact on human health, occupational exposure limits were provided for the following research. METHODS: Pregnant SD rats were randomly divided into five groups by Standard teratogenicity test, including three dose groups (5.0, 15.8, 50.0 mg/kg), the negative control (vegetable oil), and the positive control group (CP 10.0 mg/kg). Each 10 to 15 rats were in one group. Gavage was consecutive for rats during pregnancy 7 ∼ 12 d and then sacrifice after 20 d. RESULTS: There were no significantly difference between the three dose groups and negative controls in the pregnancy rate, the weight of pregnant rats, fetal weight, fetal growth, fetal malformation rate and internal organs, CONCLUSION: There were no maternal toxicity, embryo toxicity and teratogenicity for rats when DNTF in the range 5.0 ∼ 50.0 mg/kg.

[Study on acute and subchronic toxicity of ammonium dinitramide].

OBJECTIVE: To study the acute, subacute and subchronic toxicity induced by ammonium dinitramide (ADN), and to ascertain the gradation and target organs of acute toxicity induced by AND. METHODS: According to technical specifications for toxicity determination of chemicals, the oral tests for acute, subacute and subchronic toxicity induced by AND were performed for 90 days. RESULTS: The oral LDx for mouse and rat was 568.9 mg/kg and 616.6 mg/kg ADN respectively. The gradation of acute toxicity induced by AND was low level. The results of oral subacute and subchronic toxicity tests (for 28 and 90 days) showed that a gain in weight in group exposed to 123 mg/kg AND was significantly lower than that in control group (P<0.05), the TBIL and ALT in group exposed to 61.6 and 123 mg/kg AND significantly increased and the ratio of liver weight to body weight obviously decreased, as compared with control group, the number of animals with hepatic pathological changes in group exposed to 61.6 and 123 mg/kg AND was significantly higher than that in control group (P<0.05). CONCLUSION: The gradation of acute toxicity induced by ADN was low level. When the exposure dose of AND was 30.8 mg/kg, the adverse effect was not observed, and the target organ was liver.

[Study on mutagenicity and teratogenicity of ammonium dinitramide].

OBJECTIVE: To study the mutagenicity and teratogenicity induced by ammonium dinitramide(ADN). METHODS: According to technical specifications for toxicity determination of chemicals, Salmonella typhimurium reverse mutation assay (Ames assay), in vivo mammalian erythrocyte micronucleus test, sperm malformation test and teratogenesis test were used to detect the mutagenicity and teratogenicity induced by AND. RESULTS: When the exposure doses of AND were 8-5000 pg/plate, the result of Ames assay was negative. As compared with control group, the micronucleus rate of mice exposed to 113.8 mg/kg AND significantly increased(P<0.05), the sperm malformation rates of mice exposed to 54.4-272.0 mg/kg AND did not increased significantly. The survival rate of fetuses decreased, the rate of assimilated fetuses increased, the rate of fetus sternum agenesis enhanced in mice exposed to 319 mg/kg AND, as compared with controls. The rates of in the 4th-6th fetus sternum agenesis in groups exposed to 21.3, 79.7 and 319 mg/kg AND were higher than that in control group. The malformation rate of fetus bowels in groups exposed to 319 mg/kg AND was higher than that in control group. The teratogenic index of ADN was 30. CONCLUSION: AND may be a mutagen and induce the teratogenic effect.

Limonin attenuates the stemness of cervical carcinoma cells by promoting YAP nuclear-cytoplasmic translocation.

This work aimed to investigate the role and related mechanism of limonin in regulating the stemness of cervical carcinoma (CC) cells. In the present study, we constructed adriamycin-resistant CC cells and found that they exhibited greater stemness than parental cells. Additionally, limonin attenuated the stemness of CC cells that were resistant or sensitive to adriamycin, as evidenced by the decreases in spheroid formation capacity, stemness markers expression and ALDH1 activity, whereas limonin did not affect the viability of normal cervical epithelial cells. Furthermore, limonin enhanced adriamycin sensitivity and attenuated adriamycin resistance in CC cells. Mechanistically, the nuclear-cytoplasmic translocation of YAP, not TAZ, was promoted by limonin in CC cells. Additionally, YAP overexpression attenuated the inhibitory effects of limonin on CC cell stemness. Therefore, limonin can attenuate the stemness, and thus the chemoresistance, of CC cells by promoting the nuclear-cytoplasmic translocation of YAP.