Melittin exhibits high antibacterial potency against drug-resistant bacteria. However, the clinical utility of melittin is limited by its serious hemolytic activity. Thus, the need for developing novel melittin analogues with high antimicrobial activity and low hemolytic activity has grown. We designed, synthesized, and evaluated 20 novel melittin analogues with varying hydrophobic, polar or positively charged amino acids. The results showed that 8 compounds had antimicrobial activity (MIC: 1-4 μg·mL^-1) against gram-positive pathogens equal to or better than that of melittin, and 16 compounds had low hemolytic activity (HC₅₀ ≥ 11.9 μg·mL^-1). Compounds 13 (MIC: 2-4 μg·mL^-1) and 15 (MIC: 1-2 μg·mL^-1) showed equal or better antimicrobial activity against both susceptible and resistant strains of Staphylococcus aureus and Enterococcus faecium compared to melittin (MIC: 4 μg·mL^-1). Compound 13 (HC₅₀: 24.0 ± 4.3 μg·mL^-1) displayed noticeably decreased hemolytic activity compared to melittin (HC₅₀: 5.3 ± 0.4 μg·mL^-1). This work established a base for further study on the structure-activity relationships and structure-toxicity relationships of melittin.

Seven novel derivatives of aminoadamantane with 1-aminosubstituted group were synthesized from amantadine or memantine individually in order to find new neuroprotective agent. Six of them are amides of two precursors, one is a 1-amino derivative of memantine substituted with 2-hydroxy propyl. Their chemical structures were confirmed by 1H NMR and HRMS. The neuroprotective activity in vitro was evaluated primarily with 500 micromol x L(-1) glutamate damaged SY5Y cell by measurement of MTT metabolic rate and LDH leakage rate. Glutamate reduced MTT metabolic rate, but increased LDH leakage rate significantly. The addition of new derivatives elevated the MTT value with their certain concentration, reduced cell death rate. Especially as for 3d and 4c, they fully normalized LDH leakage rate with concentration of 20 micromol x L(-1) during LDH measurement. These data indicated that 3d and 4c have significant protective effect on nerve cell against glutamate injury, deserved to be further tested and maybe helpful for treatment of neurodegenerative disease.
Amantadine ; analogs & derivatives ; chemical synthesis ; pharmacology ; Cell Death ; drug effects ; Cell Line, Tumor ; Glutamic Acid ; toxicity ; Humans ; L-Lactate Dehydrogenase ; metabolism ; Memantine ; chemistry ; Neuroblastoma ; metabolism ; pathology ; Neuroprotective Agents ; chemical synthesis ; pharmacology

19 cinnamamide/ester-triazole compounds were designed, synthesized and evaluated for their anti-Alzheimer's disease (AD) activity. Among them, compound 4f displayed excellent anti-β-amyloid protein (Aβ)-mediated cytotoxicity (EC₅₀ = 2.03 ± 2.45 μmol·L^-1) in APPswe cells and acetylcholinesterase inhibiton (IC₅₀ = 4.88 ± 4.70 μmol·L^-1). Further study indicated that, at dosages of (1, 5 and 25 mg·kg^-1), compound 4f was effective in improving spatial learning and memory deficits in Aβ_1-42-impaired mice, which was achieved by promoting the nonamyloidogenic signaling and inhibiting the amyloidogenic pathway, along with the suppression of Aβ-induced Tau phosphorylation. All animal experiments in this study were approved by the Experimental Animal Care and Use Committee of the Institute of Medicinal Biotechnology (IMB-20220908D701). In conclusion, compound 4f holds promise as a lead candidate for AD treatment, and the present study lays the foundation for its subsequent development.

OBJECTIVEIt is revealed that circulating fibrocytes are elevated in patients/animals with cardiac fibrosis, and this review aims to provide an introduction to circulating fibrocytes and their role in cardiac fibrosis.

DATA SOURCESThis review is based on the data from 1994 to present obtained from PubMed. The search terms were "circulating fibrocytes " and "cardiac fibrosis ".

STUDY SELECTIONArticles and critical reviews, which are related to circulating fibrocytes and cardiac fibrosis, were selected.

RESULTSCirculating fibrocytes, which are derived from hematopoietic stem cells, represent a subset of peripheral blood mononuclear cells exhibiting mixed morphological and molecular characteristics of hematopoietic and mesenchymal cells (CD34+/CD45+/collagen I+). They can produce extracellular matrix and many cytokines. It is shown that circulating fibrocytes participate in many fibrotic diseases, including cardiac fibrosis. Evidence accumulated in recent years shows that aging individuals and patients with hypertension, heart failure, coronary heart disease, and atrial fibrillation have more circulating fibrocytes in peripheral blood and/or heart tissue, and this elevation of circulating fibrocytes is correlated with the degree of fibrosis in the hearts.

CONCLUSIONSCirculating fibrocytes are effector cells in cardiac fibrosis.

Coronary Disease ; pathology ; Fibroblasts ; physiology ; Fibrosis ; pathology ; Heart Failure ; pathology ; Humans ; Hypertension ; pathology ; Myocardium ; pathology

Adolescent ; Adult ; Aged ; Female ; Hepatitis B, Chronic ; drug therapy ; Humans ; Male ; Medicine, Chinese Traditional ; Middle Aged

Z-Ligustilide, a major phthalide isolated from a widely used traditional Chinese medicine Ligusticum chuanxiong, possesses various pharmacological activities including neuroprotective, anti-inflammatory, antiproliferative and vasorelaxing effects. However, it is unstable and inclined to degrade in natural conditions, which limits its study and application greatly. In this study, degradation behavior of Z-ligustilide and its degradation products stored at room temperature under direct sunlight were investigated and structure elucidated by HPLC-UV, UPLC-QTOF-MS and NMR. Z-ligustilide degradation and total five degradation products were generated and detected. Two degradation products were unequivocally identified as senkyunolide I and senkyunolide H by comparison with reference compounds. Another two degradation products were further isolated by semi-preparative HPLC and structure elucidated as (E)-6, 7-trans-dihydroxyligustilide and (Z)-6, 7-epoxyligustilide by 1H and 13C NMR, respectively. The degradation pathways of Z-ligustilide were finally proposed. Oxidation, hydrolysis and isomerization are the major degradation reactions.
4-Butyrolactone ; analogs & derivatives ; isolation & purification ; metabolism ; Benzofurans ; metabolism ; Chromatography, High Pressure Liquid ; Hydrolysis ; Ligusticum ; chemistry ; Magnetic Resonance Spectroscopy ; Metabolic Networks and Pathways ; Oxidation-Reduction ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Objective To explore whether the expression level of heparanase (HPA) and its coagulation proteins on leukemic blast membrane could determine the hemostatic balance on the surface of leukemia cells.Methods Forty patients of leukemia were studied,and 20 patients with iron dificient anemia as the control group.Expression of tissue factor (TF),heparanase (HPA),tissue factor pathway inhibitor (TFPI),and urokinase plasminogen activator receptor (UPAR) on leukemic blast surfaces were analyzed by flowcytometry.Results The expression of TF,UPAR,and HPA in AML,ALL,CML,CLL and CRAL groups were significantly higher compared with the control group (t =.3.289,3.507,2.701,P ＜0.05; t =2.498,0.802,3.090,P ＜0.05; t =2.642,3.308,2.696,P ＜0.05; t =3.417,3.434,2.382,P ＜0.05; t =2.193,2.272,2.263,P ＜0.05).There were no significantly differences between the leukemic cell expression of TFPI and the control group (P ＞0.05).Expression of TF,UPAR,HPA in AML patients were significantly higher than ALL,CML and CLL groups (t =2.463,2.179,2.276,P ＜0.05; t =2.637,2.402,2.095,P ＜0.05; t =2.548,2.425,2.412,P ＜0.05).The levels of TF,UPAR and HPA in M3,M4 and M5 patients were higher than that of M1,M2 groups (P ＜0.05).There were no significantly differences among M3,M4 and M5 (P ＞0.05).Conclusions These results suggest that TF,UPAR and HPA are predominately expressed on leukemic blast surface,particularly in M3and M4,5 subtypes.The expression of coagulation proteins on blast membrane might determine the hemostatic balance on the surface of leukemia cells.

OBJECTIVEto explore effects of airborne fine particulate matter exposure on human respiratory symptoms and pulmonary function.

METHODSone hundred and seven field traffic policemen were recruited as airborne fine particulate matter high-exposure group and one hundred and one male residents as common exposure group. The individual sampler was used to measure fine particulate matter exposure levels of the two groups. To obtain personal information, especially respiratory symptoms such as cough, sputum, etc. a questionnaire survey was used. The pulmonary ventilation function was detected: forced expiratory vital capacity (FVC), the first 1 second forced expiratory volume (FEV1.0), FVC/FEV1.0% and peak flow values (PEF), and the difference of fine particulate matter exposure level and respiratory function of the two groups was compared.

RESULTS24 h individual average fine particulate matter exposure concentration of traffic police and residents were respectively (115.4 ± 46.17) microg/m(3) and (74.94 ± 40.09) microg/m(3), the traffic police PM2.5 exposure levels were significantly higher than the residents. In the incidence of respiratory symptoms, compared with high-exposure group and common exposure group, coughing, expectoration, throat unwell, asthma, short of breath and nose discomfort, traffic police group was higher than residents group (P < 0.05). The abnormal rate of lung ventilation function indexes, such as FVC and FEV1.0 was 25.23% and 12.15% respectively in high-exposure group, 11.88% and 2.97% in common exposure group, there was no statistical difference between two groups. Besides, the abnormal rate of FVC and FEV1.0, showed rising trend in high-exposure group with seniority.

CONCLUSIONlong-term higher levels of airborne fine particulate matter exposure, may impact respiratory health and impair pulmonary function.

Adult ; Air Pollutants ; adverse effects ; Humans ; Male ; Middle Aged ; Occupational Exposure ; Particle Size ; Particulate Matter ; adverse effects ; Police ; Pulmonary Ventilation ; Surveys and Questionnaires

Objective:To investigate the effect of plasma exchange (PE) and continuous blood purification(CRRT) on children with bee sting poisoning and multiple organ dysfunction syndrome (MODS).Methods:From January 2016 to September 2019, 37 children aged 9 months to 11 years with bee sting and MODS were treated with dexamethasone 0.5 mg/kg or methylprednisolone 3 mg-5 mg/kg anti allergic and anti-inflammatory and organ support. Among them, 26 cases were treated with plasma exchange and continuous blood purification (treatment group), and the rest 11 cases were only given conventional treatment, but did not receive blood purification treatment (control group).The critical illness score, liver and kidney functions, myolysis, pulmonary hemorrhage/pulmonary edema, coagulation disorders, shock, hemolysis, gastrointestinal failure and other organ damage, ICU stay time, mechanical ventilation time, organ dysfunction recovery time and clinical outcomes were retrospectively analyzed. In the treatment group, 18 cases started blood purification before 12 h after MODS (early treatment group) and 8 cases started blood purification after 12 h (delayed treatment group).Results:There was no significant difference in age, sex, child critical illness score, onset time and organ function damage between the treatment and control groups ( P>0.05). The cure rate of the treatment group was higher than that of the control group [(25/26 (96.15%) vs 8/11 (72.73%), P=0.036]. There was no significant difference in ICU stay between the control group and the treatment group [(10.03±7.74) d vs (12.01±6.95) d, P>0.05]. Among the 25 survivors in the treatment group, one patient had mild renal function damage and one patient had multiple necrosis of skin, subcutaneous and muscle tissue. Compared with 4 of the 8 survivors in the control group, the residual organ function damage in the treatment group was significantly less than that in the control group [(2/25 (8.00%) vs 4/8 (50.00%), P=0.031)].The recovery of liver function, renal function, myolysis and hemolysis in the treatment group was faster than those in the control group (all P < 0.05). The initiation of blood purification within 12 h after the occurrence of MODS required fewer times of plasma exchange and shorter CRRT time, ICU stay and ventilator time (all P < 0.05). Conclusions:In children with bee sting combined with MODS, plasma exchange and continuous blood purification can achieve better therapeutic effect and better clinical outcome.

Objective To investigate the prognosis of adenoid cystic carcinoma (ACC) in salivary gland and its influencing factors.Methods Clinical and following-up data of 76 patients with ACC in salivary glands were reviewed. Major gland tumors represented 35.5％ whereas minor gland tumors comprised 64.5％ of the cohort,with 8 cases ( 10.5％ ) in stage I,23 (30.3％ ) in stage Ⅱ,18 (23.7％) in stage Ⅲ and 27 (35.5％) in stage Ⅳ. Survival rates were calculated by Kaplan-Merier method.Cumulative survival curves were evaluated using the Log-rank test. Multivariate analysis was performed by Cox proportional hazard model.Results The regional recurrence rate was 28.9％ and distant metastasis rate was 21.1％.The overall 5-year survival rate,tumor-free survival rate and tumor-related survival rate were 73.7％,61.8％ and 74.9％ respectively.The overall 10-year survival rate,tumor-free survival rate and tumor-related survival rate were 48.2％,39.8％ and 56.2％ respectively.Univariate survival analysis showed pathological type,clinical stage and perineural invasion were relevant to the prognosis of ACC and multivariate analysis showed they were the independent prognostic factors of ACC in salivary gland.Conclusions Clinical stage,pathological type and perineural invasion were the independent prognostic factors for adenoid cystic carcinoma in salivary gland. Surgery was the first choice for the treatment of adenoid cystic carcinoma in salivary gland,and postoperative radiotherapy may prolong the tumor-free survival time of patients in stage Ⅲ and Ⅳ.