ABSTRACT
Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 ≥ 64 μg/mL) could be efficiently recovered (MIC80 = 0.5-8 μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.
ABSTRACT
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent and antitumor potency. Particularly, compound was orally active and possessed excellent antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, .) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.
ABSTRACT
Objective:To investigate the effect of vagus nerve stimulation (VNS) on serum cytokines and neurotransmitters in epilepsy patients with depression.Methods:From March 2015 to 2018, 13 patients with epilepsy combined with depression undergoing VNS surgery in Brain Hospital of Hunan Province were selected as the research objects. The surgical efficacy, depression degree, serum cytokines and neurotransmitter changes before operation, 6 months and 12 months after operation were compared.Results:The effective rate of epilepsy treatment at 6 and 12 months after VNS were 61.5%(8/13) and 76.9%(10/13), respectively. After 6 months and 12 months, Hamiton Depression scale (HAMD) and self-rating depression scale (SDS) scores were significantly lower than those before operation ( P<0.05 or P<0.01). At 6 months after operation, serum 5-hydroxytryptamine (5-HT) level was significantly higher than that before operation, while serum interleukin (IL)-1α, IL-6 and tumor necrosis factor α (TNF- α) were significantly lower than those before operation ( P<0.05 or P<0.01). At 12 months after operation, 5-HT and dopamine (DA) were significantly increased, while IL-1 α, IL-2, IL-6 and TNF -α were significantly decreased ( P<0.05 or P<0.01). Conclusions:VNS may can improve epilepsy and depression by regulating the level of neurotransmitter and serum cytokines.
ABSTRACT
Tyrosyl-DNA phosphodiesterase Ⅰ (TdpⅠ ) is a recently discovered proteinthat catalyzes the hydrolysis of 3′-phosphotyrosyl bonds .Such linkages form in vivo during the interaction of DNA and topoisomerase Ⅰ (TopⅠ) .TdpⅠ has been regarded as a potential therapeutic co-target of TopⅠ because it has the functions of repairing Top Ⅰ compound and coun-teracting the effects of Top Ⅰ inhibitors .TdpⅠ inhibitors can not only synergizing with Top Ⅰ-targeting drugs (camptoth-ecins) ,but also strength the function of bleomycin ,topoisomerase Ⅱ (TopⅡ ) inhibitors (etoposide ,doxorubicin) and DNA alkylating agents .We summarized the researching advance of TdpⅠ inhibitors and focused on the introduction of the mecha-nism ,bioactivity and structure-activity relationship .
ABSTRACT
Objective: To explore early diagnostic value of combined detection of ischemia-modified albumin and other biochemical markers for acute coronary syndrome (ACS). Methods: A total of 156 patients, who received treatment within 4h because of chest pain onset, were divided into ACS group (n=112) and non-ischemic chest pain group (NICP group, n=44) according to coronary angiography (CAG). Blood sample was taken within 4h and during 4~8h after chest pain to measure cardiac biochemical markers, including ischemia-modified albumin (IMA), LDH, CK, CK-MB and cardiac troponin I (cTnI), comprehensive analysis was performed by detected results of above biochemical markers and CAG. Results: For diagnosis of ACS, within 4h after onset IMA possessed highest sensitivity (87.50%) and highest accuracy (80.77%), cTnI possessed highest specificity (95.45%); In 4～8h IMA still possessed highest sensitivity (91.07%), cTnI still possessed highest specificity（97.73%）, CK（85.90%），and IMA（85.25%）possessed highest accuracy （both CK and IMA had no significant difference）; According to comprehensive analysis, regardless of within 4h or during 4~8h after chest pain, IMA possessed highest sensitivity and highest accuracy, cTnI possessed highest specificity. Within 4h after chest pain, detection of IMA combined above-mentioned other four indexes increased sensitivity (89.28%), specificity （95.45%） and accuracy （91.02%）to highest level. Conclusion: For diagnosis of ACS, IMA possesses highest sensitivity and highest accuracy, cTnI possesses highest specificity; IMA combined above-mentioned other four indexes may increase sensitivity, specificity and accuracy to highest level.
ABSTRACT
Objective To investigate the effects of pretreatment with different concentrations of sufentanil of ketamine on the differentiation of human helper T cells in vitro. Methods Twenty-two healthy volunteers (11 males, 11 females) aged 20-45 yrs were enrolled in this study. In each volunteer 20 ml of blood was taken from peripheral vein and divided into 7 groups: control group (0.9% NaCl), 3 sufentanil groups (0.05, 0.5, 5.0 ng?ml-1) and 3 ketamine groups (100, 500, 2 500 ng?ml-1) .Whole blood and mononuclear cells from peripheral blood (PBMCs) were incubated in the presence of 0.9% NaCl or different concentrations of sufentanil or ketamine for 24 h. Then the stimulants-phorbolmyristate + lonomycin + glgistap (inhibitor of intracellular protein transport) were added to whole blood and phytohemagglutinin (PHA) was add to PBMCs. The whole blood was incubated for another 4h and PBMCs were incubated for another 48 h. Then the T-lymphocytes were collected for determination of intracellular level of IFN-?(as a marker of Th1 cells) and IL-4 (as a marker of Th2 cells) in the whole blood using three-color flow cytometry and the expression of CCR5 + (as a marker of Th1 cells) and CCR3 + (as a marker of Th2 cells) in PBMCs. The Th1/Th2 ratio was calculated. Results In sufentanil 0.5 and 5.0 ng?ml-1 groups the percentage of Th2 cells was significantly increased while the percentage of Th1 cells and Th1/Th2 ratio were significantly decreased. In ketamine 500 and 2 500 ng?ml-1 groups the percentage of both Th1 and Th2 cells were significantly decreased and the Th1/Th2 ratio was significantly increased. Conclusion Sufentanil can encourage helper cells to differentiate into Th2 cells while ketamine inhibit the helper cells to differentiate into Th1 and Th2 cells, especially the Th2 cells in a dose-dependent manner.