Design and synthesis of novel 20(S)-α-aminophosphonate derivatives of camptothecin as potent antitumor agents.

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial.

Fungicidal Activity and Mechanism of Action of Glabridin from Glycyrrhiza glabra L.

Glycyrrhiza glabra (Licorice) belongs to the Fabaceae family and its extracts have exhibited significant fungicidal activity against phytopathogenic fungi, which has mainly been attributed to the presence of phenolic compounds such as flavonoids, isoflavonoids and chalcones. In this study, a series of licorice flavonoids, isoflavonoids and chalcones were evaluated for their fungicidal activity against phytopathogenic fungi. Among them, glabridin exhibited significant fungicidal activity against ten kinds of phytopathogenic fungi. Notably, glabridin displayed the most active against Sclerotinia sclerotiorum with an EC50 value of 6.78 µg/mL and was 8-fold more potent than azoxystrobin (EC50, 57.39 µg/mL). Moreover, the in vivo bioassay also demonstrated that glabridin could effectively control S. sclerotiorum. The mechanism studies revealed that glabridin could induce reactive oxygen species accumulation, the loss of mitochondrial membrane potential and cell membrane destruction through effecting the expression levels of phosphatidylserine decarboxylase that exerted its fungicidal activity. These findings indicated that glabridin exhibited pronounced fungicidal activities against S. sclerotiorum and could be served as a potential fungicidal candidate.

Bioassay-guided isolation of two antifungal compounds from Magnolia officinalis, and the mechanism of action of honokiol.

Magnolia officinalis, as a well-known herb worldwide, has been widely used to treat multiple diseases for a long time. In this study, the petroleum ether extract from M. officinalis showed effective antifungal activity against seven plant pathogens (particularly against R. solani with an inhibition rate of 100.00% at 250 µg/mL). Honokiol and magnolol, isolated by the bioassay-guided method, exhibited greater antifungal activity than tebuconazole (EC50 = 3.07 µg/mL, p ≤ 0.001) against R. solani, which EC50 values were 2.18 µg/mL and 3.48 µg/mL, respectively. We used transcriptomics to explore the mechanism of action of honokiol against R. solani. Results indicated that honokiol may exert antifungal effects by blocking the oxidative phosphorylation metabolic pathway. Further studies indicated that honokiol induced ROS overproduction, disrupted the mitochondrial function, affected respiration, and blocked the TCA cycle, which eventually inhibited ATP production. Besides, honokiol also damaged cell membranes and caused morphological changes. This study demonstrated that the lignans isolated from M. officinalis possess the potential to be developed as botanical fungicides.

Assessing executive function following the early stage of mild Ischemic stroke with three brief screening tests.

OBJECTIVE: Executive dysfunction following stroke is well documented, but less is known about whether it occurs in mild stroke patients. The purpose of the study was to investigate executive impairment in this population and explore the correlation between executive function tests and cognitive tests of other domains. METHODS: Cross-sectional study was undertaken to compare 139 mild ischemic stroke patients (National Institute of Health Stroke Scale (NIHSS) ≤ 7) aged 40-80 with 131 normal controls matched age, gender and levels of education. All participants were administered a neuropsychological test battery including three measures of executive functioning: Clock Drawing Test (CDT), Trial Making Test-A and B (TMT-A and B), and Stroop Color Word Test (SCWT). The CDT was evaluated using three quantitative scoring rubrics, with a total score of 3,10,18, respectively and a qualitative scoring method with six types of errors. Spearman's correlations were made to analyze the correlation between executive function tests and other neuropsychological tests. RESULTS: Control group performed better than stroke group on most executive function tests at a statistical significance. Qualitative CDT showed that errors of "graphic difficulties", "conceptual deficits" and "spatial and/or planning deficits" occurred frequently in the early stage of mild stroke. Correlation data clarified that among the executive function tests, time for TMT-B correlated with global cognition most. CONCLUSION: Executive dysfunction is common following even mild strokes, and that relatively brief measures such as CDT, TMT and SCWT can be employed for it before discharge as part of rehabilitation planning.

Trends in cognitive function assessed by a battery of neuropsychological tests after mild acute ischemic stroke.

OBJECTIVE: The aim of this study is to investigate the domain-specific trends of cognitive function up to 12 months after mild acute ischemic stroke. METHODS: Enrolment of consecutive cohort of patients with mild acute ischemic stroke with recorded clinical characteristics and extensive neuropsychological assessments, including five cognitive domains. The Montreal cognitive assessment of the Beijing version (MoCA-Bj) was used to assess overall cognition. All patients completed all domain-specific examinations were categorised into three groups according to the time between the stroke onset and neuropsychological profiling, the time duration including less than one month (n = 174), one month to six months (n = 65) and over six months (n = 39). RESULTS: The final cohort consisted of 278 patients. The executive (χ2 = 6.95, P<0.05) and memory dysfunctions (χ2 = 9.6, P<0.01) showed strong improvement, especially in executive function, which prevalence was 48.85% at <1- month group and 25.64% at >6 months group. The prevalence of attention and information processing also had a declining trend, the differences, however, were not statistically significant (χ2 = 0.23 and 2.25, respectively, P>0.05). There was no significant change in language function (χ2 = 0.46, P>0.05) and the MoCA (χ2 = 0.59, P>0.05) at 3-time point groups. In 195 first-ever stroke patients, the results of memory (χ2 = 6.94 P<0.05) and executive dysfunctions (χ2 = 6.25 P<0.05) also showed significant improvement. CONCLUSION: There is varying degree of improvement tendency in executive and memory dysfunctions after mild acute ischemic stroke. Early cognitive assessments after mild acute ischemic stroke do not reflect the cognitive level of stable period.

Design, synthesis and antifungal activity evaluation of isocryptolepine derivatives.

In this paper, the nitrogen atom was inserted into the anthracycline system of the isocryptolepine nucleus to obtain the "Aza"-type structure benzo[4,5]imidazo[1,2-c] quinazoline. A series of "Aza"-type derivatives were designed, synthesized and evaluated for their antifungal activity against six plant fungi in vitro. Among all derivatives, compounds A-0, B-1 and B-2 showed significant antifungal activity against B. cinerea with the EC50 values of 2.72 µg/mL, 5.90 µg/mL and 4.00 µg/mL, respectively. Compound A-2 had the highest activity against M. oryzae with the EC50 values of 8.81 µg/mL, and compound A-1 demonstrated the most control efficacy against R. solani (EC50, 6.27 µg/mL). Moreover, compound A-0 was selected to investigate the in vivo tests against B. cinerea and the results indicated that the preventative efficacy of it up to 72.80% at 100 µg/mL. Preliminary mechanism studies revealed that after treatment with A-0 at 5 µg/mL, the B. cinerea mycelia appeared curved, collapsed and the cell membrane integrity may be damaged. The reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia have been changed, and the membrane function and cell proliferation of mycelia were destroyed. Compounds A-0, A-1, B-1 and B-2 presented weaker toxicities against two cells lines than isocryptolepine. This study lays the foundation for the future development of isocryptolepine derivatives as environmentally friendly and safe agricultural fungicides.

Anti-phytopathogenic activity and the possible mechanisms of action of isoquinoline alkaloid sanguinarine.

Isoquinoline alkaloids possess broad pharmacological activities. In this study, the antifungal activity of twelve isoquinoline alkaloids, including berberine (1), jatrorrhizine (2), coptisine (3), corydaline (4), tetrahydroberberine (5), chelidonine (6), dihydrosanguinarine (7), chelerythrine (8), sanguinarine (9), palmatine (10), tetrahydropalmatine (11) and columbamine (12) were evaluated against eight plant pathogenic fungi in vitro. All the tested compounds showed varying degrees of inhibition against the eight tested plant fungi. Among them, sanguinarine exhibited high antifungal activity (EC50 ranging from 6.96-59.36 µg/mL). It displayed the best inhibitory activity against Magnaporthe oryzae (EC50 = 6.96 µg/mL), compared with azoxystrobin (EC50 = 12.04 µg/mL), and significantly suppressed spore germination of M. oryzae with the inhibition rate reaching 100% (50 µg/mL). The optical microscopy and scanning electron microscopy observations revealed that after treating M. oryzae mycelia with sanguinarine at 10 µg/mL, the mycelia appeared curved, collapsed and the cell membrane integrity was eventually damaged. Furthermore, the reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia had been changed, and the membrane function and cell proliferation of mycelia were destroyed. These results will enrich our insights into action mechanisms of antifungal activity of sanguinarine against M. oryzae.

Angiotensin II receptor type 1 blocker candesartan improves morphine tolerance by reducing morphine­induced inflammatory response and cellular activation of BV2 cells via the PPARγ/AMPK signaling pathway.

Morphine is the most common drug of choice in clinical pain management; however, morphine tolerance presents a significant clinical challenge. The pathogenesis of morphine tolerance is known to be closely associated with angiotensin II receptor type 1 (AT1R) in microglia. As an AT1R antagonist, candesartan may serve an important role in regulating morphine tolerance. Therefore, the present study aimed to investigate the role of candesartan in morphine tolerance, and to explore the underlying mechanism. To meet this aim, BV2 microglial cells were treated with morphine or candesartan alone, or as a combination, and the expression levels of AT1R in BV2 cells were detected by reverse transcription­quantitative PCR (RT­qPCR) and western blotting. The levels of the inflammatory cytokines tumor necrosis factor­α, interleukin (IL)­1ß and IL­6 were subsequently detected by ELISA and western blotting. In addition, immunofluorescence analysis, western blotting and RT­qPCR were used to detect the expression levels of the BV2 cell activation marker, ionized calcium­binding adaptor molecule 1 (IBA­1). Western blotting was also used to detect the expression levels of peroxisome proliferator­activated receptor­Î³/AMP­activated protein kinase (PPARγ/AMPK) signaling pathway­associated proteins. Finally, the cells were treated with the PPARγ antagonist GW9662 and the AMPK inhibitor compound C to further explore the mechanism underlying the effects of candesartan on improving morphine tolerance. The expression levels of AT1R were revealed to be significantly increased following morphine induction; however, candesartan treatment inhibited the expression levels of AT1R, the levels of inflammatory cytokines and the protein expression levels of IBA­1 in morphine­induced BV2 cells in a dose­dependent manner. These processes may be associated with activation of the PPARγ/AMPK signaling pathway. Taken together, the present study revealed that treatment with candesartan reduced morphine­induced inflammatory response and cellular activation of BV2 cells via PPARγ/AMPK signaling.

The montreal cognitive assessment and mini-mental state examination visuoexecutive subtests in acute ischemic stroke patients and their correlations with demographic and clinical factors.

Visuoexecutive impairment is common among acute ischemic stroke patients. This study aimed to examine the ability of the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) visuoexecutive subtests to detect visuoexecutive abnormality in acute ischemic stroke patients and to identify the predictors for their impairments. 336 patients who completed the MMSE and MoCA were enrolled in this study. We compared the proportion of participants with incorrect MoCA visuoexecutive tasks and MMSE pentagon copying. Multivariate logistic regression analysis was used to evaluate the associations between the visuoexecutive dysfunction and demographic and clinical characteristics in the samples. Among all the participants, the MoCA detected more visuoexecutive dysfunction than the MMSE (88.69% vs. 45.83%, respectively; p < 0.001). The predictors identified by the univariate analysis included the factors of gender, age, educational level, smoking, alcohol consumption, Oxfordshire Community Stroke Project (OCSP), previous strokes, initial NIHSS score and number of old lacunar infarctions, while from the multivariate logistic regression analysis, the factors of age, educational level, NIHSS score, previous strokes and number of old lacunar infarctions served as predictive factors for the visuoexecutive impairment in acute stroke patients. In conclusion, visuoexecutive impairment is associated with the factors of the educational level, stroke severity, stroke history and number of old lacunar infarctions. Our findings may guide the clinicians to intervene the risks for the patients at an early stage after stroke and form the basis for good rehabilitation plans.

Dendritic cells in tumor microenvironment promoted the neuropathic pain via paracrine inflammatory and growth factors.

Neuropathic pain associated with cancers was caused by tumor itself or tumor therapy, which was aggravated by sensitizing nociceptor sensory neurons. The tumor microenvironment contributed to tumorigenesis, tumor progress, tumor metastasis, tumor immune resistance, tumor chemotherapy, and tumor immunotherapy. In the current study, we explored the contributions of the infiltrated dendritic cells insulted by Wnt1 in tumor microenvironment to neuropathic pain associated with cancers. The different transcriptome of infiltrated dendritic cells from lung adenocarcinoma and from juxtatumor indicated that thousands of genes were up-regulated by the tumor microenvironment, some of which were enriched in pain pathway. The paracrine factors such as TNF, WNT10A, PDGFA, and NRG1 were also elevated in tumor-infiltrating dendritic cells. The receptors of paracrine factors were highly expressed on dorsal root ganglia (DRG), and not altered in pain conditions. Single-cell RNA-seq data unveiled that TNFSF1 was expressed in neurons, microglial cells, and endothelial cells. PDGFRA was only expressed in microglial cells. ERBB3 was only expressed in neurons. FZD1 and 3 were extensively expressed in various cells. The components composed of signaling pathways associated with the above paracrine factors participated in pain networks. The transcription factors activated by paracrine factor signaling regulated the expression of genes associated with pain. TNF, WNT10A, and PDGFA were extensively expressed in multiple cancers, but their expression in patients did not distribute normally. These data indicated that infiltrated dendritic cells in tumor microenvironment promoted neuropathic pain by sensitizing nociceptor sensory neurons via paracrine factors. Blockage of paracrine factor signaling might alleviate cancer pain.

Clock-drawing test in vascular mild cognitive impairment: Validity of quantitative and qualitative analyses.

INTRODUCTION: The clock-drawing test (CDT) has been used as a screening tool to identify cognitive deficit in patients with dementia. However, it has not been extensively evaluated for categorizing patients with vascular mild cognitive impairment (vMCI). This study aimed to examine the discrimination of vMCI using various CDT scoring methods. METHOD: A total of 120 vMCI patients and 119 normal control (NC) subjects were tested using three CDT quantitative scoring systems: the one from the Montreal Cognitive Assessment (MoCA) (CDT3) and the systems of Rouleau (CDT10) and Babins (CDT18). We used a revised scoring method to evaluate the effectiveness in differentiating vMCI patients from NC subjects, which combined the CDT10 quantitative score and three qualitative errors with a significantly higher prevalence in vMCI group (called hereinafter CDTcomb, including CDTcomb13 and CDTcomb16 based on different weights of the three error types). The sensitivity and specificity of the CDT methods were determined by the receiver operating characteristic (ROC) curve. The results of the scoring systems were compared with those of the Mini-Mental State Examination (MMSE). RESULTS: The results of the ROC analyses with the CDT3, CDT10, and CDT18 systems produced a sensitivity of 71.1%, 81.8%, and 60.3%, and a specificity of 66.12%, 58.68%, and 73.55%, respectively, for the diagnosis of vMCI. Compared with the separate MMSE score, the combination of MMSE with the CDT3, CDT10 and CDT18 scores did not increase the sensitivity and specificity. When three qualitative errors were incorporated into the CDT10 quantitative score, CDTcomb13 and CDTcomb16 provided a sensitivity of 87.6% and 86.78%, and a specificity of 74.79% and 80.67%, respectively, in differentiating vMCI patients from the NC group. CONCLUSION: Our findings suggest that the combination of CDT quantitative score with qualitative observations of the clock-drawing errors can provide a better discrimination between vMCI patients and cognitively normal subjects.

Dl-3-n-Butylphthalide Promotes Remyelination and Suppresses Inflammation by Regulating AMPK/SIRT1 and STAT3/NF-κB Signaling in Chronic Cerebral Hypoperfusion.

Demyelination in vascular dementia (VD) is partly attributable to inflammation induced by chronic cerebral hypoperfusion (CCH). Remyelination contributes to the recovery of cognitive impairment by inducing the proliferation and differentiation of oligodendrocyte progenitor cells. It was previously reported that Dl-3-n-butylphthalide (NBP) promotes cognitive improvement. However, whether NBP can stimulate remyelination and suppress inflammation after CCH remains unclear. To answer this question, the present study investigated the effects of NBP on remyelination in a rat model of CCH established by bilateral carotid artery occlusion. Functional recovery was evaluated with the Morris water maze (MWM) test, and myelin integrity, regeneration of mature oligodendrocytes, and inhibition of astrocyte proliferation were assessed by immunohistochemistry and histologic analysis. Additionally, activation of 5' AMP-activated protein kinase (AMPK)/Sirtuin (SIRT)1 and Signal transducer and activator of transcription (STAT)3/nuclear factor (NF)-κB signaling pathways was evaluated by western blotting. The results showed that NBP treatment improved memory and learning performance in CCH rats, which was accompanied by increased myelin integrity and oligodendrocyte regeneration, and reduced astrocyte proliferation and inflammation. Additionally, NBP induced the activation of AMPK/SIRT1 signaling while inhibiting the STAT3/NF-κB pathway. These results indicate that NBP alleviates cognitive impairment following CCH by promoting remyelination and suppressing inflammation via modulation of AMPK/SIRT1 and STAT3/NF-κB signaling.

Clock-drawing test: Normative data of three quantitative scoring methods for Chinese-speaking adults in Shijiazhuang City and clinical utility in patients with acute ischemic stroke.

OBJECTIVE: The clock-drawing test (CDT) is a widely used screening tool for detecting cognitive decline. However, normative data for Chinese individuals are scarce. Our study aimed to provide standardized values for the three quantitative CDT scoring methods that were tailored for Chinese-speaking adults in Shijiazhuang City and explore the discriminant validity of the CDT scores in patients with acute ischemic stroke. METHODS: We conducted the CDT among 418 healthy individuals aged between 35 and 84 years. The CDT was administered and scored by five raters using the method derived from the Montreal Cognitive Assessment (MoCA), Rouleau's, and Babins' scoring systems. The influence of age, education, and sex on the performance in the CDT was analyzed. Furthermore, 336 patients with acute ischemic stroke were enrolled to explore the discriminant validity of CDT scores. RESULTS: In all three scoring systems, CDT scores were significantly correlated with age and years of education but not with sex. Normative data stratified for age and years of education were established. Interrater and intersystem reliability were high in our study. CDT total scores and subscores showed significant differences between stroke patients and healthy individuals. CONCLUSIONS: Our study provides CDT normative data using three quantitative scoring methods for Chinese-speaking adults in Shijiazhuang City. Age and education level were the key factors that affected the CDT scores. CDT total scores and subscores provided good discriminant validity for patients with acute ischemic stroke.

Design, Synthesis, and Antifungal Evaluation of 8-Hydroxyquinoline Metal Complexes against Phytopathogenic Fungi.

Phytopathogenic fungal infections have become a major threat to agricultural production, food security, and human health globally, and novel antifungal agents with simple chemical scaffolds and high efficiency are needed. In this study, we designed and synthesized 38 8-hydroxyquinoline metal complexes and evaluated their antifungal activities. The results showed that most of the tested compounds possessed remarkable in vitro antifungal activity. Especially, compound 1e exhibited the highest antifungal potency among all target compounds, with EC50 values of 0.0940, 0.125, 2.95, and 5.96 µg/mL, respectively, against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Magnaporthe oryzae. Preliminary mechanistic studies had shown that compound 1e might cause mycelial abnormalities of S. sclerotiorum, cell membrane permeability changes, leakage of cell contents, and inhibition of sclerotia formation and germination. Moreover, the results of in vivo antifungal activity of compound 1e against S. sclerotiorum showed that 1e possessed higher curative effects than that of the positive control azoxystrobin. Therefore, compound 1e is expected to be a novel leading structure for the development of new antifungal agents.

Discovery of luotonin A analogues as potent fungicides and insecticides: Design, synthesis and biological evaluation inspired by natural alkaloid.

The prevention and control of plant diseases and insect pests is the most crucial issue facing crop protection. To discover novel pesticide candidates with diverse chemical structures from natural products, a series of luotonin A analogues were designed, synthesized and evaluated for their antifungal and insecticidal activities. Most of these compounds exhibited potent activity against Botrytis cinerea, Magnaporthe oryzae and Aphis craccivora. Among them, the antifungal activity of compound 10s against B. cinerea was comparable to azoxystrobin (EC50 = 0.09 mM) and against M. oryzae (EC50 = 0.19 mM) was slightly weaker than that of azoxystrobin (EC50 = 0.17 mM). Compounds 10k and 10o are the most active compounds against A. craccivora having identical mortality value of 42.05% at 50 µg/mL, respectively, which were slightly lower than pymetrozine (51.14%) at the same concentration. Revealed morphological changes of the fungal cell surface by scanning electron microscopy indicated that luotonin A analogues might exert their antifungal activity by destroying fungal cell membrane and cell wall. Furthermore, the results of the in vivo protective and curative activities of the compound 10s against S. sclerotiorum and B. cinerea showed that the curative effect was stronger than its protective effect and the curative effects reached 67.17% and 73.82% at 80 µg/mL respectively. The above results further demonstrated the potential of luotonin A analogues as novel fungicides and insecticides.

Design, Synthesis, and Antifungal Evaluation of Neocryptolepine Derivatives against Phytopathogenic Fungi.

Neocryptolepine is an alkaloid isolated from traditional African herbal medicine Cryptolepis sanguinolenta, and its broad spectrum of biological activities has been illuminated in past decades. In this study, neocryptolepine and its derivatives (1-49) were designed and synthesized from economical and readily available starting materials. Their structures were confirmed by proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and mass spectrometry. The synthesized compounds were screened for their antifungal profile against six agriculturally important fungi Rhizoctonia solani, Botrytis cinerea (B. cinerea), Fusarium graminearum, Mycosphaerella melonis, Sclerotinia sclerotiorum, and Magnaporthe oryzae. The results of in vitro assay revealed that compounds 5, 21, 24, 35, 40, 45, and 47 presented remarkable antifungal activity against the fungi tested with EC50 values lower than 1 µg/mL. Significantly, compound 24 displayed the most effective inhibitory potency against B. cinerea (EC50 = 0.07 µg/mL), and the data from in vivo experiments revealed that compound 24 demonstrated comparable protective activity with the positive control boscalid. Preliminary mechanism studies indicated that compound 24 showed impressive spore germination inhibitory effectiveness and lower cytotoxicity than azoxystrobin, imparted on normal function of the cell membrane and cell wall, and arrested the normal function of the nucleus. Besides the excellent inhibitory activity against agriculturally important phytopathogenic fungi tested, the designed assemblage possesses several benefits with a high profile of variation in synthesized molecules, the ease of synthesis, and good cost-effectiveness of commercially available synthetic reagents, all of these have highlighted the potential worth of compound 24 as a new and highly efficient agricultural fungicide.

Design, Synthesis, and Antifungal Evaluation of Novel Quinoline Derivatives Inspired from Natural Quinine Alkaloids.

Inspired by quinine and its analogues, we designed, synthesized, and evaluated two series of quinoline small molecular compounds (a and 2a) and six series of quinoline derivatives (3a-f) for their antifungal activities. The results showed that compounds 3e and 3f series exhibited significant fungicidal activities. Significantly, compounds 3f-4 (EC50 = 0.41 µg/mL) and 3f-28 (EC50 = 0.55 µg/mL) displayed the superior in vitro fungicidal activity and the potent in vivo curative effect against Sclerotinia sclerotiorum. Preliminary mechanism studies showed that compounds 3f-4 and 3f-28 could cause changes in the cell membrane permeability, accumulation of reactive oxygen species, loss of mitochondrial membrane potential, and effective inhibition of germination and formation of S. sclerotiorum sclerotia. These results indicate that compounds 3f-4 and 3f-28 are novel potential fungicidal candidates against S. sclerotiorum derived from natural products.

Acaricidal activity and enzyme inhibitory activity of active compounds of essential oils against Psoroptes cuniculi.

Plant essential oils and its chemical compositions are commonly applied in medicinal and other industries due to their broad advanced pharmacological activities. In the present study, we systematically evaluated the acaricidal activities of twelve compounds of essential oils against Psoroptes cuniculi in vitro and in vivo. In addition, to support the clinic uses, their toxicities against immortalized human keratinocytes (HaCaT) and human liver cells (HL-7702) and skin irritation were studied for evaluating the liver and skin safety. The possible mechanism of action of certain chemical were investigated by determining the inhibitory activities against cytochrome P450 (P450) acetylcholinesterase (AChE) and glutathione-S-transferase (GST). Among all tested compounds, eugenol exhibited the best acaricidal activity with LC50 value of 56.61 µg/ml in vitro. Meanwhile, after the treatment of eugenol for five times within 10 days, the P. cuniculi were eliminated in the naturally infested rabbits, no skin irritation was found in rabbits treated by eugenol. Moreover, eugenol presented no or weak cytotoxicity against HaCaT cells and HL-7702 cells with IC50 values of greater than 100 µg/ml. Furthermore, the moderate inhibitory activities of eugenol against mites P450 and AChE were demonstrated. Above results indicated that eugenol presented the promising acaricidal activity against P. cuniculi in vitro and in vivo, is safe for both humans and animals at the given doses. This work lays the foundation for the development of eugenol as an environmentally friendly acaricide agent.

Comparison of efficacy and toxicity between nedaplatin and cisplatin in treating malignant pleural effusion.

OBJECTIVE: To evaluate the efficacy and safety of nedaplatin versus cisplatin in treating malignant pleural effusion (MPE) caused by cancers. METHODS: The clinical data of 219 MPE patients treated from January 2013 to December 2016 were retrospectively reviewed. Intrapleural infusion with nedaplatin 80 mg/m2 (n=110) or with cisplatin 40 mg/m2 (n=109) were used as the treatment. RESULTS: There was no significant difference in the overall response rate between the nedaplatin group (62.73%) and the cisplatin group (54.13%) (P=0.154). The nedaplatin group had significantly lower rates of gastrointestinal side effects and significantly less incidence of increased serum creatinine levels in comparison with the cisplatin group. The overall rate of toxicity in the nedaplatin group (40.00%) was significantly lower than in the cisplatin group (78.90%) (P⩽0.001). CONCLUSION: The efficacy of pleural perfusion with nedaplatin is noninferior to cisplatin in treating malignancy-induced MPE. Nedaplatin is associated with less toxicity in comparison with cisplatin.

Dynamic and significant changes of T-cell subgroups in breast cancer patients during surgery and chemotherapy.

OBJECTIVE: Breast cancer and its surgical treatment and chemotherapy have great impact on the immune system. This study aimed to monitor the various T cells in breast cancer patients and evaluate the immune functions. METHODS: Blood samples were collected from 249 breast cancer patients at the following time points: 1-3 days preoperative, postoperative (before the chemotherapy), after 3 chemotherapy cycles, and after 6 chemotherapy cycles. The percentages of the CD3+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells were measured using flow cytometry. Another 200 healthy women were used as control. RESULTS: Patients with stage II/III breast cancer had significantly lower percentages of CD3+, CD4+, CD8+, CD45RA+, and CD28+ T cells in comparison with normal control and those with stage I breast cancer (P < 0.05). The percentages of CD45RO+ T cells and CD4+CD25+ (Treg) cells were significantly higher in stage II/III malignancies versus stage I, and was significantly higher in stage I malignancies versus the normal control (P < 0.05). Breast cancer patients had significantly lower percentages of CD3+ and CD4+ T cells in comparison with the normal control (P < 0.05). The preoperative percentages of CD3+ and CD4+ T cells were significantly reduced after 3 cycles and after 6 cycles of chemotherapy (P < 0.05). In patients with stage II/III malignancies, there was a higher percentage of CD45RO+ T cells than CD45RA+ T cells, which was reversed after surgery. After 6 chemotherapy cycles, the percentage of Treg cells was significantly reduced in comparison with that before the chemotherapy in the patients with stage II/III malignancies. CONCLUSIONS: Patients with breast cancer had significantly suppressed immune functions. Surgical removal of the tumor may improve the immune functions. Chemotherapy significantly reduced the percentages of CD3+ and CD4+ T cells.