Natural Sesquiterpene Lactone as Source of Discovery of Novel Fungicidal Candidates: Structural Modification and Antifungal Activity Evaluation of Xanthatin Derived from Xanthium strumarium L.

As part of our ongoing efforts to discover novel agricultural fungicidal candidates from natural sesquiterpene lactones, in the present work, sixty-three xanthatin-based derivatives containing a arylpyrazole, arylimine, thio-acylamino, oxime, oxime ether, or oxime ester moiety were synthesized. Their structures were well characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry, while the absolute configurations of compounds 5' and 6a were further determined by single-crystal X-ray diffraction. Meanwhile, the antifungal activities of the prepared compounds against several phytopathogenic fungi were investigated using the spore germination method and the mycelium growth rate method in vitro. The bioassay results illustrated that compounds 5, 5', and 15 exhibited excellent inhibitory activity against the tested fungal spores and displayed remarkable inhibitory effects on fungal mycelia. Compounds 5 and 5' exhibited more potent inhibitory activity (IC50 = 1.1 and 24.8 µg/mL, respectively) against the spore of Botrytis cinerea than their precursor xanthatin (IC50 = 37.6 µg/mL), wherein the antifungal activity of compound 5 was 34-fold higher than that of xanthatin and 71-fold higher than that of the positive control, difenoconazole (IC50 = 78.5 µg/mL). Notably, compound 6'a also demonstrated broad-spectrum inhibitory activity against the four tested fungal spores. Meanwhile, compounds 2, 5, 8, and 15 showed prominent inhibitory activity against the mycelia of Cytospora mandshurica with the EC50 values of 2.3, 11.7, 11.1, and 3.0 µg/mL, respectively, whereas the EC50 value of xanthatin was 14.8 µg/mL. Additionally, compounds 5' and 15 exhibited good in vivo therapeutic and protective effects against B. cinerea with values of 55.4 and 62.8%, respectively. The preliminary structure-activity relationship analysis revealed that the introduction of oxime, oxime ether, or oxime ester structural fragment at the C-4 position of xanthatin or the introduction of a chlorine atom at the C-3 position of xanthatin might be significantly beneficial to antifungal activity. In conclusion, the comprehensive investigation indicated that partial xanthatin-based derivatives from this study could be considered for further exploration as potential lead structures toward developing novel fungicidal candidates for crop protection.

The value of 18 F-FDG PET/CT in diagnosing and localising deep sternal wound infection to guide surgical debridement.

Deep sternal wound infection (DSWI) is a severe complication in patients after open heart surgery (OHS). But there is a lack of appropriate imaging tool to detect the infection sites, which may lead to incomplete debridement. The present study aims to investigate the value of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) in comparison with CT scan in diagnosing and localising DSWI. A total of 102 patients with DSWI after OHS were retrospectively collected from January 2012 to December 2017 in our hospital. All the patients had surgical debridements for DSWI with pretreatment imaging of either 18 F-FDG PET/CT or CT scan. The sensitivity, specificity, and accuracy of localising infection sites were compared between PET/CT and CT groups, with surgical, microbiological, and histopathological findings as the gold standard. The length of hospital stays and the rate of recurrence were also compared. Ten patients in the PET/CT group had a follow-up PET/CT scan after debridement, and the correlations between the changes of PET/CT findings and surgical outcomes were analysed. 18 F-FDG PET/CT is more accurate than CT in diagnosing and localising DSWI after OHS, which leads to a more successful surgical debridement with a lower rate of recurrence and a shorter length of hospital stay. In addition, follow-up PET/CT after debridement could evaluate the treatment effect.

Comparison of post-therapeutic sequential 131I whole-body scans in the detection of metastatic thyroid cancer.

BACKGROUND: The aim was to compare the detect ability of three sequential 131I whole-body scans (tri-WBS) on the second, third, and fourth day after 131I therapy for metastatic thyroid cancer. METHODS: Differentiated thyroid cancer patients who received oral high-dose 131I therapy underwent routinely tri-WBS on the second, third, and fourth day after total or near-total thyroidectomy in Zhongshan Hospital, Fudan University. We enrolled 137 patients with 261 tri-WBSs in this study between January 2015 and November 2017. The inclusion criteria was that at least one metastasis was found in the tri-WBS. We classified radioactive uptake of metastatic lesions by visual assessment into three grades: grade 0 = no uptake, grade 1= suspicious uptake, and grade 2 = definite uptake. The fourth day 131I WBS images were also compared with concurrent pre-therapeutic 99mTc-pertechnetate WBS images when available. We also analyzed the serum Tg levels of probably statistical difference in the patients with only lymph node, lung, bone, and multiple metastases when they underwent the first radioiodine ablation. RESULTS: A total of 722 metastatic accumulations were identified in the final decisions, including 293 lymph node metastases, 261 nodular pulmonary metastases, 49 diffuse bilateral pulmonary metastases, 106 bone metastases, and 13 other metastases. The differences of intensity of uptake in sequential three day images were significant in visualization of lymph node metastasis (χ2=124.432, P<0.001), nodular pulmonary metastasis (χ2=160.334, P<0.001), diffuse bilateral pulmonary metastasis (χ2=41.710, P<0.001), and bone metastasis (χ2=22.118, P<0.001) in our study. Compared to the second day scans, the fourth day scans detected 87 (29.70%) more metastatic lymph nodes, 111 (42.53%) more nodular pulmonary metastases, 26 (53.06%) more diffuse bilateral pulmonary metastases and 17 (16.95%) more bone metastases. The differences of intensity of uptake between 99mTc-pertechnetate WBS and the fourth day 131I WBS were significant in visualization of lymph node metastasis (χ2=172.624, P<0.001), nodular pulmonary metastasis (χ2=111.004, P<0.001), diffuse bilateral pulmonary metastasis (χ2=17.400, P<0.001) and bone metastasis (χ2=46.298, P<0.001). The means of RTg in the patients with only lymph node, lung, bone metastasis, and multiple metastases were 47.20, 76.58, 89.00, and 91.56, respectively. The differences of serum Tg levels in the patients with only lymph node, lung, bone metastasis, and multiple metastases were significant (χ2=35.850, P<0.001). CONCLUSIONS: The detect ability of tri-WBS was significantly different even for consecutive three-day images on the second, third, and fourth day after 131I therapy for metastatic thyroid cancer. There was a linear trend of increasing 131I uptake from the second to fourth day 131I WBS. The pre-therapy 99mTc-pertechnetate WBS demonstrated a poor ability to detect metastatic thyroid cancer compared to 131I WBS. There was an increasing trend of the means of RTg in patients with more extensive metastases.

Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans.

Brown adipose tissue (BAT) dissipates metabolic energy and mediates non-shivering thermogenesis, thereby boosting energy expenditure. Increasing BAT mass and activity is expected to be a promising strategy for combating obesity; however, few medications effectively and safely recruit and activate BAT in humans. Berberine (BBR), a natural compound, is commonly used as a nonprescription drug to treat diarrhea. Here, we reported that 1-month BBR intervention increased BAT mass and activity, reduced body weight, and improved insulin sensitivity in mildly overweight patients with non-alcoholic fatty liver disease. Chronic BBR treatment promoted BAT development by stimulating the expression of brown adipogenic genes, enhanced BAT thermogenesis, and global energy expenditure in diet-induced obese mice and chow-fed lean mice, Consistently, BBR facilitated brown adipocyte differentiation in both mouse and human primary brown preadipocytes. We further found that BBR increased the transcription of PRDM16, a master regulator of brown/beige adipogenesis, by inducing the active DNA demethylation of PRDM16 promoter, which might be driven by the activation of AMPK and production of its downstream tricarboxylic acid cycle intermediate α-Ketoglutarate. Moreover, chronic BBR administration had no impact on the BAT thermogenesis in adipose-specific AMPKa1 and AMPKa2 knockout mice. In summary, we found that BBR intervention promoted recruitment and activation of BAT and AMPK-PRDM16 axis was indispensable for the pro-BAT and pro-energy expenditure properties of BBR. Our findings suggest that BBR may be a promising drug for obesity and related metabolic disorders in humans partially through activating BAT.

Bioengineered Magnetoferritin Nanoprobes for Single-Dose Nuclear-Magnetic Resonance Tumor Imaging.

Despite all the advances in multimodal imaging, it remains a significant challenge to acquire both magnetic resonance and nuclear imaging in a single dose because of the enormous difference in sensitivity. Indeed, nuclear imaging is almost 10(6)-fold more sensitive than magnetic resonance imaging (MRI); thus, repeated injections are generally required to obtain sufficient MR signals after nuclear imaging. Here, we show that strategically engineered magnetoferritin nanoprobes can image tumors with high sensitivity and specificity using SPECT and MRI in living mice after a single intravenous injection. The magnetoferritin nanoprobes composed of (125)I radionuclide-conjugated human H-ferritin iron nanocages ((125)I-M-HFn) internalize robustly into cancer cells via a novel tumor-specific HFn-TfR1 pathway. In particular, the endocytic recycling characteristic of TfR1 transporters solves the nuclear signal blocking issue caused by the high dose nanoprobes injected for MRI, thus enabling simultaneous functional and morphological tumor imaging without reliance on multi-injections.