Therapeutic Drug Monitoring of Ceftazidime-Avibactam Concentrations in Carbapenem-Resistant K. pneumoniae-Infected Patients With Different Kidney Statuses.

Aims: Carbapenem-resistant K. pneumoniae (CRKP) is the most common carbapenem-resistant Enterobacteriaceae with high mortality. Ceftazidime-avibactam (CAZ-AVI) has exhibited excellent in vitro activity in vivo against CRKP. However, the efficacy of CAZ-AVI in KPC-producing CRKP-infected patients with different kidney statuses varies, such as renal insufficiency, normal renal function, and augmented renal clearance (ARC). We explored the use of therapeutic drug monitoring (TDM) to evaluate the concentration and efficacy of CAZ-AVI in CRKP-infected patients with different kidney statuses. Methods: Serum concentrations for CAZ and AVI were determined by the high-performance liquid chromatography method. Bacterial identification, routine susceptibility testing, renal function index, and others were performed in standard protocols in the hospital's clinical laboratories. Results: In the two patients with ARC, in case 1, CAZ-AVI 2.5g q6h was used with good efficacy, and the concentrations were up to the pharmacokinetics/pharmacodynamics targets. In Case 2, 2.5 g q8h was used with invalid effectiveness, and AVI Cmin was only 0.797 mg/l, which is lower than the PK/PD target. Case 3 was renal insufficiency using CAZ-AVI 1.25 q8h, and case 4 was normal renal function using 2.5 g q8h. Their concentrations were both up to the PK/PD targets. Conclusion: TDM results demonstrated that CAZ-AVI steady-state plasma concentration varies among patients with different kidney statuses, providing evidence for the utility of TDM of CAZ-AVI in individualized drug dose adjustment. ARC patients may need more CAZ-AVI daily doses than the standard dose.

Potential Role of Domains Rearranged Methyltransferase7 in Starch and Chlorophyll Metabolism to Regulate Leaf Senescence in Tomato.

Deoxyribonucleic acid (DNA) methylation is an important epigenetic mark involved in diverse biological processes. Here, we report the critical function of tomato (Solanum lycopersicum) Domains Rearranged Methyltransferase7 (SlDRM7) in plant growth and development, especially in leaf interveinal chlorosis and senescence. Using a hairpin RNA-mediated RNA interference (RNAi), we generated SlDRM7-RNAi lines and observed pleiotropic developmental defects including small and interveinal chlorosis leaves. Combined analyses of whole genome bisulfite sequence (WGBS) and RNA-seq revealed that silencing of SlDRM7 caused alterations in both methylation levels and transcript levels of 289 genes, which are involved in chlorophyll synthesis, photosynthesis, and starch degradation. Furthermore, the photosynthetic capacity decreased in SlDRM7-RNAi lines, consistent with the reduced chlorophyll content and repression of genes involved in chlorophyll biosynthesis, photosystem, and photosynthesis. In contrast, starch granules were highly accumulated in chloroplasts of SlDRM7-RNAi lines and associated with lowered expression of genes in the starch degradation pathway. In addition, SlDRM7 was activated by aging- and dark-induced senescence. Collectively, these results demonstrate that SlDRM7 acts as an epi-regulator to modulate the expression of genes related to starch and chlorophyll metabolism, thereby affecting leaf chlorosis and senescence in tomatoes.

Nephrotoxicity and Efficacy Assessment of Polymyxin B Use in Renal Transplant Patients.

PURPOSE: This study investigates the nephrotoxicity and efficacy assessment of polymyxin B (PMB) use in renal transplant patients. PATIENTS AND METHODS: This retrospective study included adult (>18 years of age) renal transplant patients who received PMB intravenous drip for more than 72 hours. Efficacy assessment of PMB included clinical treatment efficacy, microbiological efficacy at the end of PMB treatment, and in-hospital all-cause mortality. Nephrotoxicity of PMB was evaluated for further group comparison. RESULTS: We enrolled 235 renal transplant patients in our study. After PMB treatment, 45 patients occurred PMB-nephrotoxicity, and the nephrotoxicity rate was 19.15%. Among them, 44 patients were RIFLE R stage, and one patient was RIFLE I stage. The dose of PMB used in patients was 40.0 (40.0-50.0) mg q12h with a loading dose of 41.8±9.8 mg. Multivariate logistic regression analysis showed that ICU admission, vasoactive agents, aminoglycosides, creatinine clearance rate before PMB use, and mean total hospital stay were independent risk factors of PMB-nephrotoxicity in kidney transplant patients. The clinical effective rate was 97.9%, and the microbiological clean rate was 66.7%. CONCLUSION: Our study demonstrated that PMB low dose regimens might achieve good efficacy and less nephrotoxicity in renal transplant patients. We should evaluate the severity of the infection and renal function of patients, avoid the combined use of other nephrotoxic drugs, and minimize the course of use to reduce the occurrence of PMB-nephrotoxicity.

Novel Bithiophene Dimers from Echinops latifolius as Potential Antifungal and Nematicidal Agents.

Three novel dimeric bithiophenes, echinbithiophenedimers A-C (1-3), along with two known thiophenes, 4 and 5, were obtained from Echinops latifolius, and their structures were identified through extensive spectroscopic analysis and electronic circular dichroism calculations. Compounds 1-3 possessed new carbon skeletons; they are dimeric bithiophenes with 1 and 2 featuring an unprecedented 1,3-dioxolane ring system and 3 featuring an unusual 1,4-dioxane ring. These compounds are the first examples of bithiophene dimers furnished by different cyclic diethers. Dimeric bithiophenes 1-3 had good antifungal activities against five phytopathogenic fungi, and compound 3 showed excellent activity against Alternaria alternate and Pyricularia oryzae, with a minimal inhibitory concentration value of 8 µg/mL, which was close to or higher than that of carbendazim. Moreover, its effect on the mycelial morphology was observed by scanning electron microscopy. Compounds 1-3, which were demonstrated to be nonphototoxic thiophenes, exhibited better nematicidal activity than the commercial nematicide ethoprophos against Meloidogyne incognita. This study revealed that dimeric bithiophenes containing 1,3-dioxolane or 1,4-dioxane rings could be used as novel antifungal and nematicidal agents for controlling plant fungal and nematode pathogens.

Constituents Leached by Tomato Seeds Regulate the Behavior of Root-Knot Nematodes and Their Antifungal Effects against Seed-Borne Fungi.

Germinating seeds can release diverse phytochemicals that repel, inhibit, or kill pathogens such as root-knot nematodes and seed-borne fungi. However, little is known about the composition of these phytochemicals and their effects on pathogens. In this study, we demonstrated that tomato seed exudates can attract the nematode Meloidogyne incognita using a dual-choice assay. Eighteen compounds were then isolated and identified from the exudates. Of these, esters (1-3), fatty acids (4-6), and phenolic acids (10-12) were proven to be the signaling molecules that facilitated the host-seeking process of second-stage juveniles (J2s) of nematodes, while alkaloids (17 and 18) disrupted J2s in locating their host. Furthermore, some phenolic acids and alkaloids showed antifungal effects against seed-borne fungi. In particular, ferulic acid (12) showed obvious activity against Aspergillus flavus (minimum inhibitory concentration (MIC), 32 µg/mL), while dihydrocapsaicin (17) showed noticeable activity against Fusarium oxysporum (MIC, 16 µg/mL). Overall, this study presents the first evidence that M. incognita can be attracted to or deterred by various compounds in seed exudates through identification of the structures of the compounds in the exudates and analysis of their effects on nematodes. Furthermore, some antifungal compounds were also found. The findings of this work suggest that seed exudates are new source for finding insights into the development of plant protective substances with nematocidal and antifungal effects.

CD11b is involved in coxsackievirus B3-induced viral myocarditis in mice by inducing Th17 cells.

Viral myocarditis (VMC) caused by coxsackievirus B3 (CVB3) infection is a life-threatening disease. The cardiac damage during VMC is not mainly due to the direct cytotoxic effect of the virus on cardiomyocytes but mostly involves the induction of immune responses. Integrin CD11b plays an important role in immune response, for instance, in the induction of Th17 cells. However, the role of CD11b in the pathogenesis of VMC remains largely unknown. In the present study, a mouse model of VMC was established by CVB3 infection and CD11b was knocked down in the VMC mice by transfection with siRNA-CD11b. The expression of CD11b and IL-17 in heart tissues, frequency of Th17 cells in spleen tissues and serum IL-17 levels were measured using quantitative RT-PCR, Western blot, immunohistochemistry, flow cytometry and ELISA. Results showed that CVB3 infection caused the pathological changes in heart tissues with the increases in the following indexes: expression of CD11b and IL-17 in heart tissues, frequency of Th17 cells in spleen tissues and serum IL-17 levels. The expression of CD11b was positively correlated with IL-17 expression in heart tissues. Depletion of CD11b attenuated the damage caused by CVB3 and decreased the frequency of Th17 cells in spleen tissues as well as in IL-17, IL-23 and STAT3 expression in heart tissues. In summary, our findings reveal that disruption of CD11b function reduced CVB3-induced myocarditis, suggesting that CD11b may be a novel therapeutic target for VMC.

Effect of celastrol on pyroptosis of macrophages RAW264.7 / 中草药

Objective: To investigate the effects and underlying mechanism of celastrol on pyroptosis in macrophage RAW264.7. Methods: Cell viability was determined by using MTT assay. Effects of celastrol on pyroptosis of macrophages were observed through AO/EB and Hoechst/PI fluorescence staining. The secretions of IL-1β in the culture supernatant were analyzed by ELISA. The protein levels of Caspase-1 was assayed by Western blotting. And Caspase-1 activity was detected with Caspase-1 activity detection kit. Results: Based on the MTT assay, the concentrations under 50 nmol/L of celastrol used were not toxic to the macrophages. PI or EB uptake induced by lipopolysaccharide (LPS) and ATP were significantly reduced by celastrol. Pretreatment with celastrol greatly reduced the secretion of IL-1β in a dose-dependent manner, and inhibited the up-regulation of cleaved-Caspase-1. Additionally, celastrol could inhibit the activation of Caspase-1 in macrophages. Conclusion: Celastrol significantly reduced pyroptosis induced by LPS and ATP through inhibition of IL-1β secretion and Caspase-1 activation.