The effect of novel aromatic heterocycle substituted aminamidine derivatives on Necator americanus.

BACKGROUND: The efficacy of current drugs against hookworms at a single dose is highly variable across regions, age groups and infection intensity. Extensive and repeated use of these drugs also leads to potential drug resistance. Therefore, novel drugs are required for sustained disease control. OBJECTIVES: Novel aromatic heterocycle substituted aminamidine derivatives (AADs) were synthesized based on tribendimine (TBD), and their in vivo potency against Necator americanus was tested. METHODS: The efficacy of the AADs was tested in male hamsters. Oral and IV pharmacokinetic parameters were determined in male Sprague-Dawley rats. The proteomic profiles of N. americanus samples treated with AADs were compared using tandem mass tag-based quantitative proteomic analyses. RESULTS: Most AADs exhibited better anthelmintic activity than TBD at a single oral dose. Compound 3c exhibited improved solubility (>50×), and the curative dose was as low as 25 mg/kg. Similar to TBD, 3c was rapidly metabolized after oral administration and transformed into p-(1-dimethylamino ethylimino)aniline (dADT), an active metabolite against intestinal nematodes. dADT from 3c had better pharmacokinetic profiles than that from TBD and achieved an oral bioavailability of 99.5%. Compound 3c possessed rapid anthelmintic activity, clearing all worms within 24 h after an oral dose of 50 mg/kg. Quantitative proteomic analysis indicated that it might be related to ATP metabolism and cuticle protein synthesis. CONCLUSIONS: Compound 3c is a novel and promising compound against N. americanus in vivo.

New exploration of ions and fatty acids in hydrophilic acrylic intraocular lens calcification.

PURPOSE: To conduct a new exploration and analysis of the ion and fatty acid levels of a medium in which calcified hydrophilic intraocular lenses (IOLs) are present. SETTING: Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China. DESIGN: Retrospective, laboratory observational case series. METHODS: 11 patients (11 eyes) who had implantation of foldable hydrophilic acrylic posterior IOLs were found to have opacification of the IOLs. In vivo and in vitro analyses included the evaluation of patients' clinical characteristics, microscopy, histological staining, energy dispersive X-ray spectroscopy (EDS), the ion level of the aqueous humor (AH) and preserving fluid (PF), and the fatty acid content of AH. RESULTS: 10 of 11 cases were female with unilateral opacification, and 7 cases had both-eye cataract surgery, including 1 first eye and 6 second eyes with IOL opacification. 4 types of similar serial numbers were counted. The analysis of AH showed that the concentrations of phosphorus and silicon were elevated but that of calcium decreased, and an increased level of silicon was detected in 3 random PFs. The palmitic (C16:0) and stearic (C18:0) fatty acids were higher than the others in the AH. The EDS confirmed that the IOL surface deposits were composed of calcium, phosphate, and a small amount of silicon. CONCLUSIONS: More silicon and higher C16:0 and C18:0 were found in the AH of patients with IOL opacification. New ideas and avenues have been proposed in the study of IOL opacification.

Macular toxicity of low-concentration cefuroxime during cataract surgery in vitrectomized eyes.

OBJECTIVE: The objective of this study was to determine the toxic effect and clinical characteristics of 1 mg/ml cefuroxime sodium on retinas after phacoemulsification in vitrectomized eyes. METHODS: Cataract patients with vitrectomized eyes were studied retrospectively. Phacoemulsification combined with intraocular lens implantation was performed uneventfully. Best Corrected Visual Acuity（BCVA）, intraocular pressure（IOP）, fundus photography, macular central thickness, and angiography were collected and analyzed. They were studied in patients with macular edema to evaluate macular toxicity. RESULTS: 92 cases (92 eyes) were enrolled, including 44 eyes of males and 48 eyes of females with an average age of 55.35 ± 12.32 years. Univariate analysis showed that the intraoperative use of balanced salt solution (BSS) containing 1 mg/ml cefuroxime sodium compound electrolyte and macular involvement in primary vitrectomy were important risk factors for macular edema on the first day after cataract surgery (P < 0.05). In addition, the characteristics of this kind of macular edema were studied; the thickness of macular fovea was significantly high at 1-day follow-up (P < 0.05), but there was no difference between pre-operation and 1-week post-operation (P > 0.05). CONCLUSION: Low-concentration cefuroxime sodium can cause acute macular edema in vitrectomized eyes, which can heal within one week after surgery.

Distance correlation application to gene co-expression network analysis.

BACKGROUND: To construct gene co-expression networks, it is necessary to evaluate the correlation between different gene expression profiles. However, commonly used correlation metrics, including both linear (such as Pearson's correlation) and monotonic (such as Spearman's correlation) dependence metrics, are not enough to observe the nature of real biological systems. Hence, introducing a more informative correlation metric when constructing gene co-expression networks is still an interesting topic. RESULTS: In this paper, we test distance correlation, a correlation metric integrating both linear and non-linear dependence, with other three typical metrics (Pearson's correlation, Spearman's correlation, and maximal information coefficient) on four different arrays (macrophage and liver) and RNA-seq (cervical cancer and pancreatic cancer) datasets. Among all the metrics, distance correlation is distribution free and can provide better performance on complex relationships and anti-outlier. Furthermore, distance correlation is applied to Weighted Gene Co-expression Network Analysis (WGCNA) for constructing a gene co-expression network analysis method which we named Distance Correlation-based Weighted Gene Co-expression Network Analysis (DC-WGCNA). Compared with traditional WGCNA, DC-WGCNA can enhance the result of enrichment analysis and improve the module stability. CONCLUSIONS: Distance correlation is better at revealing complex biological relationships between gene profiles compared with other correlation metrics, which contribute to more meaningful modules when analyzing gene co-expression networks. However, due to the high time complexity of distance correlation, the implementation requires more computer memory.

Long-term outcomes of "open iridectomy" for secondary anterior chamber epithelial iris cysts.

Epithelial cysts run a high risk of recurrence and conversion to sheet-like ingrowth after surgical intervention. In this retrospective study, we introduced a modified iridectomy for treatment of secondary epithelial iris cysts (EICs) in the anterior chamber. Twenty-nine patients (29 eyes) aged 2-61 years received "open iridectomy" for EICs between April 1995 and July 2019. After viscodissection, most of the cyst wall was cut using a 20-gauge aspiration cutter via a 2.5-mm clear corneal incision. The residue closely adhering to the iris stroma was remained to avoid photophobia and diplopia. At 3 months, best corrected visual acuity was ≥ 20/100 in 55.5% (15/27, except two pediatric patients with poor cooperation) of patients. Among the eight patients suffering partial corneal edema preoperatively, six patients received surgery treatment at 3-6.5 months, and the cornea in the other two patients became transparent after medication. In a mean follow-up of 47.4 months, recurrence occurred in 3 patients at 7, 37, and 118 months, respectively. The percentage of treatment success was 96%, 87%, and 65% at 1, 5, and 10 years, respectively. "Open iridectomy" was effective for EICs, with a minimal invasion, less damage to the corneal endothelium, and a low recurrence rate.

Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice.

BACKGROUND AND PURPOSE: Malaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy. EXPERIMENTAL APPROACH: An integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed. KEY RESULTS: Methnaridine exhibited potent antimalarial activity against P. falciparum (3D7: IC50 = 0.0066 µM; Dd2: IC50 = 0.0056 µM). In P. berghei-infected mice, oral administration effectively suppressed parasitemia (ED50 = 0.52 mg·kg-1 ·day-1 ) and cured the established infection (CD50 = 10.13 mg·kg-1 ·day-1 ). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four-dose oral regimen at a dosage of 25 mg·kg-1 achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT99 = 36.0 h) and showed no cross-resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long-lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg-1 ). In addition, following methnaridine treatment, infection-induced Th1 immune response was almost fully alleviated in mice. CONCLUSION AND IMPLICATIONS: Methnaridine is an orally bioavailable, fast-acting and long-lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.

S-1 plus cisplatin as first-line treatment of patients with advanced non-small cell lung cancer in Taiwan.

AIM: S-1 combined with cisplatin is known to be noninferior to taxanes plus platinum as the first-line treatment for patients with advanced nonsmall cell lung cancer (NSCLC) in the Japanese population. This study aimed to evaluate the efficacy and safety profiles of oral S-1 plus cisplatin (SP) in Taiwanese patients. METHODS: Patients with previously untreated stage IIIB or IV NSCLC were prospectively recruited to receive 40-60 mg of S-1 twice daily on days 1-21 plus 60 mg/m2 of cisplatin on day 8 in a 5-week cycle for up to six cycles. RESULTS: A total of 55 patients from five cancer centers in Taiwan were enrolled. Among the 46 evaluable patients, those administered with SP achieved disease control rate of 69.6% (partial response, 19.6%; stable disease, 50.0%), with median overall survival and progression-free survival (PFS) of 15.1 and 5.7 months, respectively. Moreover, a better survival trend was observed in epidermal growth factor receptor mutation-positive patients versus mutation-negative patients treated with SP (PFS, 8.6 vs 5.6 months). The most commonly observed treatment-related adverse events (AEs) were nausea (41.8%), followed by decreased appetite, anemia, and diarrhea. Grade of ≥3 AEs related to the study treatment occurred in 11 patients (20.0%). No febrile neutropenia or treatment-related death was found in this study. CONCLUSIONS: This study demonstrated that SP is an effective and safe first-line regimen for Taiwanese patients with advanced NSCLC.

Aging effects on the stabilisation and reactivity of iron-based nanoparticles green synthesised using aqueous extracts of Eichhornia crassipes.

Aging effects play a crucial role in determining applications of green-synthesised iron-based nanoparticles in wastewater treatment from laboratory scale to practical applications. In this study, iron-based nanoparticles (Ec-Fe-NPs) were synthesised using the extract of Eichhornia crassipes and ferric chloride. Scanning electron microscopy (SEM) revealed that the fresh Ec-Fe-NPs were spherical and had a narrow particle size range (50 to 80 nm). X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) demonstrated that the Ec-Fe-NPs were mainly amorphous in nature and consisted of Fe0, FeO, Fe2O3 and Fe3O4. As they aged, the particle size of the liquid Ec-Fe-NPs gradually increased and then tended to stabilise. Ec-Fe-NPs that were aged for 28 days were only 19% less efficient than fresh material at removing Cr(VI). Extracts aged up to 28 days were also tested, and their antioxidant capacity was found to be 15.4% lower than that of the fresh extracts. Furthermore, the removal efficiency of Cr(VI) using iron-based nanoparticles synthesised with the aged extracts was 67.2%. Finally, the active components of the extracts, which were responsible for the reactivity and stability of the iron-based nanoparticles, were identified by liquid chromatography-mass spectrometry. Overall, green-synthesised iron-based nanoparticles show promise for Cr(VI) removal from wastewater in practical applications.

Novel carbazole aminoalcohols as inhibitors of ß-hematin formation: Antiplasmodial and antischistosomal activities.

Malaria and schistosomiasis are two of the most socioeconomically devastating parasitic diseases in tropical and subtropical countries. Since current chemotherapeutic options are limited and defective, there is an urgent need to develop novel antiplasmodials and antischistosomals. Hemozoin is a disposal product formed from the hemoglobin digestion by some blood-feeding parasites. Hemozoin formation is an essential process for the parasites to detoxify free heme, which is a reliable therapeutic target for identifying novel antiparasitic agents. A series of novel carbazole aminoalcohols were designed and synthesized as potential antiplasmodial and antischistosomal agents, and several compounds showed potent in vitro activities against Plasmodium falciparum 3D7 and Dd2 strains and adult and juvenile Schistosoma japonicum. Investigations on the dual antiparasitic mechanisms showed the correlation between inhibitory activity of ß-hematin formation and antiparasitic activity. Inhibiting hemozoin formation was identified as one of the mechanisms of action of carbazole aminoalcohols. Compound 7 displayed potent antiplasmodial (Pf3D7 IC50 = 0.248 µM, PfDd2 IC50 = 0.091 µM) and antischistosomal activities (100% mortality of adult and juvenile schistosomes at 5 and 10 µg/mL, respectively) and exhibited low cytotoxicity (CC50 = 7.931 µM), which could be considered as a promising lead for further investigation. Stoichiometry determination and molecular docking studies were also performed to explain the mode of action of compound 7.

Metabolic changes at the early stage of sepsis induced by cecal ligation and puncture in rats and the interventional effects of Huang-Lian-Jie-Du-Tang.

Sepsis is a disease with high mortality that requires rapid diagnosis and treatment. This study used a metabolomic approach to profile the metabolic changes at the early stage of sepsis induced by cecal ligation and puncture (CLP) in rats and investigated the interventional effects of Huang-Lian-Jie-Du-Tang (HLJDT). Male SD rats were intragastrically administered 270mg/kg HLJDT 2h prior to CLP, serum extracts were profiled by liquid chromatography/quadrupole time-of-flight mass spectrometer (LC-Q-TOF-MS) and multivariate analytical (MVA) methods were employed to evaluate the metabolic changes of extracts. A Partial Least-Squares Discriminant Analysis (PLS-DA) score plot indicated that septic rats undergo significant metabolic changes 2h after CLP, and HLJDT administration could reverse the metabolic changes induced by CLP. Sixteen biomarkers involved in amino acid metabolism, unsaturated fatty acid metabolism, purine metabolism, and lipid metabolism were identified after Orthogonal Partial Least-Squares Analysis (OPLS). Among the 16 metabolites, 10 were regulated by HLJDT. This study established the foundation for further research of the early diagnosis biomarkers and therapeutic evaluation biomarkers discovery of sepsis.

Synthesis, Bioactivity Evaluation, and Toxicity Assessment of Novel Salicylanilide Ester Derivatives as Cercaricides against Schistosoma japonicum and Molluscicides against Oncomelania hupensis.

A series of novel salicylanilide ester derivatives were synthesized, characterized, and evaluated for cercaricidal potential against Schistosoma japonicum and molluscicidal potential against Oncomelania hupensis. Four derivatives exhibited remarkable cercaricidal activity superior to that of niclosamide. Among them, the most active compound, 4-chloro-2-((2-methoxy-4-nitrophenyl)carbamoyl)phenyl 4-methoxybenzoate (compound 4c), showed a marked minimum effective cercaricidal concentration as low as 0.43 µM and significant molluscicidal activity, with a 50% lethal concentration (LC50) of 0.206 g/m(2). Particularly, compound 4c displayed 88-fold decreased fish toxicity on Danio rerio and 44-fold reduced cytotoxicity on human kidney HEK293 cells in comparison with the toxicity of niclosamide. The results indicated that 4c could serve as a promising drug candidate, with environmental safety properties, against Schistosoma japonicum at transmission stages. The preliminary molecular mechanism of target compounds in Schistosoma japonicum cercariae was also investigated. Salicylanilide ester derivatives exhibited an inhibitory effect on nitric oxide synthase (NOS) but no effect on lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), and a strong and significant correlation between NOS inhibitory efficacy and cercaricidal activity was observed. In addition, 4c could downregulate the expression of NOS in a dose-dependent manner. These results suggested that NOS was probably one of the drug targets of salicylanilide esters.

[Plasma Metabolism and Protective Effect of Oral Administration of Niclosamide on Schistosoma japonicum Cercarial Invasion in Mice].

OBJECTIVE: To study the metabolism of niclosamide in plasma, and the protective effect of its oral administration on Schistosoma japonicum cercarial invasion in mice. METHODS: Twenty-four female Kunming mice were randomly divided into 8 groups, each with 3 mice. Each mouse was treated orally with 120 mg niclosamide per kilogram of body weight (120 mg/kg). The plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, 16, and 24 h after treatment by retro-orbital blood sampling. The blood drug concentration was determined by HPLC. The pharmacokinetics parameters were calculated such as peak concentration (Cmax), peak time (Tmax), mean residence time (MRT), and elimination half life (T½). Thirty Kunming mice were randomly divided into 6 groups. Among them, 5 groups were treated orally with 40, 80, 120, 160, and 200 mg/kg niclosamide, respectively. The remaining untreated group served as control. One hour post-treatment, each mouse was infected with 40 ± 2 Schistosoma japonicum cercariae. Another 35 mice treated with 200 mg/kg niclosamide were randomly divided into 7 groups. Mice in each group were infected with 40 ± 2 S. japonicum cercariae on 0.25, 1, 4, 8, 12, and 24 h after treatment, named as group A, B, C, D, E, and F. Five untreated mice served as control (group G). All mice were sacrificed 35 days post-infection. Mean worm burden and worm reduction were calculated. RESULTS: At a dose of 120 mg/kg niclosamide, the blood drug concentration was (0.40 ± 0.28) µg/ml at 0.25 h post-treatment, reached a peak of (0.91 ± 0.34) µg/ml at 1 h, and decreased to (0.49 ± 0.38) µg/ml at 2 h, and got close to 0 at 16 h. The mean residence time (MRT) in mice was (6.78 ± 1.47) h, and the elimination half time was (6.80 ± 7.05) h. No significant difference was found in worm burden between different dose groups and control group (P > 0.05). The mean worm burden in group A was significantly lower than that of the control (P < 0.05) with a mean worm reduction of 79.1%. And there was no significant difference in worm burden between other groups and the control (P > 0.05). CONCLUSIONS: The blood drug concentration increases rapidly by gavage administration of 120 mg/kg niclosamide, reaching to the maximum concentration at 1 h post-treatment. It shows a certain potective effect of oral administration of 200 mg/kg niclosamide on Schistosoma japonicum cercarial invasion at 0.25 h after treatment.

Protective Effects of Huang-Lian-Jie-Du-Tang against Polymicrobial Sepsis Induced by Cecal Ligation and Puncture in Rats.

Huang-Lian-Jie-Du-Tang (HLJDT) is a traditional formula that has long been used for treatment of inflammatory diseases in Traditional Chinese Medicine. In this study, we examined its protective effect against sepsis in an experimental septic model induced by cecal ligation and puncture (CLP) in rats. The results demonstrated that prophylactic administration of HLJDT protected rats from CLP-induced lethality and ameliorated CLP-induced liver and lung injury. HLJDT treatment suppressed the production of proinflammatory cytokines, including TNF-α, IL-1, IL-6, and IL-17A, indicating HLJDT could limit excessive inflammatory responses in septic condition. In addition, HLJDT facilitated bacterial clearance by increasing phagocytic activities of peritoneal macrophages. Furthermore, HLJDT treatment reversed CLP-induced suppression of IFN-γ expression and blocked CLP-induced increase in IL-4 expression in spleens of rats at 24 h after CLP, indicating that HLJDT could reverse the shift from Th1 to Th2 response and promote Th1/Th2 balance toward Th1 predominance in septic rats. Moreover, HLJDT also inhibited the expression of IL-17A and ROR-γt in spleens of septic rats, indicating HLJDT is able to inhibit Th17 activation in septic condition. In conclusion, the present study demonstrated the protective effects of HLJDT against sepsis and highlighted the potential of HLJDT as a medication for septic patients.