In pursuit of feedback activation: New insights into redox-responsive hydropersulfide prodrug combating oxidative stress.

Redox-responsive hydropersulfide prodrugs are designed to enable a more controllable and efficient hydropersulfide (RSSH) supply and to thoroughly explore their biological and therapeutic applications in oxidative damage. To obtain novel activation patterns triggered by redox signaling, we focused on NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1), a canonical antioxidant enzyme, and designed NQO1-activated RSSH prodrugs. We also performed a head-to-head comparison of two mainstream structural scaffolds with solid quantitative analysis of prodrugs, RSSH, and metabolic by-products by LC-MS/MS, confirming that the perthiocarbamate scaffold was more effective in intracellular prodrug uptake and RSSH production. The prodrug was highly potent in oxidative stress management against cisplatin-induced nephrotoxicity. Strikingly, this prodrug possessed potential feedback activation properties by which the delivered RSSH can further escalate the prodrug activation via NQO1 upregulation. Our strategy pushed RSSH prodrugs one step further in the pursuit of efficient release in biological matrices and improved druggability against oxidative stress.

Rhynchophylline inhibits methamphetamine dependence via modulating the miR-181a-5p/GABRA1 axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a plant species that is routinely devoted in traditional Chinese medicine to treat central nervous system disorders. Rhynchophylline (Rhy), a predominant alkaloid isolated from Uncaria rhynchophylla (Miq.) Miq. ex Havil., has been demonstrated to reverse methamphetamine-induced (METH-induced) conditioned place preference (CPP) effects in mice, rats and zebrafish. The precise mechanism is still poorly understood, thus further research is necessary. AIM OF STUDY: This study aimed to investigate the role of miRNAs in the inhibitory effect of Rhy on METH dependence. MATERIALS AND METHODS: A rat CPP paradigm and a PC12 cell addiction model were established. Microarray assays were used to screen and identify the candidate miRNA. Behavioral assessment, real-time PCR, dual-luciferase reporter assay, western blotting, stereotaxic injection of antagomir/agomir and cell transfection experiments were performed to elucidate the effect of the candidate miRNA and intervention mechanism of Rhy on METH dependence. RESULTS: Rhy successfully reversed METH-induced CPP effect and the upregulated miR-181a-5p expression in METH-dependent rat hippocampus and PC12 cells. Moreover, suppression of miR-181a-5p by antagomir 181a reversed METH-induced CPP effect. Meanwhile, overexpression of miR-181a-5p by agomir 181a in combination with low-dose METH (0.5 mg/kg) elicited a significant CPP effect, which was blocked by Rhy through inhibiting miR-181a-5p. Finally, the result demonstrated that miR-181a-5p exerted its regulatory role by targeting γ-aminobutyric acid A receptor α1 (GABRA1) both in vivo and in vitro. CONCLUSION: This finding reveals that Rhy inhibits METH dependence via modulating the miR-181a-5p/GABRA1 axis, which may be a promising target for treatment of METH dependence.

Simultaneous determination of ZL-01, a novel nucleotide prodrug, and its metabolites in rat plasma by LC-MS/MS: Application to pharmacokinetic study.

ZL-01 is a novel dual-prodrug which shows promise to be an antiviral candidate for hepatitis C virus. Here we have established a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of ZL-01 and its four metabolites (M1, M7, M8, and M9) in rat plasma with special consideration of ex vivo ZL-01, M1, and M7 stability. Several factors affecting the stability were investigated. EDTA and citric acid solution (1 M) were added to plasma to maintain the stability of analytes. The protein-precipitation method was selected with acetonitrile containing sofosbuvir as internal standard (IS). Adequate separation of ZL-01 and its metabolites was achieved on XSelect HSS T3 (3.5 µm, 4.6 × 150 mm) column by a gradient-elution with a mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0.5 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 599.2→418.5 for ZL-01, m/z 529.7→398.2 for M1, m/z 330.5→182.0 for M7, m/z 260.3→112.1 for M8, m/z 261.3→113.2 for M9 and m/z 530.4→243.4 for IS. The calibration curves exhibited good linearity (r＞0.997) for all components. The lower limit of quantitation (LLOQ) was in the range of 1-2 ng/mL. The intra-day and inter-day precisions (RSD) at three different levels were both less than 10.2% and the accuracies (RE) ranged from -3.7-7.6%. The matrix effect and extraction recovery of them ranged from 84% to 110.3% and 88.3-106.3%. This LC-MS/MS method for the simultaneous quantitation of ZL-01 and its metabolites was developed successfully and applied in the pharmacokinetic studies of these in rats. Pharmacokinetic results indicated ZL-01 would be metabolized rapidly and M8 might be the main metabolites after oral absorption.

Iminium Ion and N-Hydroxyimide as the Surrogate Components in DEAD-Promoted Oxidative Ugi Variant.

A practical metal-free oxidative Ugi-type three-component assembly has been achieved efficiently, employing a tertiary-amine-derived iminium ion as an imine surrogate, N-hydroxyimide as an acid surrogate, and DEAD as an oxidant. This dual-surrogate Ugi variant proceeded with a broad substrate scope and desired functional group tolerance, leading to a wide range of N-alkyl- N-acyl aminophthalimide and N-alkyl- N-acylaminosuccinimide derivatives in good isolated yields.

[Clinical Significance of HBV Detection in NHL Patients].

OBJECTIVE: To analyze the relation of HBV infection with clinical characteristics and prognosis in NHL patients, so as to explore the significance of HBV detection. METHODS: Sixty-eight NHL patients from December 2013 to December 2016 were enrolled in NHL group and 136 patients with other malignancies were chosen in control group, the detectable rate of HBV was compared between 2 groups. The correlation of HBV infection with sex, age, stage, cell origin, expression of P53 and BCL-2 in NHL patients was analyzed. The prognosis-related factors in NHL patients were also analyzed. RESULTS: The infection rate of HBV in NHL group was 51.47%(35/68), that in control group was 15.44% (21/136), and the difference was statistically significant(χ2=27.768,P<0.05). HBV infection correlated with cell origins and expression of BCL-2 in NHL patients(P<0.05). The prognosis of NHL patients demonstrated no correlation with sex, age, cell origins and HBV infection (P>0.05), while the prognosis was significantly related with stage, expression of P53 and BCL-2(P<0.05). CONCLUSION: HBV infection correlates with BCL-2 expression level of NHL patients, and shows influence on the prognosis of patients.

[Value of hsCRP and Alb in Evaluating the Prognosis of Patients with Systemic Lupus Erythematosus].

OBJECTIVE: To study the value of hsCRP and Alb in evaluating the prognosis of patients with systemic lupus erythematosus (SLE). METHODS: 126 SLE patients from January 2011 to January 2016 were enrolled in this study, and their clinical data were collected, including SLEDAI, hsCRP and Alb and complications. The correlation between hsCRP/Alb ratio and SLEDAI after treatment was analyzed. All patients were followed up after discharge, and the prognosis-related factors were analyzed. RESULTS: After treatment, hsCRP/Alb ratio of patients with SLEDAI 10-14 score was significantly higher than that of 5-9 and 0-4 score(P<0.05). hsCRP/Alb ratio was positively correlated with infection (r=0.574), renal damage (r=0.499) and cardiac injury (r=0.516) (P<0.05), while it demonstrated no correlation with blood system damage, CNS damage and lung injury(P>0.05). after treatment SLEDAI ≥10 score, hsCRP/Alb≥0.05 mg/g and complications significantly correlated with prognosis of patients(P<0.05). CONCLUSION: hsCRP/Alb correlates with the prognosis of patients with SLE at a certam level.

A novel Mn(2+)-doped core/shell quantum dot-based intracellular probe for fluoride anions sensing in MC3T3-E1 osteoblastic cells.

In this paper, 3-aminobenzeneboronic acid functionalized Mn(2+)-doped ZnTe/ZnSe quantum dots (APBA-dQDs) were prepared. The APBA functional groups had strong binding ability with F(-), resulting in the quenchment of dQDs photoluminescence (PL). Under the optimal condition, the fluorescence intensity of APBA-dQDs was related linearly to the concentration of F(-) in the range of 0.25-1.5µmol/L with a detection limit of 0.1µmol/L. The selectivity of fluorescence quenching of APBA-dQDs for F(-) was enhanced. Moreover, the proposed methodology for the sensing of F(-) at EM 560nm in MC3T3-E1 osteoblastic cells was demonstrated and got a satisfactory results. The results indicate that the APBA-dQDs are promising candidates for intracellular in MC3T3-E1 osteoblastic cells. To the best of our knowledge, it was the first report of F(-) sensing by using the quenched fluorescence of APBA-dQDs in non-cancerous cells.

[Clinical Analysis of 94 Patients with Neurocysticercosis in Sichuan Province].

Objective: To analyze the clinical features of neurocysticercosis（NCC） to provide evidence for clinical diagnosis and treatment of the disease. Methods: Medical records of NCC patients in the West China Hospital of Sichuan University received between January 2003 and January 2013 were reviewed retrospectively. The epidemiological data, clinical manifestations, therapeutic procedures and outcomes of the patients were analyzed. Results: A total of 94 NCC patients met the recruiting criteria, of whom 67.0%（63/94） were male, 59.6%（56/94） ranged 30-55 years old, 73.4%（69/94） had a living history in endemic regions such as Aba, Ganzi and Liangshan prefectures, 80.9%（76/94） lived in rural areas. NCC was clinically characterized by epilepsy, headache and intracranial hypertension. The positive rate for anti-T. solium antibodies by ELISA was 96.8%（91/94）, and the total positive scan rate of neuroimaging including CT and MRI was 95.7%（90/94）. In addition, 73 patients were suspected to have NCC at the first diagnosis, with a misdiagnosis rate of 22.3%（21/94）. Seventy-nine of the patients received albendazole treatmentï¼»20 mg/（kg·d）, twice per day for 10 days as one treatment course, 1-3 courses as neededï¼½. Eleven patients received praziquantel（total dose of 120-180 mg/kg, 3 times per day for 3 days as one treatment course, 1-3 courses）, and 4 received a combination of albendazole and praziquantel. Symptoms improved in 77 cases（81.9%）, but 12 of them（12/77, 15.6%） relapsed. The improvement rate of the albendazole group（6/11, 84.8%） was significantly higher than that of the praziquantel group（54.6%）（P<0.05）. Conclusion: NCC more commonly occurs in young males and lacks specific clinical manifestations. Neuroimaging combined with serum specific antibody tests is crucial for diagnosis. Albendazole has better therapeutic effects than praziquantel.

[Detection of 16S rRNA methylase genes and genotypes in ESBLs-producing enterobacteriaceae isolates from urinary tract infections].

OBJECTIVE: To study the prevalence of 16S rRNA methylase genes in extended-spectrum-lactamascs (ESBLs)-producing Enterobacteriacea, and the correlations of 16S rRNA methylase genes with anminoglycoside resistnace. METHODS: Seventy-four ESBLs-producing Enterobacteriacea stains were isolated from urinary tract infections. Minimal inhibitory concentrations (MICs) of 5 aminoglycosides against the ESBLs-producing Enterobacteriacea were detected by two-fold agar dilution method. PCR amplification and DNA sequencing were used for screening and identifying 16S rRNA methylase genes. The clonality of 16S rRNA methylase gene positive ESBLs-producing Enterobacteriaceae was assessed by multilocus sequence typing (MLST). RESULTS: The bacterial resistant rates to gentamycin, netilmicin, tobramycin,amikacin and isepamicin were 93.4%, 18.4%, 13.2%, 5.3% and 5.3%, respectively. Tweenty-two out of 74 clinical isolates were 16S rRNA methylase genes positive (29.7%), including 18 armA gene and 7 rmtB gene, and 3 strains with both genes. The resistant rates of those 22 strains to gentamycin , netilmicin, tobramycin, amikacin and isepamicin were 100%, 100%, 59.1%, 18.2% and 18.2%, respectively. Among 19 E. coli isolates, seven sequence types (STs) were identified, named as ST117 (12 strains), ST2003 (2 strains), ST3843 (1 strain), ST915 (1 strain), ST844 (1 strain), ST2581 (1 strain) and ST2922 (1 strain). MLST showed that 3 K. pneumoniae isolates were nonclonal. CONCLUSION: 16S rRNA methylase genes were widely distributed in urinary ESBLs-producing Enterobacteriacea, showing obvious relationship with the resistance to aminoglycosides. The therapy of Amikacin or Isepamicin may be considered in UTIs with 16S rRNA gene positive ESBLs-producing Enterobacteriacea.

[Nosocomial diarrhea in intensive care unit: other than Clostridium difficile].

OBJECTIVE: To investigate the incidence and clinical features of non-Clostridium difficile (C. difficile) associated nosocomial diarrhea in intensive care unit (ICU) caused by Klebsiella oxytoca and Clostridium perfringens. METHODS: The faeces of 102 patients with non-C. difficile associated nosocomial diarrhea in ICU of West China Hospital, were collected during April to November, 2012. The target bacterial genes were detected by PCR amplification and sequencing, including toxic gene pehX of Klebsiella oxytoca, species-specific 16S rRNA gene and toxic gene cpa and cpe of Clostridium perfringens, species-specific 16S rRNA gene with mapA and toxic gene hipO of Campylobacter jejuni. Clinical features of the patients with positive results were summarized. RESULTS: Among 102 patients with non-C. difficile associated nosocomial diarrhea, 4 patients (3.9%) were detected with toxic Klebsiella oxytoca while 4 patients (3.9%) were detected with toxic Clostridium perfringens. No toxic Campylobacter jejuni was detected. Most of the patients had severe underlying diseases and poor final outcome, accepted potent antibiotics which disturbed intestinal flora obviously.. CONCLUSION: Non-C. difficile associated nosocomial diarrhea in ICU caused by Klebsiella oxytoca is and Clostridium perfringens is associated with severe diseases and poor outcome, but the incidence in our hospital is relatively low in our hospital.