Peroxynitrite-Promoted Persulfide Prodrugs with Protective Potential against Paracetamol Poisoning.

The newly emerging persulfide prodrugs provide additional options for the profound study of persulfide, a fascinating molecule expected to intervene in biological functions and even diseases. Peroxynitrite is often the culprit in pathological processes characterized by oxidative stress, while the persulfide prodrug responsive to it is still pending. To enrich the family of redox-activated prodrugs, we designed prodrugs with a 2-oxo-2-phenylacetamide trigger, which achieved the release of persulfide via 1, 6-N, S-relay. The degradation of prodrugs and the formation of persulfides were confirmed to be peroxynitrite-responsible by the qualitative and quantitative studies based on LC-MS/MS methods and a spectrophotometry-based tag-switch strategy. Furthermore, these prodrugs showed potent peroxynitrite scavenging activity, cellular therapeutic potential against paracetamol poisoning in HepG2 and oxidative stress in H9c2, as well as desirable in vitro metabolic properties.

Diethyl Azodicarboxylate-Promoted Oxidative [3 + 2] Cycloaddition for the Synthesis of Pyrrolo[2,1-a]isoquinolines.

A novel metal-free protocol for the effective and efficient construction of pyrrolo[2,1-a]isoquinolines via a diethyl azodicarboxylate (DEAD)-promoted oxidative [3 + 2] cycloaddition/aromatization tandem reaction is described. Instead of the reported two-component oxidation systems, DEAD, as the sole oxidant, could smoothly transfer the tertiary amines to azomethine ylides via oxidation-deprotonation tandem process. The reaction proceeded with a broad substrate scope, giving rise to products in moderate to good isolated yields.

Cu-Catalyzed Dimerization of Indole Derived Oxime Acetate for Synthesis of Biimidazo[1,2-a]indoles.

A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-a]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.

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.

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-ß-D-glucuronide, an active metabolite of berberrubine.

Berberrubine (BRB) is the primary metabolite of berberine (BBR) that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-ß-D-glucuronide (BRBG) in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB (50 mg·kg-1·d-1, ig) for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR (120 mg·kg-1·d-1) or BRB (25 mg·kg-1·d-1). In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages (10, 40, 80 mg/kg) and in urine at different time intervals (0-4, 4-10, 10-24 h) were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line L-O2 in vitro, treatment with BRB or BRBG (5, 20, 50 µmol/L) increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-O2 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.

[Clinical efficacy and mechanism of total glucosides from white paeony for radioactive liver damage].

To discuss the effects of total glucosides from white paeony on preventing and treating radioactive liver damage, and explore its possible mechanisms. Thirty-six patients with primary hepatic carcinoma from 105th Hospital of Chinese PLA were treated with 3-dimensional conformal radiotherapy and randomly divided into simple irradiation group, total glucosides from white paeony group, and control group. The levels of AST, ALT, HA, LN, PCⅢ, CIV and TGF-ß1 in serum of various groups were determined by using ELISA method. As compared with the simple irradiation group and control group, total glucosides from white paeony could obviously decrease the levels of AST, ALT, HA, LN, PCⅢ, CIV and TGF-ß1(P<0.05, P<0.01). The results showed that the total glucosides from white paeony could effectively prevent and treat radioactive liver damage, and its mechanism might be associated with decreasing the levels of TGF-ß1, and inhibiting the synthesis of collagen synthesis.

Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.

BACKGROUND: Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children. Accumulating evidence suggests that activation of the microglia/macrophage and concomitant inflammatory response in FCD IIb and TSC may contribute to the initiation and recurrence of seizures. The membrane glycoproteins CD47 and CD200, which are highly expressed in neurons and other cells, mediate inhibitory signals through their receptors, signal regulatory protein α (SIRP-α) and CD200R, respectively, in microglia/macrophages. We investigate the levels and expression pattern of CD47/SIRP-α and CD200/CD200R in surgically resected brain tissues from patients with FCD IIb and TSC, and the potential effect of soluble human CD47 Fc and CD200 Fc on the inhibition of several proinflammatory cytokines associated with FCD IIb and TSC in living epileptogenic brain slices in vitro. The level of interleukin-4 (IL-4), a modulator of CD200, was also investigated. METHODS: Twelve FCD IIb (range 1.8-9.5 years), 13 TSC (range 1.5-10 years) patients, and 6 control cases (range 1.5-11 years) were enrolled. The levels of CD47/SIRP-α and CD200/CD200R were assessed by quantitative real-time polymerase chain reaction and western blot. The expression pattern of CD47/SIRP-α and CD200/CD200R was investigated by immunohistochemical analysis, and the cytokine concentrations were measured by enzyme-linked immune-sorbent assays. RESULTS: Both the messenger RNA and protein levels of CD47, SIRP-α, and CD200, as well as the mRNA level of IL-4, were downregulated in epileptogenic lesions of FCD IIb and TSC compared with the control specimens, whereas CD200R levels were not significantly changed. CD47, SIRP-α, and CD200 were decreasingly expressed in dysmorphic neuron, balloon cells, and giant cells. CD47 Fc and CD200 Fc could inhibit IL-6 release but did not suppress IL-1ß or IL-17 production. CONCLUSIONS: Our results suggest that microglial activation may be partially caused by CD47/SIRP-α- and CD200/CD200R-mediated reductions in the immune inhibitory pathways within FCD IIb and TSC cortical lesions where chronic neuroinflammation has been established. Upregulation or activation of CD47/SIRP-α and CD200/CD200R may have therapeutic potential for controlling neuroinflammation in human FCD IIb and TSC.

Intramolecular redox reaction for the synthesis of N-aryl pyrroles catalyzed by Lewis acids.

An efficient approach to synthesize N-aryl pyrroles via Lewis acid-mediated 1,5-hydride shift and isomerization of 2-(3-pyrroline-1-yl)arylaldehydes has been achieved in up to 89% yield. This methodology is applicable to the synthesis of fluorazene derivatives as electron donor (D)/acceptor (A) molecules.

Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolecular [1,5]-hydride shift/isomerization reaction.

Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolcular [1,5]-hydride shift/isomerization reaction has been realized, using the inherent reducing power of 3-pyrrolines. A series of N-arylpyrrole containing amines are obtained in high yields.

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.

Hydrocortisone Mitigates Alzheimer's-Related Cognitive Decline through Modulating Oxidative Stress and Neuroinflammation.

Alzheimer's disease (AD), an age-related degenerative disorder, is characterized by ß-amyloid deposition, abnormal phosphorylation of tau proteins, synaptic dysfunction, neuroinflammation, and oxidative stress. Despite extensive research, there are no medications or therapeutic interventions to completely treat and reverse AD. Herein, we explore the potential of hydrocortisone (HC), a natural and endogenous glucocorticoid known to have potent anti-inflammatory properties, in an Aß1-42-induced AD mouse model. Our investigation highlights the beneficial effects of HC administration on cognitive impairment, synaptic function enhancement, and neuronal protection in Aß1-42-induced AD mice. Notably, HC treatment effectively suppresses the hyperactivation of microglia and astrocytes, leading to a reduction in proinflammatory factors and alleviation of neuroinflammation. Furthermore, HC intervention demonstrates the capacity to mitigate the generation of ROS and oxidative stress. These compelling findings underscore the potential therapeutic application of HC in AD and present promising opportunities for its utilization in AD prevention and treatment. The implications drawn from our findings indicate that hydrocortisone holds promise as a viable candidate for adjunctive use with other anti-AD drugs for the clinical management of patients presenting with moderate to severe AD.

Development and validation for bioanalysis of VK2809, its active metabolite VK2809A and glutathione-conjugated metabolite MB06588 in rat liver using LC-MS/MS.

VK2809 is a promising drug candidate in Phase II clinical trials for the treatment of non-alcoholic steatohepatitis (NASH). It is a prodrug with a HepDirect strategy, which can achieve selective hepatic metabolic activation, generating an active metabolite VK2809A as a potent and selective agonist for thyroid hormone receptor beta (TRß), a concomitant reactive metabolite VK2809B, and a glutathione (GSH) conjugate MB06588. Currently, there is no convenient and sensitive bioanalytical method for the simultaneous determination of the above three metabolites. Herein, we established an LC-MS/MS method to separate VK2809 and its metabolites on the XSelect HSS T3 column and quantified them in negative electrospray ionization mode. Subsequently, several factors were investigated such as the use of 60% acetonitrile for homogenization to stabilize the analytes, the addition of 20 mM glutathione for the derivation of VK2809B, and the protein precipitation with methanol containing Sobetirome as the internal standard (IS). The method exhibited good linearity for all compounds (19.4-388.4 nM for VK2809; 27.4-2744.4 nM for VK2809A and 10.6-211.0 nM for MB06588) with great correlation coefficients (r > 0.996). The method validation also demonstrated acceptable precision (RSD < 13.0% for VK2809, RSD < 7.9% for VK2809A, RSD < 14.4% for MB06588) and accuracy (92.7%-103% for VK2809, 91.2%-107.3% for VK2809A, 96%-106.7% for MB06588). The matrix effect, recovery, and stability were also suitable to determine all the analytes. This method is suitable for the bioanalysis of VK2809 and its metabolites and has been successfully applied to the study of intrahepatic exposure in rats. It is expected to be further practiced in drug design, optimization, and metabolism study in the following research.

Analysis of Radioactive Iodine Trapping Mechanism by Zinc-Based Metal-Organic Frameworks with Various N-Containing Carboxylate Ligands.

This study aimed to develop effective adsorbents for capturing radioactive iodine in nuclear power waste gas. Two zinc metal-organic frameworks (Zn-MOFs) were synthesized and found to have favorable properties such as a large surface area, thermal stability, surface rich in π-electron-containing nitrogen, and redox potential. Adsorption experiments revealed maximum capacities of 1.25 and 1.96 g g-1 for the MOFs at 75 °C, with the pseudo-second-order kinetic model fitting the data well. The Langmuir equation provided a better fit in cyclohexane, with maximum adsorption amounts of 249 and 358 mg g-1 for Zn-MOF-1 and Zn-MOF-2, respectively. The MOFs were also stable during six cycles of adsorption and desorption. Furthermore, electron transfer occurred due to the synergistic adsorption of Zn, N, and O atoms, resulting in the conversion of some iodine to polyiodide. Zn-MOF-2 exhibited better chemisorption than Zn-MOF-1 due to a smaller highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap. Notably, it was discovered that N-containing radicals had stronger interactions with iodine compared to radicals without N. These findings provide valuable insights into MOF synthesis and environmental protection.

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.

A mechanistic review on aerobic denitrification for nitrogen removal in water treatment.

The traditional biological nitrogen removal technology consists of two steps: nitrification by autotrophs in aerobic circumstances and denitrification by heterotrophs in anaerobic situations; however, this technology requires a huge area and stringent environmental conditions. Researchers reached the conclusion that the denitrification process could also be carried out in aerobic circumstances with the discovery of aerobic denitrification. The aerobic denitrification process is carried out by aerobic denitrifying bacteria (ADB), most of which are heterotrophic bacteria that can metabolize various forms of nitrogen compounds under aerobic conditions and directly convert ammonia nitrogen to N2 for discharge from the system. Despite the fact that there is no universal agreement on the mechanism of aerobic denitrification, this article reviewed four current explanations for the denitrification mechanism of ADB, including the microenvironment theory, theory of enzyme, electron transport bottlenecks theory, and omics study, and summarized the parameters affecting the denitrification efficiency of ADB in terms of carbon source, temperature, dissolved oxygen (DO), and pH. It also discussed the current status of the application of aerobic denitrification in practical processes. Following the review, the difficulties of present aerobic denitrification technology are outlined and future research options are highlighted. This review may help to improve the design of current wastewater treatment facilities by utilizing ADB for effective nitrogen removal and provide the engineers with relevant references.

Synthesis and in vitro evaluation of ambrisentan analogues as potential endothelin receptor antagonists.

A series of novel 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3,3-diphenyl butyric acid derivatives were synthesized and evaluated for their antagonistic activity for endothelin-1-induced contraction in rabbit aorta. Within this series of compounds, 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-cyano-3,3-diphenylpropionic acid (4) displays comparable potency with ambrisentan (1), and warrants further investigation.

Precision-porous polyurethane elastomers engineered for application in pro-healing vascular grafts: Synthesis, fabrication and detailed biocompatibility assessment.

Unmet needs for small diameter, non-biologic vascular grafts and the less-than-ideal performance of medium diameter grafts suggest opportunities for major improvements. Biomaterials that are mechanically matched to native blood vessels, reduce the foreign body capsule (FBC) and demonstrate improved integration and healing are expected to improve graft performance. In this study, we developed biostable, crosslinked polyurethane formulations and used them to fabricate scaffolds with precision-engineered 40 µm pores. We matched the scaffold mechanical properties with those of native blood vessels by optimizing the polyurethane compositions. We hypothesized that such scaffolds promote healing and mitigate the FBC. To test our hypothesis, polyurethanes with 40 µm pores, 100 µm pores, and non-porous slabs were implanted subcutaneously in mice for 3 weeks, and then were examined histologically. Our results show that 40 µm porous scaffolds elicit the highest level of angiogenesis, cellularization, and the least severe foreign body capsule (based on a refined assessment method). This study presents the first biomaterial with tuned mechanical properties and a precision engineered porous structure optimized for healing, thus can be ideal for pro-healing vascular grafts and in situ vascular engineering. In addition, these scaffolds may have wide applications in tissue engineering, drug delivery, and implantable device.

Bio-inspired drug-dominated supramolecular nanocomplex based on low molecular weight heparin for progressive tumor therapy.

Low molecular weight heparin (LMWH) is a natural sulfated glycosaminoglycan with the affinity to proangiogenic factors, rendering it a promising agent for tumor therapy. Inspired by DOX binding to the helix of DNA, mitochondrial damage KLA peptide derivative (mKLA) and anti-angiogenic LMWH-chrysin conjugate (LC) are constructed to simulate the double strands for doxorubicin (DOX) binding (LKD nanocomplex). Initiated and "locked" by DOX, mKLA and LC temporarily aggregate by π-π stacks, electrostatic and hydrophobic interactions in aqueous condition with self-amplified DOX loading (19.07 ± 1.08 wt%). During endosome-lysosome trafficking, DOX protonated by H+ could "unlock" the LKD nanocomplex to disassemble, which enables mKLA and DOX to damage mitochondria and nucleus DNA respectively, and LMWH could also inhibit angiogenesis. Based on the strong inhibition of tumors at all stages in vivo, we hold that LKD nanocomplex provides a new opportunity based on smart construction of carbohydrate materials for clinically advanced cancer patients.

PGAM5-CypD pathway is involved in bromocriptine-induced RIP3/MLKL-dependent necroptosis of prolactinoma cells.

Bromocriptine, the most commonly used dopamine (DA) receptor agonists for prolactinoma, can effectively reduce tumor size of prolactinoma, but the mechanism was not fully understood. Apoptosis had been well-recognized to contribute to the tumor mass regression caused by bromocriptine. However, whether other types of non-apoptotic cell death involved in the bromocriptine-induced prolactinoma shrinkage had not been fully clarified. The newly discovered molecular mechanism of necroptosis provides the possibility to examine this programmed necrosis in the pharmacological function of bromocriptine. The aim of present study was to evaluate and investigate the underlying mechanism of necroptosis in involution of prolactinoma induced by bromocriptine. By immunohistochemistry, we found that the numbers of receptor-interacting serine-threonine kinase 3(RIP3) and phosphorylated mixed lineage kinase domain-like protein (pMLKL)-positive cells and their expression intensities were increased in patients with prolactinoma after bromocriptine therapy. For further exploring the mechanism of bromocriptine, prolactinoma cell line (MMQ cells) was adopted to study the mechanism of necroptosis in vitro. Cell viability and ATP level of MMQ cells were decreased, while reactive oxygen species (ROS) level was increased after bromocriptine treatment. The above effects could be partially reversed by Necrostatin-1, an inhibitor of necroptosis. Ultrastructural study further confirmed the necroptosis of MMQ cells, which was characterized by ruptured membrane, dissolved cytoplasm and especially the dramatically swollen mitochondria. Furthermore, we demonstrated that bromocriptine induced RIP3/MLKL-dependent necroptosis of prolactinoma cells and phosphoglycerate mutase family 5(PGAM5)/ Cyclophilin D (CypD) pathway was involved. The results suggested that necroptosis might be a promising target for clinical therapy for prolactinoma.

Diesel pollution biodegradation: synergetic effect of Mycobacterium and filamentous fungi.

OBJECTIVE: To biodegrade the diesel pollution in aqueous solution inoculated with Mycobacterium and filamentous fungi. METHODS: Bacteria sampled from petroleum hydrocarbons contaminated sites in Karamay Oilfield were isolated and identified as Mycobacterium hyalinum (MH) and cladosporium. Spectrophotometry and gas chromatography (GC) were used to analyze of the residual concentrations of diesel oil and its biodegradation products. RESULTS: From the GC data, the values of apparent biodegradation ratio of the bacterial strain MH to diesel oil were close to those obtained in the control experiments. Moreover, the number of MH did not increase with degradation time. However, by using n-octadecane instead of diesel oil, the real biotic degradation ratio increased to 20.9% over 5 days of degradation. Cladosporium strongly biodegraded diesel oil with a real degradation ratio of up to 34% after 5 days treatment. When the two strains were used simultaneously, a significant synergistic effect between them resulted in almost complete degradation of diesel oil, achieving a total diesel removal of 99% over 5 days of treatment, in which one part of about 80% and another part of about 19% were attributed to biotic and abiotic processes, respectively. CONCLUSION: The observed synergistic effect was closely related to the aromatics-degrading ability of Cladosporium, which favored the growth of MH and promoted the bioavailability of diesel oil.