New Development of Novel Berberine Derivatives against Bacteria.

Many berberine derivatives have been synthesized for their antibacterial activity in the past years. In order to elucidate their new Structural Activity Relationship (SAR), the recently synthesized berberine derivatives are reviewed. The newly synthesized berberine derivatives are reported in this review with novel modifications on the berberine structure at various positions. It is hoped that this article would help scientists to design and synthesize new berberine derivatives with high potency and a broad spectrum of antimicrobial activities, more effectiveness and lower toxicity for improved antimicrobial therapy. These berberine derivatives could be developed as novel antibacterial agents to treat patients with infectious diseases, especially caused by resistant bacteria.

The tiliroside derivative, 3-O-[(E)-(2-oxo-4-(p-tolyl) but-3-en-1-yl] kaempferol produced inhibition of neuroinflammation and activation of AMPK and Nrf2/HO-1 pathways in BV-2 microglia.

Neuroinflammation is now widely accepted as an important pathophysiological mechanism in neurodegenerative disorders, thus providing a critical target for novel compounds. In this study, 3-O-[(E)-(2-oxo-4-(p-tolyl)but-3-en-1-yl] kaempferol (OTBK) prevented the production of pro-inflammatory mediators TNFα, IL-6, PGE2 and nitrite from BV-2 microglia activated with LPS and IFNγ. These effects were accompanied by reduction in the levels of pro-inflammatory proteins COX-2 and iNOS. Involvement of NF-κB in the anti-inflammatory activity of OTBK was evaluated in experiments showing that the compound prevented phosphorylation, nuclear accumulation and DNA binding of p65 sub-unit induced by stimulation of BV-2 microglia with LPS and IFNγ. Exposure of mouse hippocampal HT22 neurons to conditioned media from LPS + IFNγ-stimulated BV-2 cells resulted in reduced cell viability and generation of cellular reactive oxygen species. Interestingly, conditioned media from LPS/IFNγ-stimulated BV-2 cells which were treated with OTBK did not induce neuronal damage or oxidative stress. OTBK was shown to increase protein levels of phospho-AMPKα, Nrf2 and HO-1 in BV-2 microglia. It was further revealed that OTBK treatment increased Nrf2 DNA binding in BV-2 microglia. The actions of the compound on AMPKα and Nrf2 were shown to contribute to its anti-inflammatory activity as demonstrated by diminished activity in the presence of the AMPK antagonist dorsomorphin and Nrf2 inhibitor trigonelline. These results suggest that OTBK inhibits neuroinflammation through mechanisms that may involve activation of AMPKα and Nrf2 in BV-2 microglia.

Novel non-invasive biomarkers diagnostic of acute rejection in renal transplant recipients: A systematic review.

BACKGROUND AND OBJECTIVES: Acute rejection is a significant complication detrimental to kidney transplant function. Current accepted means of diagnosis is percutaneous renal biopsy, a costly and invasive procedure. There is an urgent need to detect and validate non-invasive biomarkers capable of replacing the biopsy. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Comprehensive literature searches of Medline, EMBASE and Cochrane Central Register of Controlled Trials databases were performed. Eligible studies were included as per inclusion criteria and assessed for quality using the GRADE quality of evidence tool. Outcomes evaluated included biomarker diagnostic performance, number of patients/samples, mean age and gender ratio, immunosuppression regime, in addition to clinical applications of the biomarker(s) tested. PRISMA guidelines were followed. Where possible, statistical analysis of comparative performance data was performed. RESULTS: 23 studies were included in this review, including 19 adult, 3 paediatric and 1 mixed studies. A total of 2858 participants and 50 candidate non-invasive tests were identified. Sensitivity, specificity and area under the curve performance values ranged 36%-100%, 30%-100% and 0.55-0.98, respectively. CONCLUSIONS: Although larger, more robust multi-centre validation studies are needed before non-invasive biomarkers can replace the biopsy, numerous candidate tests have demonstrated significant promise for various facets of postoperative management. Suggested uses include: ruling out patients with a low risk of acute rejection to avoid the need for biopsy, non-invasive testing where the biopsy is contraindicated and a prompt diagnosis is needed, and integration into a serial blood monitoring protocol in conjunction with serum creatinine.

Intramolecular azide to alkene cycloadditions for the construction of pyrrolobenzodiazepines and azetidino-benzodiazepines.

The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics.