Ginsenosides act as positive modulators of P2X4 receptors

We investigated the selectivity of protopanaxadiol ginsenosides from Panax ginseng acting as positive allosteric modulators on P2X receptors. ATP-induced responses were measured in stable cell lines overexpressing human P2X4 using a YOPRO-1 dye uptake assay, intracellular calcium measurements, and whole-cell patch-clamp recordings. Ginsenosides CK and Rd were demonstrated to enhance ATP responses at P2X4 by ∼twofold, similar to potentiation by the known positive modulator ivermectin. Investigations into the role of P2X4 in mediating a cytotoxic effect showed that only P2X7 expression in HEK-293 cells induces cell death in response to high concentrations of ATP, and that ginsenosides can enhance this process. Generation of a P2X7-deficient clone of BV-2 microglial cells using CRISPR/ Cas9 gene editing enabled an investigation of endogenous P2X4 in a microglial cell line. Compared with parental BV-2 cells, P2X7-deficient BV-2 cells showed minor potentiation of ATP responses by ginsenosides, and insensitivity to ATP 2 or ATP 1 ginsenoside-induced cell death, indicating a primary role for P2X7 receptors in both of these effects. Computational docking to a homology model of human P2X4, based on the open state of zfP2X4, yielded evidence of a putative ginsenoside binding site in P2X4 in the central vestibule region of the large ectodomain

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Isolation of a Novel N-acetyl-d-lactosamine Specific Lectin from Alocasia cucullata (Schott.)

An N-acetyl-D-lactosamine (LacNAc) specific lectin from tubers of Alocasia cucullata was purified by affinity chromatography on asialofetuin-linked amino activated silica. The pure lectin showed a single band in SDS-PAGE at pH 8.8 and was a homotetramer with a subunit molecular mass of 13.5 kDa and native molecular mass of 53 kDa. It was heat stable up to 55 �C for 15 min and showed optimum hemagglutination activity from pH 2 to 11. The lectin was affected by denaturing agents such as urea (2 M), thiourea (2 M) and guanidine�HCl (0.5 M) and did not require Ca2+ and Mn2+ for its activity. It was a potent mitogen at 10 lg/ml towards human peripheral blood mononuclear cells with 50% growth inhibitory potential towards SiHa (human cervix ) cancer cell line at 100 lg/ml

LED-array photocalorimetry: instrument design and application to photostability of nifedipine

A photocalorimeter was designed to analyse quantitatively the photostability of pharmaceuticals. Its application is demonstrated with reference to two solution phase test systems; the photodegradations of 2-nitrobenzaldehyde (2-NB) and nifedipine. Light emitting diode (LED) arrays were used to illuminate the sample and reference channels of the calorimeter. Five LEDs were used to create an array from 360 to 700 nm. A power supply system was constructed that zeroed the instrument by supplying a preset voltage to the sample side LEDs and varying that supplied to the reference LEDs until a zero calorimetric signal was obtained. The photodegradation of 2-NB was zero-order and varied in proportion to the input voltage supplied to the LED array. Analysis of the data (the rate of reaction was determined to be equal 1.04 × 10−6 mol dm−3 s−1 by pH titration) determined a reaction enthalpy of 5.0 ± 0.6 kJ mol−1. In the case of nifedipine, the LEDs in the array were operated individually in order to determine the causative wavelength of degradation. This was found to be 360 nm, in agreement with the literature

Multifocal repetitive transcranial magnetic stimulation — a novel paradigm in migraine treatment

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation method used for analyzing structural and functional interactions in brain, assess cortical reactivity, and map functionally relevant brain regions inducing a controlled current pulse in a defined region of the cortex. From a clinical point of view, TMS has shown promising results in the therapeutic approach in a large number of psychiatric and neurological conditions such as anxiety, depression, OCD, headache disorders—migraine being one of the most encountered, etc. In patients with migraine, the pharmacologic therapy can be divided in abortive and preventive treatment of the attack. Usually the treatment is started with simple analgesics and non-steroidal inflammatory; nevertheless, many individuals continue to have attacks refractory to various prophylactic and/or abortive therapies, while others are at high risk of developing medication overuse headache. Among non-pharmacologic therapies TMS has been broadly studied as a preventive migraine treatment with good outcome results