Natural product-inspired synthesis of coumarin–chalcone hybrids as potential anti-breast cancer agents

Twelve novel neo-tanshinlactone–chalcone hybrid molecules were constructed through a versatile methodology involving the Horner–Wadsworth–Emmons (HWE) olefination of 4-formyl-2H-benzo [h]chromen-2-ones and phosphonic acid diethyl esters, as the key step, and evaluated for anticancer activity against a series of four breast cancers and their related cell lines, viz. MCF-7 (ER + ve), MDA-MB-231 (ER-ve), HeLa (cervical cancer), and Ishikawa (endometrial cancer). The title compounds showed excellent to moderate in vitro anti-cancer activity in a range of 6.8–19.2 µM (IC50). Compounds 30 (IC50 = 6.8 µM and MCF-7; IC50 = 8.5 µM and MDA-MB-231) and 31 (IC50 = 14.4 µM and MCF-7; IC50 = 15.7 µM and MDA-MB-231) exhibited the best activity with compound 30 showing more potent activity than the standard drug tamoxifen. Compound 30 demonstrated a strong binding affinity with tumor necrosis factor α (TNF-α) in molecular docking studies. This is significant because TNFα is linked to MCF-7 cancer cell lines, and it enhances luminal breast cancer cell proliferation by upregulating aromatase. Additionally, virtual ADMET studies confirmed that hybrid compounds 30 and 31 met Lipinski’s rule; displayed high bioavailability, excellent oral absorption, favorable albumin interactions, and strong penetration capabilities; and improved blood–brain barrier crossing. Based on the aforementioned results, compound 30 has been identified as a potential anti-breast cancer lead molecule

Durable vesicles for reconstitution of membrane proteins in biotechnology

The application of membrane proteins in biotechnology requires robust, durable reconstitution systems that enhance their stability and support their functionality in a range of working environments. Vesicular architectures are highly desirable to provide the compartmentalisation to utilise the functional transmembrane transport and signalling properties of membrane proteins. Proteoliposomes provide a native-like membrane environment to support membrane protein function, but can lack the required chemical and physical stability. Amphiphilic block copolymers can also self-assemble into polymersomes: tough vesicles with improved stability compared with liposomes. This review discusses the reconstitution of membrane proteins into polymersomes and the more recent development of hybrid vesicles, which blend the robust nature of block copolymers with the biofunctionality of lipids. These novel synthetic vesicles hold great promise for enabling membrane proteins within biotechnologies by supporting their enhanced in vitro performance and could also contribute to fundamental biochemical and biophysical research by improving the stability of membrane proteins that are challenging to work with

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Biodegradable Hybrid Block Copolymer – Lipid Vesicles as Potential Drug Delivery Systems

The anticipated benefits of nano-formulations for drug delivery are well known: for nanomedicines to achieve this potential, new materials are required with predictive and tuneable properties. Excretion of excipients following delivery is advantageous to minimise the possibility of adverse effects; biodegradability to non-toxic products is therefore desirable. With this in mind, we aim to develop tuneable hybrid lipid-block copolymer vesicle formulations where the hydrophilic polymer block is polyethylene glycol (PEG), which has accepted biocompatibility, and the hydrophobic block of the polymer is biodegradable: polycaprolactone (PCL) or polylactide (PLA). We investigate five different block copolymers for the formation of 1:1 phospholipid:polymer hybrid vesicles, compare their properties to the appropriate unitary liposome (POPC) and polymersome systems and assess their potential for future development as nanomedicine formulations. The PEG-PCL polymers under investigation do not form polymersomes and exhibit poor colloidal and/or encapsulation stability in hybrid formulations with lipids. The properties of PEG-PLA hybrid vesicles are found to be more encouraging: they have much enhanced passive loading of a hydrophilic small molecule (carboxyfluorescein) compared to their respective polymersomes and exhibit more favourable release kinetics in the presence of serum compared to the liposome. Significantly, burst release from hybrid vesicles can be substantially reduced by making the polymer components of the hybrid vesicle a mixture containing 10 mol% of PEG16-PLA25 that is intermediate in size between the phospholipid and larger PEG45-PLA54 components. We conclude that hybrid lipid/PEG-PLA vesicles warrant further assessment and development as candidate drug delivery systems.</p

Genetics and Genomics of Chronic Pancreatitis with a Focus on Disease Biology and Molecular Pathogenesis

Chronic pancreatitis is a long-term fibroinflammatory condition of the pancreas with varying incidences across countries. The recent increase in its occurrence implies the involvement of genetic, hereditary, and unconventional risk factors. However, there is a lack of updated literature on recent advances in genetic polymorphisms of chronic pancreatitis. Therefore, this review aims to present recent findings on the genetic implications of chronic pancreatitis based on individual gene mechanisms and to discuss epigenetics and epistasis involved in the disease. Four mechanisms have been implicated in the pathogenesis of chronic pancreatitis, including premature activation of proteases, endoplasmic reticulum stress, ductal pathway dysfunction, and inflammatory pathway dysfunction. These mechanisms involve genes such as PRSS1, PRSS2, SPINK, CEL, PNLIP, PNLIPRP2, CFTR, CaSR, CLDN2, Alpha 1 antitrypsin, and GGT1. Studying genetic polymorphisms on the basis of altered genes and their products may aid clinicians in identifying predispositions in patients with and without common risk factors. Further research may also identify associations between genetic predispositions and disease staging or prognosis, leading to personalized treatment protocols and precision medicine

Regulating photosalient behavior in dynamic metal-organic crystals

Dynamic photoactuating crystals have become a sensation due to their potential applications in developing smart medical devices, molecular machines, artificial muscles, flexible electronics actuators, probes and microrobots. Here we report the synthesis of two iso-structural metal-organic crystals, [Zn(4-ohbz)2(4-nvp)2] (1) and [Cd(4-ohbz)2(4-nvp)2] (2) {H4-ohbz = 4-hydroxy benzoic acid; 4-nvp = 4-(1-naphthylvinyl)pyridine} which undergo topochemical [2 + 2] cycloaddition under UV irradiation as well as sunlight to generate a dimerized product of discrete metal-complex [Zn(4-ohbz)2(rctt-4-pncb)] {rctt-4-pncb = 1,3-bis(4′-pyridyl)-2,4-bis(naphthyl)cyclobutane} (1′) and one-dimensional coordination polymer (1D CP) [Cd(4-ohbz)2(rctt-4-pncb)] (2′) respectively, in a single-crystal-to-single-crystal (SCSC) process. The Zn-based compound demonstrates photosalient behaviour, wherein crystals show jumping, splitting, rolling, and swelling upon UV irradiation. However, the Cd-based crystals do not show such behaviour maintaining the initial supramolecular packing and space group. Thus the photomechanical behaviour can be induced by choosing a suitable metal ion. The above findings are thoroughly validated by quantitative density functional theory (DFT) calculations which show that the Zn-based crystal shifts towards an orthorhombic structure to resolve the anisotropic UV-induced mechanical strain. Furthermore, the mechano-structure-property relationship has been established by complimentary nanoindentation measurements, which are in-line with the DFT-predicted single crystal values.</p

A reconstitution method for integral membrane proteins in hybrid lipid-polymer vesicles for enhanced functional durability

Hybrid vesicles composed of lipids and block copolymers hold promise for increasing liposome stability and providing a stable environment for membrane proteins. Recently we reported the successful functional reconstitution of the integral membrane protein cytochrome bo3 (ubiquinol oxidase) into hybrid vesicles composed of a blend of phospholipids and a block copolymer (PBd-PEO). We demonstrated that these novel membrane environments stabilise the enzymes’ activity, prolonging their functional lifetime [Chem. Commun. 52 (2016) 11020–11023]. This approach holds great promise for applications of membrane proteins where enhanced durability, stability and shelf-life will be essential to creating a viable technology. Here we present a detailed account of our methods for membrane protein reconstitution into hybrid vesicles and discuss tips and challenges when using block copolymers compared to pure phospholipid systems that are more common materials for this purpose. We also extend the characterisation of these hybrid vesicles beyond what we have previously reported and show: (i) hybrid membranes are less permeable to protons than phospholipid bilayers; (ii) extended enzyme activity data is presented over a period of 500 days, which fully reveals the truly remarkable enhancement in functional lifetime that hybrid vesicles facilitate