Extracellular regulation of metalloproteinases

Matrix metalloproteinases (MMPs) and adamalysin-like metalloproteinase with thrombospondin motifs (ADAMTSs) belong to the metzincin superfamily of metalloproteinases and they play key roles in extracellular matrix catabolism, activation and inactivation of cytokines, chemokines, growth factors, and other proteinases at the cell surface and within the extracellular matrix. Their activities are tightly regulated in a number of ways, such as transcriptional regulation, proteolytic activation and interaction with tissue inhibitors of metalloproteinases (TIMPs). Here, we highlight recent studies that have illustrated novel mechanisms regulating the extracellular activity of these enzymes. These include allosteric activation of metalloproteinases by molecules that bind outside the active site, modulation of location and activity by interaction with cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu by low-density lipoprotein receptor-related protein 1 (LRP1)

Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics

In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term ‘prebiotic’ by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Development and Validation of Reverse Phase High Performance Chromatography Method for Determination of Olanzapine in Microsample Rat Plasma: Application to Preclinical Pharmacokinetic Study

Purpose: To develop a sensitive and validated reverse phase-high performance liquid chromatographic (RP-HPLC) method for quantification of olanzapine in micro-sample of rat plasma using UV detection.Methods: A single oral dose of olanzapine (7 mg/kg) was given to overnight fasted rats (n = 6). Rat plasma samples containing the drug were extracted by liquid-liquid extraction using a combination of dichloromethane: n-hexane (80:20). A reverse phase chromatographic column C18 hypersil-BDS was used for chromatographic separation with a mobile phase consisting of 50 mM phosphate buffer pH 5.5, acetonitrile and methanol (50:30:20, v/v/v) pumped at a flow rate of 1.2 ml/min. Olanzapine was measured using ultraviolet (UV) detection at 214 nm. The method was validated for precision and accuracy.Results: Separation of compounds of interest was not affected by endogenous interference. Good linearity within the concentration range of 1 - 500 ng/ml in rat plasma was obtained with coefficient of regression (r2) of 0.9986. Liquid-liquid extraction produced comparable recovery to solid phase extraction. Retention time of olanzapine and internal standard (fluoxetine) was 5.0 and 13.4 min, respectively. Lowest limit of quantification (LLOQ) was 1 ng/ml while inter-day and intra-day precision was < 12.5 and 5.1 %, respectively. Accuracy of the method was between 94 and 105 % and the variation of results between two analysts was not significant (p = 0.626). Mean maximum plasma concentration (Cmax) of olanzapine was 412.7 ng/ml, time to attain maximum plasma concentration (tmax) was 1 h and half life (t½) was 2.54 h.Conclusion: The proposed method has been successfully validated for precision and accuracy that are within the limits of U.S. Food and Drug Administration (FDA)’s guidance for bioanalyitcal assay validation. The method was successfully applied to preclinical pharmacokinetic analysis of olanzapine in rats.Keywords: Olanzapine, Antipsychotic, Pharmacokinetics, Rat, Plasma, Bioanalytical assay Olanzapine, Antipsychotic, Pharmacokinetics, Rat, Plasma, Bioanalytical assa

Effect of feeding whole linseed as a source of polyunsaturated fatty acids on performance and egg characteristics of laying hens kept at high ambient temperature

The present study was conducted to evaluate the effects of feeding whole linseed on the laying performance and egg characteristics in laying hens kept at high ambient environmental temperatures (average 34 ºC; the diurnal temperature range 26 ºC to 41 ºC). Two hundred and forty 38-wk-old white Leghorn laying hens were fed diets containing 0, 5, 10 or 15% whole linseed (as a source of n-3 polyunsaturated fatty acids) for a period of 12 weeks. Egg production was recorded daily, while feed intake and egg characteristics were monitored on weekly basis. The results of the study demonstrated that egg production and feed intake decreased, while feed conversion ratio (FCR) per dozen of eggs increased (p < 0.05) with increasing dietary linseed levels. Egg weight, yolk weight, albumen height, eggshell weight, and eggshell thickness were not influenced (p > 0.05) by linseed levels in the diets offered to the laying hens. The results of the present trial suggest that feeding linseed to the laying hens in hot climates has no detrimental effects on egg characteristics, but has suppressive effects on egg production, feed intake and feed efficiency of laying hens

Dexibuprofen nanocrystals with improved therapeutic performance: fabrication, characterization, in silico modeling, and in vivo evaluation

Naseem Ullah,1 Shahzeb Khan,1 Shaimaa Ahmed,2 Thirumala Govender,2 Hani S Faidah,3 Marcel de Matas,4 Muhammad Shahid,5 Muhammad Usman Minhas,6 Muhammad Sohail,7 Muhammad Khurram8 1Department of Pharmacy, University of Malakand, Chakdara, Pakistan; 2Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; 3Department of Microbiology, Faculty of Medicine, Umm Al Qura University, Makkah, Kingdom of Saudi Arabia; 4SEDA Pharmaceutical Development Services, The BioHub at Alderley Park, Cheshire, UK; 5Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, Pakistan; 6Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Punjab, Pakistan; 7Department of Pharmacy, COMSATS, Abbottabad, Pakistan; 8Department of Pharmacy, Shaheed Benazir Bhutto University, Sheringal, Pakistan Background: The aim of this study was to prepare and evaluate the impact of polymers on fabricating stable dexibuprofen (Dexi) nanocrystals with enhanced therapeutic potential, using a low energy, anti-solvent precipitation method coupled with molecular modelling approach. Methods: Dexi nanocrystals were prepared using antisolvent precipitation with syringe pump. Crystallinity of the processed Dexi particles was confirmed using differential scanning calorimetry and powdered X-ray diffraction and transmission electron microscopy. Dissolution of Dexi nanocrystals was compared with raw Dexi and marketed tablets. Molecular modelling study was coupled with experimental studies to rationalise the appropriate polymers for stable Dexi nanocrystals. Antinociceptive study was carried out using balb mice. Results: Combinations of hydroxypropyl methylcellulose (HPMC)&ndash;polyvinyl pyrrolidone (PVP) and HPMC&ndash;Eudragit (EUD) were shown to be very effective in producing stable Dexi nanocrystals with particle sizes of 85.0&plusmn;2.5&nbsp;nm and 90&plusmn;3.0&nbsp;nm, and polydispersity of 0.179&plusmn;0.01, 0.182&plusmn;0.02, respectively. The stability studies conducted for 90 days demonstrated that nanocrystals stored at 2&deg;C&ndash;8&deg;C and 25&deg;C were more stable than those at 40&deg;C. The maximum recovery of Dexi nanocrystals was observed from the formulations using the combination of HPMC&ndash;PVP and HPMC&ndash;EUD, which equated to 98% and 94% of the nominal active drug content respectively. The saturation solubility of the Dexi nanocrystals was substantially increased to 270.0&plusmn;3.5&nbsp;&micro;g/mL compared to the raw Dexi in water (51.0&plusmn;2.0&nbsp;&micro;g/mL) and stabilizer solution (92.0&plusmn;3.0&nbsp;&micro;g/mL). Enhanced dissolution rate (P&lt;0.05) was observed for the Dexi nanocrystals compared to the unprocessed drug substance and marketed tablets. Dexi nanocrystals produced the analgesic effect at much lower doses (5&nbsp;mg/kg) than that of control standard, diclofenac sodium (20&nbsp;mg/kg) and Dexi counterparts (40&nbsp;mg/kg). Conclusion: HPMC-PVP and HPMC-EUD were found the best polymer combination to stabilise Dexi nanocrystals. The Dexi nanocrystals exhibited significant dissolution, solubility and analgesic effect compared to the raw Dexi and the control standard diclofenac sodium. Keywords: dexibuprofen, nanocrystals, dissolution, antinociceptive activity, molecular modeling, stabilit