A flavonoid-rich fraction of Euphorbia peplus attenuates hyperglycemia, insulin resistance, and oxidative stress in a type 2 diabetes rat model

Background: Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR) and hyperglycemia. Plants are valuable sources of therapeutic agents for the management of T2D. Euphorbia peplus has been widely used as a traditional medicine for the treatment of various diseases, but its beneficial role in T2D has not been fully explored.Methods: The anti-diabetic efficacy of E. peplus extract (EPE) was studied using rats with T2D induced by high-fat diet (HFD) and streptozotocin (STZ). The diabetic rats received 100, 200, and 400 mg/kg EPE for 4 weeks.Results: Phytochemical fractionation of the aerial parts of E. peplus led to the isolation of seven known flavonoids. Rats with T2D exhibited IR, impaired glucose tolerance, decreased liver hexokinase and glycogen, and upregulated glycogen phosphorylase, glucose-6-phosphatase (G-6-Pase), and fructose-1,6-bisphosphatase (F-1,6-BPase). Treatment with 100, 200, and 400 mg/kg EPE for 4 weeks ameliorated hyperglycemia, IR, liver glycogen, and the activities of carbohydrate-metabolizing enzymes. EPE attenuated dyslipidemia, serum transaminases, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and liver lipid accumulation, nuclear factor (NF)-κB p65, and lipid peroxidation, nitric oxide and enhanced antioxidants. All EPE doses upregulated serum adiponectin and liver peroxisome proliferator-activated receptor γ (PPARγ) in HFD/STZ-induced rats. The isolated flavonoids showed in silico binding affinity toward hexokinase, NF-κB, and PPARγ.Conclusion:E. peplus is rich in flavonoids, and its extract ameliorated IR, hyperglycemia, dyslipidemia, inflammation and redox imbalance, and upregulated adiponectin and PPARγ in rats with T2D

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Cadmium-induced lung injury is associated with oxidative stress, apoptosis, and altered SIRT1 and Nrf2/HO-1 signaling; protective role of the melatonin agonist agomelatine

Cadmium (Cd) is a hazardous heavy metal extensively employed in manufacturing polyvinyl chloride, batteries, and other industries. Acute lung injury has been directly connected to Cd exposure. Agomelatine (AGM), a melatonin analog, is a drug licensed for treating severe depression. This study evaluated the effect of AGM against Cd-induced lung injury in rats. AGM was administered in a dose of 25 mg/kg/day orally, while cadmium chloride (CdCl2) was injected intraperitoneally in a dose of 1.2 mg/kg to induce lung injury. Pre-treatment with AGM remarkably ameliorated Cd-induced lung histopathological abrasions. AGM decreased reactive oxygen species (ROS) production, lipid peroxidation, suppressed NDAPH oxidase, and boosted the antioxidants. AGM increased Nrf2, GCLC, HO-1, and TNXRD1 mRNA, as well as HO-1 activity and downregulated Keap1. AGM downregulated Bax and caspase-3 and upregulated Bcl-2, SIRT1, and FOXO3 expression levels in the lung. In conclusion, AGM has a protective effect against Cd-induced lung injury via its antioxidant and anti-apoptotic effects mediated via regulating Nrf2/HO-1 and SIRT1/FOXO3 signaling

Acetovanillone augmented the cardioprotective effect of carvedilol against cadmium-induced heart injury via suppression of oxidative stress and inflammation signaling pathways

Abstract Cardiac toxicity is a public health issue that can be caused by both environmental and occupational exposures. The current study aimed to investigate the effectiveness of carvedilol (CV), Acetovanillone (ACET), and their combination for ameliorating cadmium (Cd)-induced oxidative stress, inflammation, and necroptosis. Rats were assigned to; the normal group, Cd group (2 mg/kg; i.p., single dose), and the other three groups received orally CV (10 mg/kg), ACET (25 mg/kg), and CV plus ACET, respectively and a single dose of Cd. Oral administration of CV, ACET, and their combination significantly dampens cardiac oxidative injury by increasing antioxidants GSH and SOD levels, while it decreases MDA and NADPH oxidase levels mediated by decreasing cardiac abundance of Nrf2, HO-1, and SIRT1 and downregulating KEAP-1 and FOXO-3 levels. Also, they significantly attenuated inflammatory response as indicated by reducing MPO and NOx as well as proinflammatory cytokines TNF-α and IL-6 mediated by downregulating TLR4, iNOS, and NF-κB proteins expression as well as IκB upregulation. Moreover, they potently counteracted cardiac necroptosis by downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins expression. Of note, the combination of CV and ACET have marked protection that exceeded each drug alone. Conclusively, CV ad ACET potently mitigated Cd-induced cardiac intoxication by regulating NADPH oxidase, KEAP-1/Nrf2/HO-1, SIRT1/FOXO-3, TLR4/NF-κB/iNOS, and RIPK1/RIPK3/MLKL signals

The protective effect of 7-hydroxycoumarin against cisplatin-induced liver injury is mediated via attenuation of oxidative stress and inflammation and upregulation of Nrf2/HO-1 pathway

Cisplatin (CIS) is an effective chemotherapy against different solid cancers. However, the adverse effects, including hepatotoxicity, limit its clinical use. 7-hydroxycoumarin (7-HC) possesses antioxidant and hepatoprotective activities, but its protective effect against CIS hepatotoxicity has not been investigated. This study evaluated the effect of 7-HC on liver injury, oxidative stress (OS), and inflammation provoked by CIS. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 2 weeks followed by intraperitoneal injection of CIS (7 mg/kg) at day 15. CIS increased serum transaminases, alkaline phosphatase (ALP), and bilirubin and provoked tissue injury accompanied by elevated reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO). Liver nuclear factor (NF)-κB p65, inducible NO synthase (iNOS), pro-inflammatory cytokines, Bax, and caspase-3 were upregulated, and antioxidant defenses and Bcl-2 were decreased in CIS-treated rats, while 7-HC prevented liver injury and ameliorated OS, inflammatory and apoptosis markers. In addition, 7-HC enhanced nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase (HO)-1 in CIS-administered rats and in silico studies revealed its binding affinity toward HO-1. In conclusion, 7-HC protected against CIS hepatotoxicity by mitigating OS and inflammatory response and modulating Nrf2/HO-1 pathway

Targeting SIRT1/FoxO3a/Nrf2 and PI3K/AKT Pathways with Rebamipide Attenuates Acetic Acid-Induced Colitis in Rats

Rebamipide is a quinolone derivative that has been commonly used for the treatment of gastric and duodenal ulcers. However, the molecular mechanisms of rebamipide against acetic acid-evoked colitis have not been adequately examined. Hence, the current study aimed to investigate the ameliorative effect of rebamipide in a rat model of acetic acid-evoked ulcerative colitis and the linked mechanisms pertaining to SIRT1/FoxO3a/Nrf2 and PI3K/AKT pathways. Herein, colitis was induced by the intrarectal administration of 3% acetic acid solution in saline (v/v) while rebamipide was administered by oral gavage (100 mg/kg/day) for seven days before the colonic insult. The colonic injury was examined by macroscopical and microscopical examination. The current findings demonstrated that rebamipide significantly improved the colonic injury by lowering the colonic disease activity index and macroscopic mucosal injury score. Moreover, it mitigated the histopathological aberrations and microscopical damage score. The favorable outcomes of rebamipide were driven by combating inflammation evidenced by dampening the colonic expression of NF-κBp65 and the pro-inflammatory markers CRP, TNF-α, and IL-6. In the same context, rebamipide curtailed the colonic pro-inflammatory PI3K/AKT pathway as seen by downregulating the immunostaining of PI3K and p-AKT(Ser473) signals. In tandem, rebamipide combated the colonic pro-oxidant events and augmented the antioxidant milieu by significantly diminishing the colonic TBARS and replenishing GSH, SOD, GST, GPx, and CAT. In the same regard, rebamipide stimulated the colonic upstream SIRT1/FoxO3a/Nrf2 axis by upregulating the expression of SIRT1, FoxO3a, and Nrf2, alongside downregulating Keap-1 gene expression. These antioxidant actions were accompanied by upregulation of the protein expression of the cytoprotective signal PPAR-γ in the colons of rats. In conclusion, the present findings suggest that the promising ameliorative features of rebamipide against experimental colitis were driven by combating the colonic inflammatory and oxidative responses. In perspective, augmentation of colonic SIRT1/FoxO3a/Nrf2 and inhibition of PI3K/AKT pathways were engaged in the observed favorable outcomes

Berberine attenuates inflammation and oxidative stress and modulates lymphocyte E-NTPDase in acute hyperlipidemia

Hyperlipidemia is a common clinically encountered health condition worldwide that promotes the development and progression of cardiovascular diseases, including atherosclerosis. Berberine (BBR) is a natural product with acknowledged anti-inflammatory, antioxidant, and metabolic effects. This study evaluated the effect of BBR on lipid alterations, oxidative stress, and inflammatory response in rats with acute hyperlipidemia induced by poloxamer-407 (P-407). Rats were pretreated with BBR (25 and 50 mg/kg) for 14 days and acute hyperlipidemia was induced by a single dose of P-407 (500 mg/kg). BBR ameliorated hypercholesterolemia, hypertriglyceridemia, and plasma lipoproteins in P-407-adminsitered rats. Plasma lipoprotein lipase (LPL) activity was decreased, and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was enhanced in hyperlipidemic rats. The expression of low-density lipoprotein receptor (LDL-R) and ATP-binding cassette transporter 1 (ABCA1) was downregulated in hyperlipidemic rats. BBR enhanced LPL activity, upregulated LDL-R, and ABCA1, and suppressed HMG-CoA reductase in P-407-administered rats. Pretreatment with BBR ameliorated lipid peroxidation, nitric oxide (NO), pro-inflammatory mediators (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon-γ, IL-4 and IL-18) and enhanced antioxidants. In addition, BBR suppressed lymphocyte ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) as well as NO and TNF-α release by macrophages isolated from normal and hyperlipidemic rats. In silico investigations revealed the binding affinity of BBR toward LPL, HMG-CoA reductase, LDL-R, PSK9, ABCA1, and E-NTPDase. In conclusion, BBR effectively prevented acute hyperlipidemia and its associated inflammatory responses by modulating LPL, cholesterolgenesis, cytokine release, and lymphocyte E-NTPDase and E-ADA. Therefore, BBR is an effective and safe natural compound that might be employed as an adjuvant against hyperlipidemia and its associated inflammation

Berberine alleviates chlorpyrifos-induced nephrotoxicity in rats via modulation of Nrf2/HO-1 axis

Chlorpyrifos (CPS), an organophosphorus insecticide, is widely used for agricultural and non-agricultural purposes with hazardous health effects. Berberine (BBR) is a traditional Chinese medicine and a phytochemical with anti-inflammatory and anti-oxidative properties. The present study evaluated the effects of BBR against kidney damage induced by CPS and the underlying mechanisms. An initial study indicated that BBR 50 mg/kg was optimal under our experimental conditions. Then, 24 rats (6/group) were randomized into: control, BBR (50 mg/kg/day), CPS (10 mg/kg/day), and CPS + BBR. BBR was administration 1 h prior to CPS. Each treatment was delivered daily for a period of 28 consecutive days using a gastric gavage tube. Compared to CPS-alone treated rats, BBR effectively improved renal function by preventing the rise in serum urea, creatinine, and uric levels. The reno-protective effects of BBR were confirmed through a histological examination of kidney tissues. BBR restored oxidant-antioxidant balance in renal tissues mediated by Keap1/Nrf2/HO-1 axis modulation. In addition, BBR decreased nitric oxide (NO) and myeloperoxidase (MPO) activity. This was paralleled with the potent down-regulation of NF-κB. Furthermore, BBR exhibited anti-apoptotic activities supported by the upregulation of Bcl-2 and down-regulation of Bax and caspase-3 expression. In conclusion, our data suggest that BBR attenuates CPS-induced nephrotoxicity in rats by restoring oxidant-antioxidant balance and inhibiting inflammatory response and apoptosis in renal tissue. This is mediated, at least partly, by modulation of the Nrf2/HO-1 axis