Novel Epigallocatechin-3-Gallate (EGCG) Derivative as a New Therapeutic Strategy for Reducing Neuropathic Pain after Chronic Constriction Nerve Injury in Mice

Abstract Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG) polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI). First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi). We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p.) during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN), a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain

Detrimental effect on the gut microbiota of 1,2-dicarbonyl compounds after in vitro gastro-intestinal and fermentative digestion

This study, investigated the stability of dicarbonyl compounds (DCs), 3-deoxyglucosone (3-DG), glyoxal (GO) and methylglyoxal (MGO) during simulated gastrointestinal digestion processes and the impact these compounds have on the gut microbiota. DCs pass almost unaltered through the in-vitro gastrointestinal digestion phases (concentration loss: 11% for 3-DG, 24% for GO and MGO) and have an effect on the fermentative digestion process, reducing the total gut bacterial population up to 6 Log10 units. Previous studies have shown no antimicrobial activity for 3-DG, however, for the first time it has been shown that when incubated with faecal bacteria 3-DG strongly depressed this microbial community. The influence of dicarbonyl compounds on the anaerobic fermentation processes was confirmed by the reduced production of short-chain fatty acids. Considering the modern Western diet, characterised by high consumption of ultra-processed foods rich in dicarbonyl compounds, this could lead to a reduction of bacteria important for the microbiome

New synthetic inhibitors of fatty acid synthase with anticancer activity

Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds 5-­30 that have been evaluated for their cytotoxic capacity in SK-­Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC50 < 50 M have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 M), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-­1 (CPT-­1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer

Celulosa y microcelulosa de residuos del cultivo de caña de azúcar (Saccharum spp.)

Objective: To characterize the structure, texture and thermal properties of cellulose and cellulose microfibers (MFC) of three sugarcane crops and the development of a biocomposite. Design / methodology / approach: The celluloses were extracted by the Kraft method and the MFCs of the cultures MEX-69-290, CP-72-2086 and MEX-68-P23, using oxidative and mechanical processes; for its characterization spectroscopic, microscopic and thermal techniques were used; and were analyzed with a completely randomized design, where the treatments were cellulose and CFM extracted from the three cultivars of sugarcane; In addition to the fusion processing of a biocomposite from polylactic acid and CMF. Results: Cellulose and CFM were obtained from the straw of the three crops, the similar quality, the percentage of moisture in the straw and the cellulose having the same behavior, the chemical composition of the cellulose is of high purity. The results of XRD and FTIR have characteristic bands and similar amounts of cellulose in the crystalline phase. TGA indicates that cellulose decomposes at higher temperatures of polylactic acid (PLA), which supports melt mixing processes. Limitations of the study / implications: The varieties of sugarcane pajamas have different characteristics in the cellulose phase and in the CFM phase; but similar between cultivars. Findings / conclusions: The crystallinity by XRD and the identification of functional groups by FTIR show us characteristic bands of the cell in the crystalline phase and how the amorphous part of the straw is lost without treatment, becoming more crystalline when it becomes cellulose and mostly in microcellulose; as well as the similarity that exists in the three cultivars of said components and in similar quantities. The resistance properties of the biocomposite will be affected when the CFMs are added to the polylactic acid.Objetivo: Caracterizar la estructura, textura y propiedades térmicas de celulosas y microfibras de celulosa (MFC) de tres cultivares de caña de azúcar y la elaboración de un biocompuesto. Diseño/metodología/aproximación: Las celulosas fueron extraídas por el método Kraft y las MFC de los cultivares MEX-69-290, CP-72-2086 y MEX-68-P23, utilizando procesos oxidativos y mecánicos; para su caracterización se emplearon técnicas espectroscópicas, microscópicas y térmicas; y fueron analizadas con un diseño completamente al azar, donde los tratamientos fueron la celulosa y MFC extraídas de los tres cultivares de caña de azúcar; además de la elaboración por fusión de un biocompuesto a partir de ácido poliláctico y las MCF. Resultados: Se obtuvieron celulosa y MFC de la paja de los tres cultivares, la cual presentó similitud, teniendo el mismo comportamiento el porcentaje de humedad en la paja y la celulosa, la composición química de la celulosa es de alta pureza. Los resultados de XRD y FTIR presentan bandas características y cantidades similares de celulosa en fase cristalina. TGA indica que la celulosa se descompone a temperaturas más altas de ácido poliláctico (PLA), lo que apoya los procesos de mezcla en fusión. Limitaciones del estudio/implicaciones: Las variedades de paja de caña de azúcar presentan características diferentes en la fase de celulosa y en fase de MFC; pero similar entre cultivares. Hallazgos/conclusiones: La cristalinidad mediante XRD y la identificación de grupos funcionales por FTIR nos muestran bandas características de celulosa en fase cristalina y cómo se va perdiendo la parte amorfa de la paja sin tratamiento, volviéndose más cristalina al convertirse en celulosa y mayormente en microcelulosa; así como también la similitud que existe en las tres cultivares de dichos componentes y en cantidades semejantes. Las propiedades de resistencia del biocompuesto se vieron afectadas cuando las MFC´s se agregaron al ácido poliláctico

A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines

Introduction: Inhibiting the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of breast carcinoma cells, and this is linked to human epidermal growth factor receptor 2 (HER2) signaling pathways in models of simultaneous expression of FASN and HER2. Methods: In a xenograft model of breast carcinoma cells that are FASN+ and HER2+, we have characterised the anticancer activity and the toxicity profile of G28UCM, the lead compound of a novel family of synthetic FASN inhibitors. In vitro, we analysed the cellular and molecular interactions of combining G28UCM with anti-HER drugs. Finally, we tested the cytotoxic ability of G28UCM on breast cancer cells resistant to trastuzumab or lapatinib, that we developed in our laboratory. Results: In vivo, G28UCM reduced the size of 5 out of 14 established xenografts. In the responding tumours, we observed inhibition of FASN activity, cleavage of poly-ADPribose polymerase (PARP) and a decrease of p-HER2, p- protein kinase B (AKT) and p-ERK1/2, which were not observed in the nonresponding tumours. In the G28UCM-treated animals, no significant toxicities occurred, and weight loss was not observed. In vitro, G28UCM showed marked synergistic interactions with trastuzumab, lapatinib, erlotinib or gefitinib (but not with cetuximab), which correlated with increases in apoptosis and with decreases in the activation of HER2, extracellular signal-regulated kinase (ERK)1/2 and AKT. In trastuzumab-resistant and in lapatinib-resistant breast cancer cells, in which trastuzumab and lapatinib were not effective, G28UCM retained the anticancer activity observed in the parental cells. Conclusions: G28UCM inhibits fatty acid synthase (FASN) activity and the growth of breast carcinoma xenografts in vivo, and is active in cells with acquired resistance to anti-HER2 drugs, which make it a candidate for further pre-clinical development

Diversity and ethics in trauma and acute care surgery teams: results from an international survey

Background Investigating the context of trauma and acute care surgery, the article aims at understanding the factors that can enhance some ethical aspects, namely the importance of patient consent, the perceptiveness of the ethical role of the trauma leader, and the perceived importance of ethics as an educational subject. Methods The article employs an international questionnaire promoted by the World Society of Emergency Surgery. Results Through the analysis of 402 fully filled questionnaires by surgeons from 72 different countries, the three main ethical topics are investigated through the lens of gender, membership of an academic or non-academic institution, an official trauma team, and a diverse group. In general terms, results highlight greater attention paid by surgeons belonging to academic institutions, official trauma teams, and diverse groups. Conclusions Our results underline that some organizational factors (e.g., the fact that the team belongs to a university context or is more diverse) might lead to the development of a higher sensibility on ethical matters. Embracing cultural diversity forces trauma teams to deal with different mindsets. Organizations should, therefore, consider those elements in defining their organizational procedures. Level of evidence Trauma and acute care teams work under tremendous pressure and complex circumstances, with their members needing to make ethical decisions quickly. The international survey allowed to shed light on how team assembly decisions might represent an opportunity to coordinate team member actions and increase performance

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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries