A comparative study of the digestion behavior and functionality of protein from chia (Salvia hispanica L.) ingredients and protein fractions.

Protein derived from chia (Salvia hispanica L.), characterized by a balanced amino acid composition, represents a potentially healthier and environmentally friendly alternative poised for innovation within the plant-based food sector. It was hypothesized that the growing location of chia seeds and processing techniques used might influence protein digestion patterns, which in turn could affect the biological functions of the digestion products. To examine this hypothesis, we assessed the gastrointestinal fate of degummed-defatted flour (DDF), protein concentrate (PC), and isolated albumin (Alb) and globulin (Glo) fractions. Furthermore, we compared the antioxidant and anti-inflammatory activities of the resulting digesta by means of in vitro and cellular assays. Post-gastrointestinal digestion, the PC exhibited elevated levels of soluble protein (7.6 and 6.3 % for Mexican and British PC, respectively) and peptides (24.8 and 27.9 %, respectively) of larger molecular sizes compared to DDF, Alb, and Glo. This can be attributed to differences in the extraction/fractionation processes. Leucine was found to be the most prevalent amino acids in all chia digesta. Such variations in the digestive outcomes of chia protein components significantly influenced the bioactivity of the intestinal digestates. During gastrointestinal transit, British Glo exhibited the best reactive oxygen species (ROS) inhibition activity in oxidative-stressed RAW264.7 macrophages, while Mexican digesta outperformed British samples in terms of ROS inhibition within the oxidative-stressed Caco-2 cells. Additionally, both Mexican and British Alb showed effectively anti-inflammatory potential, with keratinocyte chemoattractant (KC) inhibition rate of 82 and 91 %, respectively. Additionally, Mexican PC and Alb generally demonstrated an enhanced capacity to mitigate oxidative stress and inflammatory conditions in vitro. These findings highlight the substantial potential of chia seeds as functional food ingredients, resonating with the shifting preferences of health-conscious consumers.

Protein Hydrolysates and Bioactive Peptides as Mediators of Blood Glucose-A Systematic Review and Meta-Analysis of Acute and Long-Term Studies.

Type 2 diabetes mellitus (T2DM) is a major public health concern associated with high mortality and reduced life expectancy. Since diabetes is closely linked with lifestyle, not surprisingly, nutritional intervention and increased physical activity could play a vital role in attenuating the problems related to diabetes. Protein hydrolysates (PHs) and their bioactive peptides (BP) have been shown to exert a wide range of biological effects, including antioxidative, antihypertensive, and in particular, hypoglycaemic activities. To better understand the efficacy of such interventions, a systematic review and meta-analysis of randomised controlled trials (RCTs) were performed concerning the influence of protein hydrolysates on glycaemic biomarkers in subjects with and without hyperglycaemia. Five different databases were used to search for RCTs. In total, 37 RCTs were included in the systematic review and 29 RCTs in the meta-analysis. The meta-analysis revealed a significant reduction in postprandial blood glucose response (PPGR) in normoglycaemic (-0.22 mmol/L; 95% CI -0.43, -0.01; p ≤ 0.05) and in hyperglycaemic adults (-0.88 mmol/L; 95% CI -1.37, -0.39; p ≤ 0.001) compared with the respective control groups. A meta-regression analysis revealed a dose-dependent response for PPGR following PH consumption in normoglycaemic adults, specifically for doses ≤ 30 g. The postprandial blood insulin responses (PPIR) were significantly higher after the ingestion of PHs in both the group with and the group without hyperglycaemia, respectively (23.05 mIU/L; 95% CI 7.53, 38.57; p ≤ 0.01 and 12.57 mIU/L; 95% CI 2.72, 22.41; p ≤ 0.01), compared with controls. In terms of long-term responses, there was a small but significant reduction in both fasting blood glucose (FBG) and fasting glycated haemoglobin (HbA1c) in response to PH compared with the control group (p < 0.05). The PHs significantly improved the parameters of glycaemia in adults and, hence, it may contribute to the management and regulation of the future risk of developing T2DM.

Current state of insect proteins: extraction technologies, bioactive peptides and allergenicity of edible insect proteins.

This review aims to provide an updated overview of edible insect proteins and the bioactivity of insect-derived peptides. The essential amino acid content of edible insects is compared with well-known protein sources to demonstrate that edible insects have the potential to cover the protein quality requirements for different groups of the population. Then the current methodologies for insect protein extraction are summarized including a comparison of the protein extraction yield and the final protein content of the resulting products for each method. Furthermore, in order to improve our understanding of insect proteins, their functional properties (such as solubility, foaming capacity, emulsifying, gelation, water holding capacity and oil holding capacity) are discussed. Bioactive peptides can be released according to various enzymatic hydrolysis protocols. In this context, the bioactive properties of insect peptides (antihypertensive, antidiabetic, antioxidant and anti-inflammatory properties) have been discussed. However, the allergens present in insect proteins are still a major concern and an unsolved issue for insect-based product consumption; thus, an analysis of cross reactivity and the different methods available to reduce allergenicity are proposed. Diverse studies of insect protein hydrolysates/peptides have been ultimately promoting the utilization of insect proteins for future perspectives and the emerging processing technologies to enhance the wider utilization of insect proteins for different purposes.

In silico analysis of the interaction of de novo peptides derived from Salvia hispanica with anticancer targets.

Cancer is one of the leading causes of death worldwide. Conventional cancer therapies are not selective to cancer cells resulting in serious side effects on patients. Thus, the need for complementary treatments that improve the patient's response to cancer therapy is highly important. To predict and evaluate the physicochemical characteristics and potential anticancer activity of the peptides identified from S. hispanica protein fraction <1 kDa through the use of in silico tools. Peptides derived from Salvia hispanica's protein fraction <1 kDa were identified and analyzed for the prediction of their physicochemical properties. The characterized peptide sequences were then submitted to a multi-criteria decision analysis to identify the peptides that possess the characteristics to potentially exert anticancer activity. Through molecular docking analysis, the potential anticancer activity of the Potentially Anticancer Peptide (PAP)-1, PAP-2, PAP-3, PAP-4, and PAP-5 was estimated by their binding interactions with cancer and apoptosis-related molecules. All five evaluated PAPs exhibited strong binding interactions (< -100 kcal/mol). However, PAP-3 showed the lowest binding free energies with several of the targets. Thus, PAP-3 shows potential to be used as a nutraceutical or ingredient for functional foods that adjuvate in cancer treatment. Conclusions: Through the molecular docking studies, the binding of the PAPs to target molecules of interest for cancer treatment was successfully simulated, from which PAP-3 exhibited the lowest binding free energies. Further in vitro and in vivo studies are required to validate the predictions obtained by the in silico analysis.Communicated by Ramaswamy H. Sarma.

Identification of antidiabetic peptides derived from in silico hydrolysis of three ancient grains: Amaranth, Quinoa and Chia.

The antidiabetic potential of bioactive peptides derived from simulated gastrointestinal digestion (SGID) of proteins present in amaranth quinoa and chia was evaluated using their bioactivity profile and theoretical interaction with DPP-IV and α-glucosidases. In silico SGID generated 52 different fragments with in vitro antidiabetic activity where fragments PW, PF, PPG, PM, SW, IW, SF, PP, PPL, PG, PY, VW and PL scored highly in bioactivity probability, with molecular weights ranging from 172.2 to 325.44 Da; positive bulkiness index and hydrophobicity (except PP and PY) and no toxic properties. Fragments IW and PW presented the lowest free energy values for enzymes DPP-IV, maltase-glucoamylase, pancreatic α-amylase and sucrase-isomaltase (-8.2, -7.5, -7.7 and -7.5 kcal/mol; and -7.8, -7.4, -8.2, -7.4 kcal/mol respectively) We can conclude that proteins from amaranth, quinoa and chia may be a good source of antidiabetic BP and may exert antidiabetic activity through the release of BP after digestion.

Profiling modifications in physicochemical, chemical and antioxidant properties of wild blackberry (Rubus sp.) during fermentation with EC 1118 yeast.

Mexico is an extensively diverse country with a wide variety of wild species of blackberries (Rubus spp.), which are rich in bioactive compounds, however, these fruits are underutilized. Fermentation is a process that transforms the chemical compounds of fruits and increases nutraceutical properties. This study aimed to determine the physicochemical changes and the bioactive compounds profile that take place during the fermentation of wild blackberries using yeast EC 1118 and to evaluate its relationship with antioxidant activity (AOx). The results indicated that after 96 h of fermentation the content of carbohydrates (56%), total phenolic compounds (37%), and anthocyanins (22%), decreased, respectively. The physicochemical parameters showed statistic differences (p ≤ 0.05) at the endpoint of fermentation. The diversity of fatty acids was increased (55%), compared with unfermented blackberries. The modification of carbohydrates, anthocyanins, catechin, gallic and ellagic acid profiles were also monitored performing chromatographic techniques. The AOx, determined by ORAC and DPPH assays, showed the highest results for ORAC at 96 h increased a 140.2%, while DPPH values enhanced a 36.6% at 48 h of bioprocessing. Strong positive correlations were found between fermentation time and DPPH values (r = 0.8131), between ORAC and gallic acid content (r = 0.8688), and between anthocyanin content and pH (r = 0.9126). The fermentation of wild blackberries with EC 1118 yeast represents an alternative for development and formulation of potential ingredients for functional foods. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s13197-020-04953-x).

Anticancer activity of protein fractions from chia (Salvia hispanica L.).

Salvia hispanica demonstrated to be a source of protein fractions with anticancer activity. The effect of the protein fractions <1, 1-3, and 3-5 kDa, obtained by ultrafiltration of the S. hispanica hydrolysate, was evaluated on the cellular viability of four cancer cell lines (MCF-7, Caco2, PC-3, and HepG2) and on human fibroblasts (hFB) at different concentrations (0.25, 0.5, 0.75, and 1 mg/ml). The protein fractions did not show cytotoxic effects on hFB. The protein fraction <1 kDa at 1 mg/ml showed the highest statistical effect on the cellular viability of all evaluated cancer lines; thus, its amino acid sequence was analyzed. From the multicriteria decision analysis of the peptide sequences obtained by mass spectrometry, the peptide KLKKNL with potential anticancer activity was selected. In conclusion, protein fractions could represent a therapeutic option for cancer treatment. However, further investigations are necessary to establish conclusive arguments. PRACTICAL APPLICATION: The work of this article is based on the background of the increasing potential of peptides for the treatment of chronic diseases. The results of this study present peptides of low molecular weight, obtained from chia seeds, as a potential adjuvant option for cancer treatment.

In vitro gastrointestinal digestion impact on stability, bioaccessibility and antioxidant activity of polyphenols from wild and commercial blackberries (Rubus spp.).

Gastrointestinal digestion (GID) is a physiological process that transforms the stability, bioaccessibility and antioxidant activity (AOX) of polyphenols from blackberries (Rubus spp.). This study aimed to investigate the effect of the INFOGEST® GID protocol on the phenolic stability, bioaccessibility and AOX of Mexican wild (WB) and commercial (CB) blackberries. After GID, the total phenolic and anthocyanin contents in blackberries decreased by ≥68% and ≥74%, respectively. More than 40 phenolics were identified during GID; most of them degraded completely during digestion. GID had a negative effect on the AOX of both fruits (>50%), but WB showed the highest antioxidant activities, as assessed by the ORAC, DPPH, reducing power and ß-carotene bleaching methods. In Caco-2 cells, the cell-based antioxidant activity of digested blackberries (p < 0.05) decreased by 48% in WB and by 56% in CB. The capacity to inhibit intracellular ROS decreased by 50% in WB and by up to 86% in CB, after digestion. GID is a complex process that impacts on the bioactive properties of food nutrients, especially phenolics. In vitro and cellular AOX of WB polyphenols withstood the gastrointestinal environment better than CB phenolics. The in vitro assays results suggest that phenolics from underutilized WB have a higher bioaccessibility and antioxidant capacity than the polyphenols from the most frequently consumed CB. However, whether this corresponds to a better bioaccessibility in humans remains to be determined in future work.

Comparison of alcalase- and pepsin-treated oilseed protein hydrolysates - Experimental validation of predicted antioxidant, antihypertensive and antidiabetic properties.

There is emerging evidence on the importance of food-derived bioactive peptides to promote human health. Compared with animal derived proteins, plant proteins, in particular oilseed proteins, are considered as affordable and sustainable sources of bioactive peptides. Based on our previous bioinformatic analysis, five oilseed proteins (flaxseed, rapeseed, sunflower, sesame and soybean) were enzymatically hydrolysed using alcalase and pepsin (pH 1.3 and pH 2.1). Further, low molecular weight (Mw â€‹< â€‹3 â€‹kDa) fractions were generated using ultrafiltration. The protein hydrolysates and their low Mw fractions were evaluated for their in vitro antioxidant, antihypertensive and antidiabetic capabilities, in comparison with samples obtained from two dairy proteins (whey and casein). Apart from dipeptidyl-peptidase IV inhibition, significantly stronger bioactivities were detected for the low Mw fractions. In partial agreement with in silico predictions, most oilseed hydrolysates exerted comparable angiotensin-converting enzyme inhibitory capability to dairy proteins, whilst whey protein was the most promising source of dipeptidyl-peptidase IV inhibitors. Apart from alcalase-treated soybean, dairy proteins were more efficient in releasing antioxidant peptides as compared to oilseed proteins. On the other hand, soybean protein hydrolysates showed the highest α-glucosidase inhibitory activity amongst all protein sources. Overall, there was limited correlation between in silico predictions and in vitro experimental results. Nevertheless, our results indicate that oilseed proteins have potential as bioactive peptide sources, and they might therefore be suitable replacers for dairy proteins as well as good sources for development of functional foods.

Impact of in vitro gastrointestinal digestion on peptide profile and bioactivity of cooked and non-cooked oat protein concentrates.

Oat (Avena sativa) is one of the most cultivated and consumed cereals worldwide. Recognized among cereals for its high protein content (12%-24%), it makes it an excellent source of bioactive peptides, which could be modified during processes such as heating and gastrointestinal digestion (GID). This work aims to evaluate the impact of heat treatment on the proteolysis of oat proteins and on the evolution of antioxidant peptide released during in vitro static GID, in terms of comparative analysis between cooked oat protein concentrate (COPC) and non-heated oat protein concentrate (OPC) samples. The protein extraction method and cooking procedure used showed no detrimental effects on protein quality. After GID, the proportion of free amino acids/dipeptides (<0.2 â€‹kDa) reached >40% for both samples (OPC and COPC), thus producing peptides with low molecular weight and enhanced bioactivity. Furthermore, during GID, the amino acid profile showed an increase in essential, positively-charged, hydrophobic and aromatic amino acids. At the end of GID, the reducing power of OPC and COPC increased >0.3 and 8-fold, respectively, in comparison to the non-digested samples; while ABTS•+ and DPPH• showed a >20-fold increase. Fe2+ chelating capacity of OPC and COPC was enhanced >4 times; similarly, Cu2+ chelation showed a >19-fold enhancement for OPC and >10 for COPC. ß-carotene bleaching activity was improved 0.8 times in OPC and >9 times in COPC; the oxygen radical antioxidant capacity assay increased 2 times in OPC and >4.7 times in COPC, respectively. This study suggests that OPC after cooking and GID positively influenced the nutritional and bioactive properties of oat peptides. Thus, COPC could be used as a functional food ingredient with health-promoting effects, as hydrothermal treatment is frequently used for this type of cereals.

Active Pharmacovigilance in Peruvian Population: Surveillance of a Timolol/Brimonidine/Dorzolamide Ophthalmic Fixed Combination.

PURPOSE: In this study active pharmacovigilance was used in an uncontrolled population to enrich the safety profile and canvass the Adverse Drug Reactions (ADRs) associated with the use of a fixed combination of 0.5% timolol + 0.2% brimonidine + 2.0% dorzolamide (TBD). METHODS: Active pharmacovigilance consisting of 3 follow-up calls within 60 days was used to monitor the product's safety and identify new risks by searching for unexpected ADRs and increased incidence, tolerability, drug interactions and special population-related ADRs. RESULTS: Ninety-four ADRs were reported by a total of 246 patients (0.38 ADRs/patient); all of them were classified as "mild". We found an increased risk of ADRs with a Relative Risk (RR) for simultaneous use of TBD + ophthalmic ciprofloxacin and TBD + oral atorvastatin; 2.0309 (95% CI, 1.2467-3.3083) and 1.8864 (95% CI, 1.0543-3.3754), respectively. Two unexpected ADRs were discovered, both of which presented belonged to the System Organ Class (SOC) of "infections and infestations" and the preferred term (PT) of "nasopharyngitis.". CONCLUSION: Three safety signals were identified, two of them corresponded to an increase in the incidence of ADRs and the last one is associated with 2 unexpected ADR. Nevertheless, we found a good tolerability profile for TBD in the study population.

A Drug Safety Surveillance Study of a Ciprofloxacin/Dexamethasone Ophthalmic Fixed Combination in Peruvian Population.

(1) Background: drugs provide a significant benefit for patients who require medical treatment; however, their use implies an intrinsic potential danger, with the possibility of causing unwanted effects. These effects are known as adverse drug reactions (ADRs). Post-marketing drug safety surveillance detects unknown risks that have not been identified in clinical trials, and it is necessary to monitor marketed medications under real-life practice. Due to the scarce information about fixed combination of ciprofloxacin 0.3%/dexamethasone 0.1% (SDO), we performed a drug safety surveillance study. (2) Methods: A prospective non-controlled drug safety surveillance study was conducted in Peruvian population. A total of 236 patients prescribed SDO were included derived from 12 sites. Patients' standardized information was collected through two phone calls, including demographics, medical history, prescribing patterns of SDO, concomitant medication, and ADRs in detail. The ADRs were classified by causality and severity, followed by outcome measures to identify new risk. (3) Results: 236 patients prescribed with SDO participated in the study and 220 were included. A total of 82 ADRs/220 patients were reported after the use of SDO, presenting a ratio 0.37 ADR/patient. The most frequent ADR with SDO administration was eye irritation (30%). All ADRs were classified as non-serious, and 97.5% (n = 80) were classified as mild while 2.5% as moderate (n = 2). No cases under the severe category were identified. (4) Conclusion: No new risks were found in the population where this study was conducted.

Methodological assessment of Mexican Clinical Practice Guidelines: GRADE framework adherence and critical appraisal.

BACKGROUND AND OBJECTIVE: Clinical Practice Guidelines (CPGs) provide evidence-based recommendations to healthcare professionals, policy makers, patients and other stakeholders. Mexico is the biggest producer of CPGs in Latin America and Caribbean countries. The National Healthcare Technology Excellence Center (acronym in Spanish: CENETEC) is responsible for the CPG development, adaptation and update. The aim of this study was to assess the adherence to the GRADE framework and to critically appraise the Mexican CPGs with the AGREE-II tool. STUDY DESIGN: We conducted a descriptive cross-sectional study with a random sample of 86 CPGs produced by CENETEC between 2015 and 2017 and published in an online database called "Catalogo Maestro". We assessed the adherence to the GRADE framework and performed a critical appraisal with the AGREE II tool. RESULTS: Of the 86 CPGs, 34 were published in 2015, 21 in 2016 and 31 in 2017. Of the 86 CPGs, 25 (29%) used the GRADE framework; adherence to GRADE standards was, however, inconsistent and generally poor. The overall methodological quality by AGREE II proved a median of 16.6% (Min 16.6%, Max 50%). CONCLUSION: CPGs produced by CENETEC during this period had a poor adherence to the GRADE framework and low score by AGREE II standards. A concerted initiative could rapidly improve CENETEC guidelines.

A study of medication errors during the prescription stage in the pediatric critical care services of a secondary-tertiary level public hospital.

BACKGROUND: Medication Errors (MEs) are considered the most common type of error in pediatric critical care services. Moreover, the ME rate in pediatric patients is up to three times higher than the rate for adults. Nevertheless, information in pediatric population is still limited, particularly in emergency/critical care practice. The purpose of this study was to describe and analyze MEs in the pediatric critical care services during the prescription stage in a Mexican secondary-tertiary level public hospital. METHODS: A cross-sectional study to detect MEs was performed in all pediatric critical care services [pediatric emergency care (PEC), pediatric intensive care unit (PICU), neonatal intensive care unit (NICU), and neonatal intermediate care unit (NIMCU)] of a public teaching hospital. A pharmacist identified MEs by direct observation as the error detection method and MEs were classified according to the updated classification for medication errors by the Ruíz-Jarabo 2000 working group. Thereafter, these were subclassified in clinically relevant MEs. RESULTS: In 2347 prescriptions from 301 patients from all critical care services, a total of 1252 potential MEs (72%) were identified, and of these 379 were considered as clinically relevant due to their potential harm. The area with the highest number of MEs was PICU (n = 867). The ME rate was > 50% in all pediatric critical care services and PICU had the highest ME/patient index (13.1). The most frequent MEs were use of abbreviations (50.9%) and wrong speed rate of administration (11.4%), and only 11.7% of the total drugs were considered as ideal medication orders. CONCLUSION: Clinically relevant medication errors can range from mild skin reactions to severe conditions that place the patient's life at risk. The role of pharmacists through the detection and timely intervention during the prescription and other stages of the medication use process can improve drug safety in pediatric critical care services.

Effect of the carrier material, drying technology and dissolution media on the viability of Lactobacillus fermentum K73 during simulated gastrointestinal transit.

The goal of this study was to determine the effect of the carrier material, drying technology and dissolution media during the passage of L. fermentum K73 through a dynamic in vitro digestion system (IViDiS). The carrier materials were (i) culture medium with growing micro-organisms and (ii) culture medium with maltodextrin : sweet whey [0.6 : 0.4]. The carrier materials were dried by spray-drying and freeze-drying to obtain four types of powders. The dissolution media consisted of water and 1% fat milk. The powders were tested using an in vitro dynamic digestion system (IViDiS). The results showed that powders derived from culture medium had the highest protective effect on the viability of L. fermentum K73 in both dissolution media and that survival increased when the powders were tested in milk. The modified Gompertz model was used to model L. fermentum K73 behaviour during the digestion process. The model showed that cells entrapped in culture medium had the longest lag phase and the slowest inactivation rate when evaluated in milk.

Starch Digestion Enhances Bioaccessibility of Anti-Inflammatory Polyphenols from Borlotti Beans (Phaseolus vulgaris).

The consumption of beans has been associated with chronic disease prevention which may be attributed to the polyphenols present in the seed coat and endosperm. However, their bioaccessibility is likely to be limited by interactions with bean matrix components, including starch, protein and fibre. The aim of this project was to evaluate the effect of domestic processing and enzymatic digestion on the bioaccessibility of polyphenols from Borlotti beans (Phaseolus vulgaris) and to test their anti-inflammatory properties in a macrophage cell model. In vitro digestion of cooked beans released twenty times more polyphenols (40.4 ± 2.5 mg gallic acid equivalents (GAE)/g) than domestic processing (2.22 ± 0.1 mg GAE/g), with starch digestion contributing to the highest release (30.9 ± 0.75 mg GAE/g). Fluorescence microscopy visualization of isolated bean starch suggests that polyphenols are embedded within the granule structure. LC-MS analysis showed that cooked Borlotti bean contain flavonoids, flavones and hydroxycinnamic acids, and cooked bean extracts exerted moderate anti-inflammatory effects by decreasing mRNA levels of IL1ß and iNOS by 25% and 40%, respectively. In conclusion, the bioaccessibility of bean polyphenols is strongly enhanced by starch digestion. These polyphenols may contribute to the health benefits associated with bean consumption.

Malva species: Insights on its chemical composition towards pharmacological applications.

Malvaceae family is typical from the Mediterranean region, contains 240 genera and more than 4,200 species. They are most commonly used as ornamental plants, although they can also be conceived as a food resource and remedy for various diseases, such as digestive, respiratory, genitourinary, throat infections, and skeletal and skin disorders, as also injuries where they are profoundly applied for skin care and as antiseptic and demulcent. They also possess diuretic, lenitive, spasmolytic, and laxative effects, besides to be used as antidiarrheal. Thus, the present review provides in-depth data on Malva spp. potential applications and phytochemical composition for food and pharmaceutical industries. Habitat and cultivation conditions and the clinical reports related to its biological effects are also emphasized. Malva spp. possess a wide variety of chemical constituents (such as polysaccharides, coumarins, flavonoids, polyphenols, vitamins, terpenes, and tannins) found in different plant organs, especially in leaves and flowers, connected to their biological activity. In general, Malva spp. have rather moderate antimicrobial activity, high antiinflammatory and wound healing activities, strong antioxidant activity, and anticancer properties. Results from in vitro and in vivo experiments encourage more in-depth studies, namely clinical trials, towards to improve knowledge on the use of Malva spp. for the treatment of various health conditions in humans.

Modafinil for people with schizophrenia or related disorders.

BACKGROUND: People with schizophrenia have a range of different symptoms, including positive symptoms (hallucinations and delusions), negative symptoms (such as social withdrawal and lack of affect), and cognitive impairment. The standard medication for people with schizophrenia is antipsychotics. However, these medications may not be effective for all symptoms of schizophrenia, as cognitive and negative symptoms are usually hard to treat. Additional therapies or medications are available for the management of these symptoms. Modafinil, a wakefulness-promoting agent most frequently used in narcolepsy or shift work sleep disorder, is one intervention that is theorised to have an effect of these symptoms. OBJECTIVES: The primary objective of this review was to assess the effects of modafinil for people with schizophrenia or related disorders. SEARCH METHODS: On 27 April 2015, 24 May 2017, and 31 October 2019, we searched the Cochrane Schizophrenia Group's register of trials, which is based on regular searches of CENTRAL, MEDLINE, Embase, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials. There are no language, time, document type, or publication status limitations for the inclusion of records in the register. SELECTION CRITERIA: We selected all randomised controlled trials comparing modafinil with placebo or other treatments for people with schizophrenia or schizophrenia-spectrum disorders. DATA COLLECTION AND ANALYSIS: We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CI. We used a random-effects model for the meta-analysis. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for the included studies. MAIN RESULTS: Eleven studies including a total of 422 participants contributed to data analyses. Most studies had a small population size (average 38 people per study) and were of short duration. We also detected a high risk of bias for selective outcome reporting in just under 50% of the trials. We therefore rated the overall methodological quality of the included studies as low. We considered seven main outcomes of interest: clinically important change in overall mental state, clinically important change in cognitive functioning, incidence of a clinically important adverse effect/event, clinically important change in global state, leaving the study early for any reason, clinically important change in quality of life, and hospital admission. All studies assessed the effects of adding modafinil to participants' usual antipsychotic treatment compared to adding placebo to usual antipsychotic treatment. Six studies found that adding modafinil to antipsychotic treatment may have little or no effect on overall mental state of people with schizophrenia, specifically the risk of worsening psychosis (RR 0.91, 95% CI 0.28 to 2.98; participants = 209; studies = 6, low-quality evidence). Regarding the effect of modafinil on cognitive function, the trials did not report clinically important change data, but one study reported endpoint scores on the MATRICS Consensus Cognitive Battery (MCCB): in this study we found no clear difference in scores between modafinil and placebo treatment groups (MD -3.10, 95% CI -10.9 to 4.7; participants = 48; studies = 1, very low-quality evidence). Only one study (N = 35) reported adverse effect/event data. In this study one serious adverse event occurred in each group (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). One study measured change in global state using the Clinical Global Impression - Improvement Scale. This study found that adding modafinil to antipsychotic treatment may have little or no effect on global state (RR 6.36, 95% CI 0.94 to 43.07, participants = 21; studies = 1, very low-quality evidence). Nine studies found that modafinil has no effect on numbers of participants leaving the study early (RR 1.26, 95% CI 0.63 to 2.52 participants = 357; studies = 9, moderate-quality evidence). None of the trials reported clinically important change in quality of life, but one study did report quality of life using endpoint scores on the Quality of Life Inventory, finding no clear difference between treatment groups (MD -0.2, 95% CI -1.18 to 0.78; participants = 20; studies = 1, very low-quality evidence). Finally, one study reported data for number of participants needing hospitalisation: one participant in each group was hospitalised (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). AUTHORS' CONCLUSIONS: Due to methodological issues, low sample size, and short duration of the clinical trials as well as high risk of bias for outcome reporting, most of the evidence available for this review is of very low or low quality. For results where quality is low or very low, we are uncertain or very uncertain if the effect estimates are true effects, limiting our conclusions. Specifically, we found that modafinil is no better or worse than placebo at preventing worsening of psychosis; however, we are uncertain about this result. We have more confidence that participants receiving modafinil are no more likely to leave a trial early than participants receiving placebo. However, we are very uncertain about the remaining equivocal results between modafinil and placebo for outcomes such as improvement in global state or cognitive function, incidence of adverse events, and changes in quality of life. More high-quality data are needed before firm conclusions regarding the effects of modafinil for people with schizophrenia or related disorders can be made.

Aminoguanidine reduces diabetes-associated cardiac fibrosis.

Aminoguanidine (AG) inhibits advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP) accumulated as a result of excessive oxidative stress in diabetes. However, the molecular mechanism by which AG reduces AGE-associated damage in diabetes is not well understood. Thus, we investigated whether AG supplementation mitigates oxidative-associated cardiac fibrosis in rats with type 2 diabetes mellitus (T2DM). Forty-five male Wistar rats were divided into three groups: Control, T2DM and T2DM+AG. Rats were fed with a high-fat, high-carbohydrate diet (HFCD) for 2 weeks and rendered diabetic using low-dose streptozotocin (STZ) (20 mg/kg), and one group was treated with AG (20 mg/kg) up to 25 weeks. In vitro experiments were performed in primary rat myofibroblasts to confirm the antioxidant and antifibrotic effects of AG and to determine if blocking the receptor for AGEs (RAGE) prevents the fibrogenic response in myofibroblasts. Diabetic rats exhibited an increase in cardiac fibrosis resulting from HFCD and STZ injections. By contrast, AG treatment significantly reduced cardiac fibrosis, α-smooth muscle actin (αSMA) and oxidative-associated Nox4 and Nos2 mRNA expression. In vitro challenge of myofibroblasts with AG under T2DM conditions reduced intra- and extracellular collagen type I expression and Pdgfb, Tgfß1 and Col1a1 mRNAs, albeit with similar expression of Tnfα and Il6 mRNAs. This was accompanied by reduced phosphorylation of ERK1/2 and SMAD2/3 but not of AKT1/2/3 and STAT pathways. RAGE blockade further attenuated collagen type I expression in AG-treated myofibroblasts. Thus, AG reduces oxidative stress-associated cardiac fibrosis by reducing pERK1/2, pSMAD2/3 and collagen type I expression via AGE/RAGE signaling in T2DM.