Comparison of the Modulating Effect of Anthocyanin-Rich Sour Cherry Extract on Occludin and ZO-1 on Caco-2 and HUVEC Cultures.

Increased permeability of the epithelial and endothelial cell layers results in the onset of pathogenic mechanisms. In both cell types, cell-cell connections play a regulatory role in altering membrane permeability. The aim of this study was to investigate the modulating effect of anthocyanin-rich extract (AC) on TJ proteins in inflammatory Caco-2 and HUVEC monolayers. Distribution of Occludin and zonula occludens-1 (ZO-1) were investigated by immunohistochemical staining and the protein levels were measured by flow cytometry. The mRNA expression was determined by quantitative real-time PCR. The transepithelial electrical resistance (TEER) values were measured during a permeability assay on HUVEC cell culture. As a result of inflammatory induction by TNF-α, redistribution of proteins was observed in Caco-2 cell culture, which was reduced by AC treatment. In HUVEC cell culture, the decrease in protein and mRNA expression was more dominant during inflammatory induction, which was compensated for by the AC treatment. Overall, AC positively affected the expression of the examined cell-binding structures forming the membrane on both cell types.

Composition of Nonextractable Polyphenols from Sweet Cherry Pomace Determined by DART-Orbitrap-HRMS and Their In Vitro and In Vivo Potential Antioxidant, Antiaging, and Neuroprotective Activities.

Sweet cherry pomace is an important source of phenolic compounds with beneficial health properties. As after the extraction of phenolic compounds, a phenolic fraction called nonextractable polyphenols (NEPs) remains usually retained in the extraction residue, alkaline and acid hydrolyses and enzymatic-assisted extraction (EAE) were carried out in this work to recover NEPs from the residue of conventional extraction from sweet cherry pomace. In vitro and in vivo evaluation of the antioxidant, antihypertensive, antiaging, and neuroprotective capacities employing Caenorhabditis elegans was achieved for the first time. Extractable phenolic compounds and NEPs were separated and identified by families by high-performance thin-layer chromatography (HPTLC) with UV/Vis detection. A total of 39 phenolic compounds were tentatively identified in all extracts by direct analysis in real-time high-resolution mass spectrometry (DART-Orbitrap-HRMS). EAE extracts presented the highest in vitro and in vivo antioxidant capacity as well as the highest in vivo antiaging and neuroprotective capacities. These results showed that NEPs with interesting biological properties are retained in the extraction residue, being usually underestimated and discarded.

In vitro assessment of the bioavailability of bioactive non-extractable polyphenols obtained by pressurized liquid extraction combined with enzymatic-assisted extraction from sweet cherry (Prunus avium L.) pomace.

In vitro digestion and absorption simulation processes of non-extractable polyphenols (NEPs) obtained by pressurized liquid extraction combined with enzymatic-assisted extraction with Promod enzyme (PLE-EAE) from the residue of conventional extraction of sweet cherry pomace were studied. In general, total phenolic and proanthocyanidin contents decreased in each phase of the digestion. However, the antioxidant capacity increased when the digestion process progressed. In addition, the highest total phenolic and proanthocyanidin contents and antioxidant capacity were obtained in the absorbed fraction. NEPs from PLE-EAE extract, digestive fractions, absorbed and unabsorbed fractions were analyzed by ultra-high-performance liquid chromatography coupled to electrospray ionization quadrupole Exactive-Orbitrap mass spectrometry (UHPLC-ESI-Q-Orbitrap-MS). Fifteen NEPs were identified in the intestinal fraction and five in the absorbed fraction after the digestion process. Results obtained in this study define for the first time the bioavailability of antioxidant NEPs obtained from sweet cherry pomace.

Comparative Assessment of Phytochemical Compounds and Antioxidant Properties of Kernel Oil from Eight Sour Cherry (Prunus cerasus L.) Cultivars.

New plant oils as a potential natural source of nutraceutical compounds are still being sought. The main components of eight cultivars ('Koral', 'Lucyna', 'Montmorency', 'Naumburger', 'Wanda', 'Wigor', 'Wolynska', and 'Wróble') of sour cherry (Prunus cerasus L.) grown in Poland, including crude fat, protein, and oil content, were evaluated. The extracted oils were analysed for chemical and biological activity. The oils had an average peroxide value of 1.49 mEq O2/kg, acid value of 1.20 mg KOH/g, a saponification value of 184 mg of KOH/g, and iodine value of 120 g I2/100 g of oil. The sour cherry oil contained linoleic (39.1-46.2%) and oleic (25.4-41.0%) acids as the major components with smaller concentrations of α-eleostearic acid (8.00-15.62%), palmitic acid (5.45-7.41%), and stearic acid (2.49-3.17%). The content of sterols and squalene varied significantly in all the studied cultivars and ranged between 336-973 mg/100 g and 66-102 mg/100 g of oil. The contents of total tocochromanols, polyphenols, and carotenoids were 119-164, 19.6-29.5, and 0.56-1.61 mg/100 g oil, respectively. The cultivar providing the highest amounts of oil and characterised by the highest content of PUFA (including linoleic acid), plant sterols, α-and ß-tocopherol, as well as the highest total polyphenol and total carotenoids content was been found to be 'Naumburger'. The antioxidant capacity of sour cherry kernel oils, measured using the DPPH• and ABTS•+ methods, ranged from 57.7 to 63.5 and from 38.2 to 43.2 mg trolox/100 g oil, respectively. The results of the present study provide important information about potential possibilities of application of Prunus cerasus kernel oils in cosmetic products and pharmaceuticals offering health benefits.

Comparative evaluation of phenolic profile and antioxidant activity of new sweet cherry (Prunus avium L.) genotypes in Turkey.

INTRODUCTION: Sweet cherry (Prunus avium L.), one of the most consumed fruits in the world, is rich in phenolic and especially anthocyanin content. OBJECTIVE: The aim of this study was to evaluate the phenolic properties of 11 different sweet cherry genotypes collected from Giresun, Turkey. METHODS: Total phenol, flavonoid, anthocyanin and antioxidant properties were observed spectrophotometrically in three different extraction (conventional, microwave-assisted and ultrasound-assisted) processes. Major phenolic, anthocyanin and antioxidant structures were visually assessed by high-performance thin layer chromatography (HPTLC). Various phenolics in its structure were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: T2 and E5 genotypes had the highest content in terms of total phenol, flavonoid, anthocyanin and antioxidant activity. In HPTLC, cherry samples contained high levels of chlorogenic acid, neochlorogenic acid, p-coumaroylquinic acid, rutin and cyanidin-3 rutinoside. Among the phenolics examined in the LC-MS/MS method, the major compounds in the structure of cherry were found to be chlorogenic acid, rutin and catechin. The T2 genotype had higher phenolics than the other cherry samples (chlorogenic acid 19.3 mg/100 g; catechin; 3.8 mg/100 g; rutin 33.1 mg/100 g). CONCLUSION: As a result, T2 and E5 genotypes had higher phenolic and antioxidant activity compared to other genotypes and commercial cultivars. It can be said that the antioxidant contents of these genotypes are due to the high anthocyanin amount in their structures. In addition, T2 genotype contained more major phenolics than other cherries. In the next stage, it is recommended to carry out studies on the cultivation of these two varieties.

Anti-Inflammatory and Antiproliferative Properties of Sweet Cherry Phenolic-Rich Extracts.

Cherries have largely been investigated due to their high content in phenolics in order to fully explore their health-promoting properties. Therefore, this work aimed to assess, for the first time, the anti-inflammatory potential of phenolic-targeted fractions of the Saco cherry, using RAW 264.7 macrophages stimulated with lipopolysaccharide. Additionally, the cytotoxic effects on gastric adenocarcinoma (AGS), neuroblastoma (SH-SY5Y) and normal human dermal fibroblast (NHDF) cells were evaluated, as well as the ability to protect these cellular models against induced oxidative stress. The obtained data revealed that cherry fractions can interfere with cellular nitric oxide (NO) levels by capturing NO radicals and decreasing inducible nitric oxide synthase and cyclooxygenase-2 expression. Furthermore, it was observed that all cherry fractions exhibited dose-dependent cytotoxicity against AGS cells, presenting cytotoxic selectivity for these cancer cells when compared to SH-SY5Y and NHDF cells. Regarding their capacity to protect cancer cells against oxidative injury, in most assays, the total cherry extract was the most effective. Overall, this study reinforces the idea that sweet cherries can be incorporated into new pharmaceutical products, smart foods and nutraceuticals.

Sweet Cherries as Anti-Cancer Agents: From Bioactive Compounds to Function.

Sweet cherries (Prunus avium L.) are among the most appreciated fruits worldwide because of their organoleptic properties and nutritional value. The accurate phytochemical composition and nutritional value of sweet cherries depends on the climatic region, cultivar, and bioaccessibility and bioavailability of specific compounds. Nevertheless, sweet cherry extracts are highly enriched in several phenolic compounds with relevant bioactivity. Over the years, technological advances in chemical analysis and fields as varied as proteomics, genomics and bioinformatics, have allowed the detailed characterization of the sweet cherry bioactive phytonutrients and their biological function. In this context, the effect of sweet cherries on suppressing important events in the carcinogenic process, such as oxidative stress and inflammation, was widely documented. Interestingly, results from our research group and others have widened the action of sweet cherries to many hallmarks of cancer, namely metabolic reprogramming. The present review discusses the anticarcinogenic potential of sweet cherries by addressing their phytochemical composition, the bioaccessibility and bioavailability of specific bioactive compounds, and the existing knowledge concerning the effects against oxidative stress, chronic inflammation, deregulated cell proliferation and apoptosis, invasion and metastization, and metabolic alterations. Globally, this review highlights the prospective use of sweet cherries as a dietary supplement or in cancer treatment.

The pleiotropic effects of Prunus avium L. extract against oxidative stress on human fibroblasts. An in vitro approach.

There is a persistent interest in innovative and multifunctional ingredients in biology research. With regards to this, natural sources have an important role due to their multiple benefits. Thus, this study aims to present the pleiotropic activity of Prunus avium L. extract on human primary fibroblasts for proving its efficacy in dermis-related processes. We focused on the safety and efficacy assessments based on cytotoxicity and gene expression analysis under oxidative stress. Specifically, Prunus avium L. extract was proved non-cytotoxic in human fibroblasts. The gene expression analysis unveiled that this extract has in vitro protective properties on human dermal fibroblasts under oxidative stress related to antioxidant activity, anti-inflammatory response, cell proliferation and cell- aging. Our study demonstrated for the very first time that the Prunus avium L. extract is a multifunctional ingredient as it mediates several human dermis-related in vitro processes highlighting its potential to be used as an active ingredient in skin care products.

Comparative chemical analysis of six ancient italian sweet cherry (Prunus avium L.) varieties showing antiangiogenic activity.

In this study, cherry fruits and petioles from six ancient Italian Prunus avium L. varieties (Ferrovia, Capellina, Morellina, Ciambellana, Napoletana, and Bianca), were compared by chemical and bioinformatic analyses and evaluated for their antiangiogenic activity. The highest levels of total phenols and flavonoids were found in Napoletana petioles, and Morellina and Capellina fruits. HPLC-PDA-MS analyses showed similar phenolic profiles for all fruit extracts, with cyanidin-3-O-rutinoside, flavonols glycosides, and quinic acid derivatives as major components. Flavonoid glycosides were found in all petiole extracts, while proanthocyanidins B type were predominant in Capellina, Napoletana and Bianca. Accordingly to their higher polyphenolic content, petiole extracts exhibited stronger radical scavenging activity compared to the fruits. The best antiangiogenic response was exhibited by Morellina, Ferrovia, and Ciambellana petiole extracts, and by Ferrovia, Morellina, and Capellina fruit extracts; by bioinformatic studies rutin and cyanidin 3-O-rutinoside were recognised as the best candidate bioactive compounds. In conclusion, sweet cherry varietes were confirmed as valuable sources of phenols, showing also potential angiomodulator properties.

Tart Cherry Juice and Seeds Affect Pro-Inflammatory Markers in Visceral Adipose Tissue of High-Fat Diet Obese Rats.

BACKGROUND: Tart cherries (Prunus cerasus L.) are a rich source of anthocyanins. They are phytochemical flavonoids found in red and blue fruits, and vegetables that can reduce hyperlipidemia. Visceral Adipose Tissue (VAT) has emerged as a major player in driving obesity-related inflammatory response. METHODS: This study has investigated the potential positive effects of tart cherries on rats with Diet-Induced Obesity (DIO). In particular, the inflammatory status in retroperitoneal (RPW) and perigonadal (PGW) adipose tissue were studied. Rats were fed ad libitum for 17 weeks with a hypercaloric diet with the supplementation of tart cherries seeds powder (DS) and seeds powder plus tart cherries juice containing 1mg of anthocyanins (DJS). In RPW and PGW, expression of CRP, IL-1 ß, TNF-α, CCL2 and CD36, were measured by qRT-PCR, Western blot and immunohistochemistry techniques. RESULTS: No differences in the weight of RPW and PGW animals were found between DS and DJS groups compared to DIO rats. However, an increase of inflammatory markers was observed in DIO group in comparison with control lean rats. A modulation of these markers was evident upon tart cherry supplementation. CONCLUSION: Study results suggest that tart cherry enriched-diet did not modify the accumulation of visceral fat, but it decreased inflammatory markers in both tissues. Therefore, this supplementation could be useful, in combination with healthy lifestyles, to modify adipose tissue cell metabolism limiting-obesity related organ damage.

Effects of high fat diets and supplemental tart cherry and fish oil on obesity and type 2 diabetes in male and female C57BL/6J and TALLYHO/Jng mice.

Obesogenic and diabetogenic high fat (HF) diets can influence genetic factors in disease development with sexual dimorphic responses. We investigated potential protective effects of tart cherry (TC), fish oil (FO) and TC+FO supplementation in TALLYHO/Jng (TH) and C57BL/6J (B6) mice fed HF diets. Male and female TH and B6 mice were weaned onto five different diets; low fat (LF), HF, and HF supplemented with TC, FO, or TC+FO and maintained. For both males and females on LF, TH mice were heavier and fatter than B6, which was accentuated by HF in males, but not in females. TH males, but not others, developed severe glucose intolerance and hyperglycemia on HF, with reduced mRNA levels of Adipoq and Esr1 in adipose tissue. Considering energy balance, locomotor activity was lower in TH mice than B6 for both sexes without diet effects, except B6 females where HF decreased it. Compared to LF, HF decreased energy expenditure, RER, and food intake (in grams) for both sexes without strain differences. In all mice, but B6 males, HF increased plasma IL6 levels compared to LF. No preventive effects of TC, FO or TC+FO were noted for HF-induced obesity or energy imbalance, but FO alleviated glucose intolerance in TH males. Further, TC and FO decreased plasma IL6 levels, especially in females, without additive or synergistic effects of these two. Collectively, obesogenic and diabetogenic impacts of HF diets differed depending on the genetic predisposition. Moreover, sexually dimorphic effects of dietary supplementation were observed for glucose metabolism and inflammatory markers.

U.S. Montmorency Tart Cherry Juice Decreases Bone Resorption in Women Aged 65-80 Years.

Pre-clinical studies have demonstrated that tart cherries, rich in hydroxycinnamic acids and anthocyanins, protect against age-related and inflammation-induced bone loss. This study examined how daily consumption of Montmorency tart cherry juice (TC) alters biomarkers of bone metabolism in older women. Healthy women, aged 65-80 years (n = 27), were randomly assigned to consume ~240 mL (8 fl. oz.) of juice once (TC1X) or twice (TC2X) per day for 90 d. Dual-energy x-ray absorptiometry (DXA) scans were performed to determine bone density at baseline, and pre- and post-treatment serum biomarkers of bone formation and resorption, vitamin D, inflammation, and oxidative stress were assessed. Irrespective of osteoporosis risk, the bone resorption marker, tartrate resistant acid phosphatase type 5b, was significantly reduced with the TC2X dose compared to baseline, but not with the TC1X dose. In terms of indicators of bone formation and turnover, neither serum bone-specific alkaline phosphatase nor osteocalcin were altered. No changes in thiobarbituric acid reactive substances or high sensitivity C-reactive protein were observed in response to either TC1X or TC2X. We conclude that short-term supplementation with the higher dose of tart cherry juice decreased bone resorption from baseline without altering bone formation and turnover biomarkers in this cohort.

Recovery of anthocyanins from sour cherry (Prunus cerasus L.) peels via microwave assisted extraction: monitoring the storage stability.

Utilization of economical and environmental methods as an alternative process to recover the industrial crops and food products into high-added value compounds is of great significant. In the current study, microwave assisted extraction (MAE) was optimized by response surface methodology (RSM) in order to evaluate the waste of sour cherry as a source of phenolic compounds rich in anthocyanins. The process parameters (microwave power, irradiation time and ethanol solvent concentration) of MAE method were optimized by face centered composite design of RSM. Responses such as total phenolic componds (TPC), total anthocyanin (TA) contents and antioxidant capacity (DPPH) of extracts were measured spectrophotometrically after extractions of samples. The optimized result of MAE was 500 W of microwave power, 90 s of irradation time and 80% ethanol solvent concentration. Antioxidant capacity was tested using by 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical. Chromatographic analysis (HPLC) was also used to measure the concentration of major anthocyanin (cyanidin-3-glucoside) of the samples. Maximum predicted TPC, TA and DPPH yields on optimized conditions were 44.15 mg-GAE/g-FM (mg- gallic acid equivalent per g- fresh matter), 12.47 mg-cyanidin-3-glucoside/g-FM and 69.90 (%, inhibition), respectively. A stability assay under different conditions (light, dark, ambient condition, refrigerator and deep freezer) has been also performed in order to display the stability of bioactivity profile. All of the process parameters were significant at the level of p < 0.0001.

Three Types of Red Beetroot and Sour Cherry Based Marmalades with Enhanced Functional Properties.

The importance of bioactive compounds such as betalains and anthocyanins was highlighted in the present study by the valorization of red beetroot and sour cherry as an attempt to develop healthy products. The aim of the study was to obtain and characterize three types of marmalade based on red beetroot, sour cherry and both in 1:1 combination, obtained by heating at 95 °C for 30 min. Changes in total phenolic content, total flavonoids, betalains, anthocyanins and antioxidant activity were evaluated before and after the thermal treatment. Several other analyses such as color, rheological and textural analyses and confocal laser microscopy were performed to provide further information about the quality of the added-value food products. A significant decrease of 34% in betalains content was registered in the red beetroot marmalade due to the chemical changes in bioactives induced by the temperature. A satisfactory ABTS radical scavenging activity of 8.12 ± 0.38 mMol Trolox/g dry weight (dw) was obtained for the red beetroot and sour cherry based marmalade. The gelled structure was validated by the rheological and textural characteristics. The results highlighted the potential use of red beetroot and sour cherry as food raw materials, due to their particular profile of bioactive compounds.

Chemical Composition of 21 Cultivars of Sour Cherry (Prunus cerasus) Fruit Cultivated in Poland.

Sour cherry (Prunus cerasus L.) is a very important fruit crop for producers as well as consumers. To obtain information on sour cherry fruit, we determined the sugar and organic acid composition and phenolic compound contents of twenty-one cultivars and genotypes of Prunus cerasus L. by HPLC quantification. Antioxidant capacity was determined by DPPH radical scavenging, reducing power (FRAP) and determination of substances reacting with Folin-Ciocalteu reagent (FCRS). The main organic acids in sour cherries were malic and malonic acids, and the main sugars were glucose and fructose. The highest sugar content was found in the "Lucyna" cultivar and the highest organic acids in "Paraszt Meggy" and "Suda Hardy". The richest in phenolic compounds were "Wielun 17", "Sokówka Nowotomyska", "Grosenkirch" "Sokówka Nowotomyska" "Grosenkirch" (anthocyanins, flavanols and total phenolics), and "Meteor" (phenolic acids). Flavan 3-ols were not quantified in every cultivar. "Dradem, "Turgieniewka", "Wróble", and "Nana" contained the smallest amounts of phenolic compounds. Antioxidant capacity was highly correlated with phenolic compound composition. According to principal component analysis (PCA), it was concluded that cultivars whose harvest maturity was medium to late contained more flavonols and anthocyanins and were characterized by higher antioxidant capacity than those whose harvest maturity was classified as early or early to medium.

Detection of flavone C-glycosides in the extracts from the bark of Prunus avium L. and Prunus cerasus L.

The extracts from the bark of Prunus avium and Prunus cerasus have been analyzed by using high pressure liquid chromatography/electrospray ionization mass spectrometry. For the first time in the bark of Prunus species flavonoid C-glycosides have been detected. On the basis of the characteristic fragmentation patterns of their [M-H]- and [M + H]+ ions, three flavonoid C-glycosides have been identified, namely apigenin-6,8-di-C-glucoside (vicenin-2), apigenin-6-C-glucoside (isovitexin) and chrysin-8-C-glucoside. Taking into account the widely studied biological activities of flavonoid C-glycosides, the barks of these common fruit trees seem to be interesting materials of potential medical or cosmetic application.

The Dynamic of Polyphenols Concentrations in Organic and Conventional Sour Cherry Fruits: Results of a 4-Year Field Study.

Sour cherry fruits are a perfect source of polyphenols, including flavonols, phenolic acids and anthocyanins. According to the literature, organic fruits contain more bioactive compounds, especially polyphenols, compared to conventional fruits. Given that only one two-year experiment on the status of polyphenols in sour cherry fruits in an organic farm was previously conducted and found in the existing scientific literature, the aim of this study was to analyse and compare the concentration of bioactive compounds in organic and conventional sour cherries and to determine the effects of cultivation year and the proper cultivar. Four sour cherry cultivars ("Oblacinska", "Kelleris 16", "Pandy 103" and "Dobroceni Bötermo") harvested in organic and conventional experimental orchards were assessed in this study. The dry matter and polyphenol contents in the fruits were determined. We observed a significantly higher concentration of dry matter in organic samples only in 2015 and 2017. In the case of total polyphenols, including phenolic acid (2015 and 2017-2018), and total flavonoids, including quercetin-3-O-rutinoside, the higher concentration was found in 2016 and 2018. Two individual anthocyanins were identified in sour cherry fruits. Cyanidin-3-O-rutinoside is the predominant form in the pool of total anthocyanins.

Phytopharmacological Possibilities of Bird Cherry Prunus padus L. and Prunus serotina L. Species and Their Bioactive Phytochemicals.

Wild cherry is a plant observed in the form of trees or shrubs. This species comprises about twenty kinds of plants and the most popular are two, Prunus padus L. and Prunus serotina L., whose properties and content of phytochemical compounds are subject to studies. Wild cherry contains many active compounds, including tocopherols, vitamins, polyphenols and terpenes, which can have beneficial effects on health. On the other hand, wild cherry contains cyanogenic glycosides. Nevertheless, current research results indicate pro-health properties associated with both P. serotina and P. padus. The aim of this study was to collect and present the current state of knowledge about wild cherry and to review available in vitro and in vivo studies concerning its antioxidant, anti-inflammatory, antibacterial and antidiabetic activity. Moreover, the current work presents and characterizes phytochemical content in the leaves, bark and fruits of P. padus and P. serotina and compiles data that indicate their health-promoting and functional properties and possibilities of using them to improve health. We find that the anatomical parts of P. padus and P. serotina can be a valuable raw material used in the food, pharmaceutical and cosmetic industries as a source of bioactive compounds with multi-directional action.

An artificial class modelling approach to identify the most largely diffused cultivars of sweet cherry (Prunus avium L.) in Italy.

The nutritional and commercial value of the sweet cherry provides it a great economic importance in Italy. The aim of this study was to characterize 35 sweet cherry cultivars and one of sour cherry, by analyzing values of different pomological and nutraceutical traits, identifying cultivars with antioxidant activity and total anthocyanins content closest to those present in literature for Ferrovia (largely diffused in Italy). To this goal, a multivariate metric index through the Soft Independent Modeling of Class Analogy analyzing an artificial dataset and testing a real one, two hierarchical clustering and a principal component analysis, were performed. The multivariate analyses result simultaneously investigated all the variables highlighting cvs. Sylvia, Graffione nero Col di Mosso, Ferrovia, Mora della Punta, Bianchetta Nuchis and Sandra to be more similar to literature data of Ferrovia. This matrix index was a useful tool, to select the most commercial promising varieties.

Efficacy, acceptability, and tolerability of all available treatments for insomnia in the elderly: a systematic review and network meta-analysis.

OBJECTIVES: Symptoms of insomnia are highly prevalent in the elderly. A significant number of pharmacological and non-pharmacological interventions exist, but, up-to-date, their comparative efficacy and safety has not been sufficiently assessed. METHODS: We integrated the randomized evidence from every available treatment for insomnia in the elderly (>65 years) by performing a network meta-analysis. Several electronic databases were searched up to May 25, 2019. The two primary outcomes were total sleep time and sleep quality. Data for other 6 efficacy and 8 safety outcomes were also analyzed. RESULTS: Fifty-three RCTs with 6832 participants (75 years old on average) were included, 43 of which examined the efficacy of one or more drugs. Ten RCTs examined the efficacy of non-pharmacological interventions and were evaluated only with pairwise meta-analyses because they were disconnected from the network. The overall confidence in the evidence was very low primarily due to the small amount of data per comparison and their sparse connectedness. Several benzodiazepines, antidepressants, and z-drugs performed better in both primary outcomes, but few comparisons had data from more than one trial. The limited evidence on non-pharmacological interventions suggested that acupressure, auricular acupuncture, mindfulness-based stress reduction program, and tart cherry juice were better than their control interventions. Regarding safety, no clear differences were detected among interventions due to large uncertainty. CONCLUSIONS: Insufficient evidence exists on which intervention is more efficacious for elderly patients with insomnia. More RCTs, with longer duration, making more direct interventions among active treatments and presenting more outcomes are urgently needed.