Scurrula and Viscum mistletoes. Both mistletoes were found to have anticancer, antimicrobial, antioxidant and antihypertensive properties. Plants from the genus Scurrula were found to inhibit cancer growth due to presence of phytoconstituents such as quercetin and fatty acid chains. Similar to plants from the genus Viscum, Scurrula also possesses TNFα activity to strengthen the immune system to combat cancer. In line with its anticancer activity, both mistletoes are rich in antioxidants that confer protection against cancer as well as neurodegeneration. Extracts from plants of both genera showed evidence of vasodilation and thus, antihypertensive effects. Other therapeutic effects such as weight loss, postpartum and gastrointestinal healing from different plants of the genus Scurrula are documented. As the therapeutic effects of plants from Scurrula are still in exploration stage, there is currently no known clinical trial on these plants. However, there are few on-going clinical trials for Viscum album that demonstrate the functionalities of these mistletoes. Future work required for exploring the benefits of these plants and ways to develop both parasitic plants as a source of pharmacological drug are explained in this article.The mistletoes, stem hemiparasites of Asia and Europe, have been used as medicinal herbs for many years and possess sophisticated systems to obtain nutrients from their host plants. Although knowledge about ethnomedicinal uses of mistletoes is prevalent in Asia, systematic scientific study of these plants is still lacking, unlike its European counterparts. This review aims to evaluate the literature on  Parasitic plants obtain nutrients and water from other flowering plants (hosts) via a well-developed system known as haustoria to connect to the host plants ,2,3,4. TParasitic angiosperms are classified according to their dependence on hosts for nutrients (hemi- or holoparasitic plants), their required association with hosts (obligate or facultative parasitic plants) or where they attach to hosts (root or shoot parasitic plants). With regard to the carbon dependence of parasitic angiosperms on hosts, most parasitic angiosperms lie between complete heterotrophic xylem- and phloem-feeders and complete autotrophic xylem-feeders . About 4Viscum genus from the Santalaceae family and the Scurrula genus from the Loranthaceae family. Plants from both Viscum and Scurrula genera have been used as traditional medicinal herbs and documented for their anticancer, antimicrobial, antioxidant and antihypertensive activities. The properties of these plants will be further elaborated in the later sections.Mistletoes originates from the Celtic name, meaning “all-heal” as they have been used to treat a wide range of human illnesses in the past . TaxonomCuscuta reflexa increased stomatal opening, transpiration rate and net photosynthesis of infected Coleus blumei and Ricinus communis host plants due to a sink-source effect but still suppressed the growth and dry matter accumulation in hosts [Parasitic plant-host relationships have been elucidated by coupling the information of water and nutrient relations from fundamental processes such as transpiration and photosynthesis ,7. Parasin hosts ,19. Incrin hosts ,21. The in hosts .Pinus ponderosa increased resources to the mistletoe Arceuthobium vaginatum subsp. cryptopodum [Dendrophthoe curvata parasitizing different host species varied significantly [Viscum album also exhibited different levels of total phenolic acids and antioxidant activity when parasitizing different host species [Host nature might influence the growth of parasites and ptopodum . Similarficantly ,25,26. T species . Thus th species . ParasitScurrula and Viscum. The former is a prevalent genus of parasitic plants found in Asia with little information in the literature about any clinical trials, while the latter, the European mistletoe Viscum album has undergone many clinical trials in Germany and other European countries. Scurrula plants with their other known names. Evidence of the ethnopharmacological effects of Scurrula parasitic plants has been sparsely documented. Unravelling the knowledge of phytochemical and ethnopharmacological effects will open up avenues for drug design and treatment of various ailments. Analysis of literature review on the clinical trials of Viscum album will shed light on similar potential of Scurrula plants. Nevertheless, the potential of Scurrula plants is not limited to the knowledge gained from Viscum album.In this review, we will focus on parasitic plants of the genera Scurrula species has not been extensively studied in terms of its phytochemistry. Although a few studies have identified flavonols to be present in the Scurrula species [Scurrula ferruginea, and subsequently reported their cytotoxicity on human cancer cell lines  [O-acetylquercitrin, the latter acetylated derivative is uncommon in higher plants. The acetylated quercitrin  had previously been isolated in several flowers and ferns, but not in the Scurrula genus. Quercitrin has recently been found to mediate the protective effects on endothelial progenitor cells, that in turn, repair damage endothelium and have anti-atherosclerosis effects [The  species ,39,40, o7, U251) . Lohézic effects . Quercet effects , as well effects . TherefoLoranthus parasiticus [Loranthus parasiticus is a hemiparasitic plant and as such it derives its phytochemical constituents and subsequently the biological activity from its respective hosts. The coriaria lactones include sesquiterpinoids such as coriamytrin, tutin, corianin, and coriatin. These compounds are not usually native to the Scurrula species, and it was indicated that these compounds were directly transported from the host plant to the mistletoes [Scurrula plants.Moghadamtousi et al. have also isolated another family of chemicals known as coriaria lactones from the asiticus . Loranthstletoes . Table 3Scurrula, there are reports of the isolation of various chemicals from Scurrula plants. Flavonoids in general have been studied to determine the relationship between structure and biological activity [Despite the limited phytochemistry research on activity . Flavonoactivity . Deregulactivity ,51. TherScurrula ferruginea and Scurrula oortiana (Indonesian tea mistletoe). In a screen for antiviral and cytotoxic activities of various Indonesian medicinal plants, Scurrula ferruginea exhibited significant cytotoxic activity, particularly against U251 glioma cells, with an IC50 (50% inhibitory concentration) of 19 µg/mL [Scurrula ferruginea was followed by isolation of the flavanol quercetin and two other flavanols from the plant. Quercetin proved to be the compound responsible for the cytotoxic activity on glioblastoma cells, with an IC50 of 35 µM [Various mistletoe species have been traditionally used to treat cancer in Indonesia, including 19 µg/mL . Furtherof 35 µM .Scurrula species have been the focus of various scientific studies looking at the anti-cancer properties of the mistletoe plants. Ohashi et al. used a bioassay guided separation of compounds to isolate various bioactive compounds from Scurrula atropurpurea. They have identified octadeca-8,10,12-triynoic acid as the main biologically active compound in the anti-cancer activity of Scurrula atropurpurea using the MM1 cell invasion assay. Octadeca-8,10,12-triynoic acid is able to inhibit most of the invasion of the tumour cells in rats. C18-triyne fatty acid and the C16-triyne fatty acids were also identified as potent cancer cell-invasion inhibitory compounds in a second study by the same group. They concluded that the number of unsaturated bonds in the fatty acids appear to strengthen the invasion inhibition activity of a compound [However, other compound ,47.Scurrula atropurpurea found that the treatment of HeLa cells with plant extract led to decreased expression of murine double minute 2 (MDM2), which acts as an inhibitor of the p53 tumour suppressor, which, in turn, is an activator of p21 [A study investigating effect of the extract of r of p21 . ConversScurrula oortiana to investigate whether the response of tumour cells towards TNFα is affected by the extracts. The assay used consisted of measuring changes in cell viability in TNFα-mediated lysis, after treatment with plant extracts. The author found that the stem extract was more effective in modulating the response of WEHI-164 cancer cells towards TNFα treatment, and made the cells more sensitive to cell lysis due to TNFα [TNFα is a cytokine produced by activated macrophages that has potent anti-cancer activities , and has to TNFα . Neverth to TNFα ,59. A re to TNFα .Scurrula extracts, Viscum extracts also possess TNFα activity. Aqueous extract of Korean mistletoe  retards tumour metastasis via expression of TNFα [Scurrula or Viscum, have shown anticancer and immunomodulatory effects that enhances its role as anticancer agent. These mistletoes also possess antioxidative and other beneficial effects, such as antimicrobial and antihypertensive effects as explained in later sections.Similar to  of TNFα . The pro of TNFα . This in of TNFα . TherefoViscum album lipophilic extract are known for their immunomodulatory and anticancer properties through macrophages. Data from the study demonstrates their positive influence on modulation of in vitro monocyte chemotactic transmigration resulting in anticancer activity. This also showed down regulation of IL-6 and up-regulation of TNF-α. Moreover, the site of occurrence of tumors influences the role of TNF-α as pro- or anti-tumour agent [Viscum preparations stimulate the maturation and activation of human dendritic cells, which may facilitate anti-tumoral immune responses [Pentacyclic triterpenes present in ur agent . Tumor cesponses , thus suViscum preparations exhibited dose-dependent reduction of PGE2 secretion in A549 cells which was proportional to reduced selective COX-2 expression, which was beneficial in reducing the side effects [PGE2 overproduction is observed in many pro-tumoral conditions in association with COX-2, leading to inflammation. As known through various studies there is an intricate relationship between inflammation and cancer. Many anti-tumour phytotherapeutics are pronounced anti-inflammatory agents.  effects . Moreove effects  in the hViscum album lectins stimulated proliferation of CD4+ T-cells which attributes to the anti tumour activity [Viscum lectins for cell proliferation on human acute myeloid leukaemia cells. Dose-dependent induced apoptosis was observed through the caspase-8 and -9 dependent pathways. Simultaneous down-regulation of apoptosis inhibitor members and proteins of Bcl-2 family was elucidated from the experiments. Moreover, synergism of all three extracts and significant reduction of tumour weight was demonstrated in acute myeloid leukaemia mouse model experiments; the therapeutic effectiveness of Viscum triterpenes was comparable to cytarabine [activity . Mistletactivity . Subsequtarabine .Smoldering inflammation is of interest in cancer as it is has been proposed as cancer’s seventh hallmark. The innate leukocyte macrophages release reactive nitrogen and oxygen intermediates inducing DNA damage; also these cells promote chronic inflammation state by the secretion of (TNF)-α, interleukin (IL)-6 and IL-1β, proinflammatory cytokines .Scurrula is still in its infancy and so far, there are no documented clinical trials on Scurrula. On the other hand, Viscum album has been developed into drugs, with the most well-known one named Iscador. Currently, Iscador is the most commonly used oncological drug in Germany. In other parts of Europe, Iscador is used as complementary cancer therapy. Iscador, Viscum album extract, has been found to prolong survival of cancer patients and seems to stimulate self-regulation [The study of gulation . As a cogulation .Viscum album extracts have mostly been used as adjuvant therapy in cancer patients [Viscum album extracts as the main therapy in cancer patients [Viscum album extracts exert their anti-cancer effects both by modulating the immune system as well as directly having cytotoxic activities on cancer cells, with a less potent effect on normal, healthy cells [Viscum album extracts are additionally able to reduce the metastatic potential of glioblastoma cells in vitro [patients . Howeverpatients ,75. Vischy cells ,76. Remain vitro . These dTaxillus chinensis, have been found to inhibit fatty acid synthase (FAS) [Mistletoes, like se (FAS) . FAS is se (FAS) . Therefose (FAS) .A recent study has shown that a novel FAS inhibitor TVB-3166, induces apoptosis in breast and prostate cancer cell lines, without affecting non-cancer cell lines. In addition, weight loss was not significant in TVB-3166 treated mice compared to vehicle-treated mice. TVB-3166 alters lipid raft distribution in the membrane, disrupts palmitoylated protein localization, and inhibits the PI3K-AKT-mTOR and β-catenin signal transduction pathways as well as modulate the expression genes involved in metabolic, proliferative and apoptotic genes . The autScurrula ferruginea for bioactive FAS inhibitors with minimal toxicity/side effects and understanding their mode of action and associated target signaling pathways would pave the way for the identification of novel, anti-cancer biomolecules.Dietary products rich in phytoconstituents which may inhibit FAS are potential natural alternatives for anti-cancer therapy . ScreeniInvestigations of the anti-cancer activities of various mistletoe species are few, but promising. Interestingly, various compounds isolated from different mistletoe species appear to exert their cytotoxic activities on cancer cells through different mechanisms. Therefore, a comprehensive study on the anti-cancer activities of the various mistletoe species would prove useful for anti-cancer therapy. Scurrula plants members have been shown to possess promising anti-microbial activity. A study by Marvibaigi et al. [Scurrula ferruginea crude acetone extract had good anti-bacterial activities against a range of Gram positive and negative bacteria. Notably, the leaves and stems Scurrula ferruginea extract has potent anti-microbial activity against the clinically relevant skin pathogen, Staphyloccocous aureus [Loranthus family member Loranthus micranthus species, where potent anti-bacterial activity was observed against Staphyloccocous aureus and other bacteria including Bacillus subtilis and Pseudomonas aeruginosa [Scurrula atropurpurea plant extract was shown to be inhibitory using an agar well diffusion assay technique against a number of Gram negative bacteria including Bacillus subtilis, Klebsella pneumoniae, Vibrio cholerae and Escherichia coli [Scurrula atropurpurea have been shown to have growth inhibiting activity against Enterobacter sakazakii in an agar disc diffusion assay [Enterobacter sakazakii accounts for over 50% of premature infant death from sepsis and meningitis [Scurrula plants have an intrinsic anti-microbial ability against a broad spectrum of different types of bacteria. However, current work only focuses on the anti-bacterial effect of crude extracts. Future work looking at the anti-bacterial effects of further fractionated extracts is needed to determine the most antibacterial active fraction for further downstream drug discovery applications. These findings could open the possibility to potential chemical classes of antibiotics and selective agents for infectious diseases management and control.Indonesian plants have been traditionally used by the indigenous people for generations as their main source of medicine against infections. Several i et al. , showed s aureus . This obruginosa . Whole Shia coli . Leaf anon assay . Commonlningitis . In contningitis . HoweverScurrula plants have also shown to possess anti-viral properties. Crude methanol Scurrula ferruginea extracts inhibited replication of poliovirus with a remarkable IC50 of 62 µg/mL [In ovo injection of crude Scurrula oortiana extract preparations into embryonated chicken eggs was shown to be protective when challenged with Marek’s Disease virus (MDV), a highly contagious virus that causes poultry disease [Ethnopharmacological studies show that indigenous people of Indonesia could diagnose viral infections and could cure them by using specific Indonesian-native plant preparations . Althoug62 µg/mL . In cont62 µg/mL . In ovo  disease .Scurrula plants against other viruses have not yet been investigated. Given the strong ethnopharmacological evidence it is possible that Scurrula plants can be effective against a range of viruses, at least to those viruses that are endemic to the people in a particular region.The potential anti-viral effects of extracts Viscum plants. The first demonstration of this was the clear inhibitory effect of some Viscum album subspecies (ssp.) extracts on the growth of Mycobacterium tuberculosis, a pathogen that causes tuberculosis [album, ssp. austriacum, ssp. abietis and ssp. austriacum exhibited anti-mycobacterial activity at a minimum inhibitory concentration (MIC) of 200 µg/mL. Another study showed that extracts from Viscum album ssp. abietis showed varying anti-microbial effects on a range of bacteria and fungi [n-hexane extract of Viscum album ssp. abietis varying levels of anti-bacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae and Proteus vulgaris and anti-fungal activity against Candida albicans. Using a similar assay, another study similarly showed anti-bacterial activity of ethanol extracts of Viscum album leaves on common bacterial pathogens Staphylococcus aureus, Escherichia coli and Proteus vulgaris [Viscum album showed prominent activity against several bacteria, including Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Bordetella bronchisiptica, Pseudomonas aeruginosa, and Pseudomonas syringae. Overall, the evidence to date suggest that extracts from Viscum plants may possess promising antibacterial properties. However, the active antimicrobial constituent responsible for this effect and its subsequent mode of action remains to be investigated. In addition to the actual Viscum plant, work should also focus on the potential antibacterial properties of the endophytic fungi that lives on the plant. Recent work by showed that lectin isolated from endophytes from Viscum album had good inhibitory activity on the growth of a number of tested pathogenic bacteria including Proteus mirabilis, Serratia marcescens and Staphylococcus aureus [Viscum plants may possess potential anti-viral activity. In a plaque formation assay on human parainfluenza virus type 2 in Vero cells, the aqueous leaf extract of Viscum album. ssp. album was found to reduce plaque numbers [Viscum plants extracts.A handful of studies have also investigated the anti-microbial effects of rculosis . In a mind fungi . The disvulgaris . Later wvulgaris  showed ts aureus . Interes numbers . When th2O2), superoxide anion (O2−•) as well as the peroxyl radical (HO2•), whereas nitrogen dioxide radical (NO2•) radical and nitric oxide radical (NO•) are some examples of RNS. Any atom or molecule with one or more unpaired electrons is a free radical [Both reactive nitrogen species (RNS) and reactive oxygen species (ROS) are common forms of free radicals. Examples of ROS are hydroxyl radical (OH•), hydrogen peroxide  . Free raPlants are enriched in beneficial bioactive compounds with antioxidant properties. Majority of antioxidant compounds present in plants are secondary metabolites-phenolic compounds  which exhibit their protective properties through scavenging free radicals ,114,115.Scurrula ferruginea were assessed and the data suggested that the stem extract contained the highest level of phenolic compounds [Scurrula ferruginea [Scurrula ferruginea exhibited higher antioxidant activity than dried tender leaves as indicated by four different in vitro antioxidant assays: ascorbate iron (II) induced lipid peroxidation inhibition assay, DPPH  free radical scavenging activity, ferric reducing antioxidant potential and total phenol content [Scurrula ferruginea showed higher antioxidant activity in comparison to the aqueous leaf extract [In a recent study, the total phenolic content of stem, leaf and flower extracts of ompounds . Furtherrruginea . Interes content . This is content  and henc extract .Scurrula ferruginea [Loranthus genus have been widely investigated for their antioxidant activity. The leaves and leafy twigs of the African mistletoe, Loranthus micranthus are enriched with polyphenols. Polyphenols and phenolic glycosides isolated from methanol extracts of Loranthus micranthus leafy twigs parasitic on the host Hevea brasiliensis demonstrated significant antioxidant activity through a 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging assay. Among the tested polyphenols, tutin and peltatoside in particular exhibited the most prominent radical scavenging activity [Loranthus micranthus leaves parasitic on host Kola acuminata, −(−) catechin-7-O-rhamnoside, −(−) catechin-3-O-rhamnoside and 4′-methoxy-catechin-7-O-rhamnoside are the most potent antioxidant polyphenols [Although there is only one paper published (to date) supporting the antioxidant role of rruginea , within activity . Meanwhiyphenols .Loranthus regularis were also tested. Partitioning of the crude (methanol) extract results in subfractions of petroleum ether, chloroform, ethyl acetate extract and n-butanol fractions. As the crude extract and its associated ethyl acetate fraction demonstrated the highest antioxidant activity, it was postulated that majority of the antioxidant compounds are enriched in the ethyl acetate fraction. Indeed, activity-guided fractionation and repeated column chromatography of the ethyl acetate fraction, in combination with mass spectrometry and comparing the spectral data to known literature compounds lead to isolation/identification of three novel quercetin glycosides in L. regularis: quercetin 3-O-β-d-galactopyranoside; (2) quercetin 3-O-β-l-arabinopyranoside and (3) quercetin 3-O-α-l-rhamnopyranoside [Loranthus tanakae [n-butanol fractions as well as the isolated quercetin glycosides of Loranthus regularis exhibited considerable antioxidant activity as demonstrated through their ability to scavenge DPPH free radical where the antioxidant activity was similar to that of ascorbic acid (positive control). Meanwhile, only the ethyl acetate and n-butanol fractions (at 1 mg/mL), and the isolated quercetin glycosides of Loranthus regularis demonstrated antioxidant properties through the alternative β-carotene/linoleic acid antioxidant assay [The antioxidant properties of the crude (methanol) extract obtained from the aerial parts  of another species, ranoside . These q tanakae . At 50 ant assay .Loranthus parasiticus against hydrogen peroxide (H2O2)-induced oxidative damage in NG108-15 hybridoma (mouse neuroblastoma x rat glioma hybridoma cells) were also investigated. Neuroprotection was assessed by performing a MTT -2,5-diphenyltetrazolium bromide) assay, a cell viability assay. MTT assay results indicate that the aqueous fraction of Loranthus parasiticus (LPAF) is highly neuroprotective [2O2 induced oxidative stress in NG108-15 hybridoma cells. (+)-catechin also prevents the termination of mitochondrial membrane potential (MMP), and inhibited cell cycle arrest at sub-G1 population following H2O2 insult. Besides decreasing ROS generation, (+)-catechin also decreases the early and late apoptotic population . (+)-catechin is a flavanol abundant in green tea well-characterized for its anti-cancer and neuroprotective roles [Increased oxidative stress in the brain and decreased antioxidant capability is a key factor in the etiology of neuropsychiatric diseases . As the otective . The neuve roles . TherefoLoranthus parasiticus has been used for the treatment of schizophrenia [Loranthus parasiticus leaves contains sesquiterpene lactones such as corianin, coriamyrtin, coriatin and tutin which are the postulated anti-schizophrenic compounds [Loranthus parasiticus exhibit high antioxidant activity (in a dose-dependent manner), compared to the methanol and ethyl acetate extracts. Concordantly, the aqueous fraction of Loranthus parasiticus contains the highest total phenolic content comprising anthocyanins, flavonoids, phenolic acids, and tannins [2O2 [In South-West China, ophrenia . Ethanolompounds . Studies tannins . Furtherins [2O2 . These dAs free radicals may induce initiation of cancer through DNA damage and mutations , it can Loranthaceae family members may account for differences in composition as well as amount/activity of bioactive compounds isolated from each genus or species within a genus. Host-parasite-specific interaction may modulate generation and therefore metabolism of bioactive compounds within the Loranthaceae family, resulting in differences in availability/composition of phytoconstituents. Geographic differences may also account for these differences between species of the genus Loranthus. Indeed, it has been shown that seasonal factors (harvesting time) may account for differences in constituent composition/components of Loranthus micranthus [The semi-parasitic nature of cranthus .Scurrula ferruginea remains under-reported, there are several studies documenting the antioxidant properties of its European counterpart, Viscum album (European mistletoe). Pre-treatment of HeLa cells with methanolic extracts of Viscum album parasitic on three host trees  inhibits oxidative mitochondrial DNA damage and the effect of this inhibition is dependent on the host tree. The extract from Viscum album parasitic on lime tree and locust tree completely suppressed oxidative mitochondrial DNA damage, whereas that from the hedge maple tree is only half as effective in inhibiting oxidative mitochondrial DNA damage [While the antioxidant effect of A damage .Viscum album ethanolic extracts (semiparasitic on the host tree Quercusacutissima) as a natural source of antioxidants/preservatives in uncooked meat products. This is due to various antioxidant assays  supporting the antioxidant potential of Viscum album extracts due to their high phenolic and flavonoid contents [A recent study also proposed the use of contents .Viscum album leaf and stem extracts from northwest Romania parasitic on five different host trees, Acer campestre (VAA), Mallus domestica (VAM), Fraxinus excelsior (VAF), Populus nigra (VAP) and Robinia pseudoacacia (VAR) identified 17 compounds and these include a pentacyclic triterpene (betulinic acid), 12 phenolic acids  and four polyphenols  [Viscum album contain higher concentration of bioactive compounds compared to stems [Another study utilizing HPLC to analyze the phenolic compounds composition of ic acid) . In addito stems .Scurrula ferruginea, the phytoconstituents of Viscum album is affected by seasonal factors (harvesting time) and the nature of the host tree [Viscum album leaves and stem extracts harvested at different seasons and also from different host trees. It has also been reported that younger plants (harvested in May) have higher antioxidant potential compared with older plants (harvested in July the same year) [Similar to ost tree . This mame year) .Scurrula ferruginea stem extracts elicit higher antioxidant activity (due to their higher phenolic content) compared to the leaf extract, whereas Viscum album leaf extracts are postulated to have higher antioxidant potential compared to the stem extract due to lower concentration of bioactive compounds present in the stem extract. Although, Scurrula ferruginea flower extract demonstrates some protection against oxidative damage [Viscum album flower extract remains to be investigated. The other major difference between Scurrula ferruginea and Viscum album in terms of antioxidant capability is the maturity level of leaves; Scurrula ferruginea mature leaf extracts tend to have higher antioxidant capabilities compared to tender leaf extracts [Viscum album, young leaf extracts have more potent antioxidant effects [Unlike its European counterpart, e damage , the antextracts  whereas  effects .Viscum album and Scurrula ferruginea and understanding how various factors affect differences in composition of constituents within all mistletoe families are also valuable avenues to explore. In addition, understanding how host-parasite interaction, geographical and seasonal variation, harvesting time and, maturity of leaves affects phytoconstituents in mistletoes Viscum album and Scurrula ferruginea will provide useful insights in terms of optimizing isolation of antioxidant rich bioactive compounds. As there is only one study published to date regarding the antioxidant role of Scurrula ferruginea, further studies that need to be addressed in the future include profiling of phytoconstituents present in Scurrula ferruginea and other genus of the Loranthaceae family, as well as dissection of the role/biosynthetic pathway of all bioactive plant compounds with antioxidant properties. Identification of bioactive plant constituents may help maintain antioxidant status and confer protection against free radical damage-induced diseases including cancer and neurodegeneration.Comparing the phytochemicals present in Scurrula ferruginea. The vasorelaxant properties of Scurrula ferruginea using both in vitro and in vivo animal experimental approaches were studied. The aerial parts of the plants  were collected, dried and pulverized into powder. Hot extraction of the powder with chloroform, petroleum ether, methanol, ethyl acetate and water was then carried out, generating five different extracts. Various responses of isolated rat aortic ring towards different doses of noradrenaline in the presence of the extracts were measured. The methanolic extract produced a significant dose-dependent inhibition in the maximum response, suggestive of containing non-competitive inhibitory activity compounds. This result is corroborated by the in vivo experiments where the most potent extract for blood pressure lowering activity in anesthesized normotensive Sprague Dawley rat model was the methanolic extract [By 2030, approximately 23 million people are projected to die per annum from cardiovascular complications. Hypertension, an important risk factor for cardiovascular disease, has been found to be modulated by the methanolic extract of  extract . This stScurrula ferruginea was obtained using Soxhlet extraction method. These extracts were administered into Sprague Dawley (SD) rats in intravenous boluses of 25, 50, 100 and 200 mg/kg concentrations. The results illustrate that there was a dose-dependent reduction of the mean arterial pressure of the rats. This hypotensive effect of the extract was reduced in the presence of atropine, a nonselective muscarinic antagonist and L-NAME (Nω-nitro-l-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor. This dose-dependent effect of the methanolic extract of Scurrula ferruginea, together with the reduction of effect in the presence of atropine, was replicated in guinea pig ileum. Conversely, neostigmine (acetylcholinesterase inhibitor) enhanced the contraction of the guinea pig ileum. These observations led to a conclusion that the methanolic extract of Scurrula ferruginea exerts is hypotensive effect via stimulation of muscarinic receptors and/or stimulation of nitric oxide (NO) release [Scurrula ferruginea still requires further investigation [To investigate the hypotensive mechanism of the extract, the methanolic extract of  release . The wortigation . The invScurrula ferruginea was further carried out by fractionating the methanolic extract fraction with ethyl acetate, chloroform and n-butanol. In vitro experiments showed that the n-butanol fraction of the methanolic extract of Scurrula ferruginea acts in a concentration-dependent mode to inhibit the isolated rat aortic rings’ contractions induced by phenylephrine (PE) and KCl. In vivo experiments with anesthetized adult male Sprague-Dawley rats showed that n-butanol methanolic extract of Scurrula ferruginea decreases the blood pressure in a dose-dependent mode for a more prolonged period. Chromatographic analyses of this fraction suggested the presence of terpenoid constituents [Scurrula ferruginea methanolic extract  displayed that the n-butanol fraction of methanolic extract of Scurrula ferruginea has the highest EC50 value, the median concentration needed to bring about 50% reduction of the maximum contraction caused by the respective agonist, as reported from the concentration-response curve of methanolic extract of Scurrula ferruginea. The Rmax  responses values was also the highest for n-butanol fraction.A more detailed analysis of the methanolic extract of tituents . CompariScurrula ferruginea is via reversible noncompetitive antagonism [Scurrula ferruginea is via noncompetitive antagonism are needed. However, identification of the exact bioactive component in the n-butanol methanolic extract of Scurrula ferruginea is needed. In addition, as the bioactive components responsible for the vasorelaxing effect have been suspected to be terpenoids, comparison of the mode of action profile of the methanolic extract of Scurrula ferruginea with those of known terpenoids would have yield precious insights into the mode of action [n-butanol methanolic extract of Scurrula ferruginea was mediated via muscarinic receptor stimulation of the endothelium, as removal of the endothelium diminished the vasorelaxant effect exerted by the extract. The biological active component in the n-butanol methanolic extract of Scurrula ferruginea was found to activate the NO-cGMP pathway and/or enhancement of prostacyclin PGI2 release with possible cross-signaling modified by responses to Acetylcholine and sodium nitroprusside or stabilizing nitric oxide half-life. Chemical analysis of the n-butanol methanolic extract of Scurrula ferruginea reported 0.4% of flavonoids, 6.3% phenolic compounds, 0.3% total antioxidant activity and 0.04% free radical scavenging activity [Scurrula ferruginea is a parasitic plant with medicinal effects in the treatment of antihypertension. Exploration of the compounds contained within this plant may unravel a wide array of therapeutics.Ameer and team reported that the mode of vasorelaxant effect of the methanolic extract of tagonism . The stuf action . The modactivity . In summViscum album was recorded in 1907 by a French physician, Renѐ Gaultier. Viscysate, a commercially available mistletoe preparation from around 1930s to 1950s, was used as a vasodilator [Viscum album re-emerged, resurrecting the evidence of vasodilation of the genus Viscum. In 2007, a study by Ofem et al. indicated that the leaves extract of Viscum album induced a significant decrease in blood pressure without causing any change in heart rate. This led the team to postulate that Viscum album most likely decrease blood pressure via the sympathetic pathway [Viscum album also showed promise [Viscum album were mentioned and these activities are facilitated by the phytochemicals, such as lectins, phenylpropanoids and flavonoids in these mistletoes. Relatedly, these phytochemicals also promote lowering of blood pressure and extracts of Viscum album, especially aqueous extract, have been used in treatment of hypertension [Viscum articulum has been noted to exert antihypertensive effects in hypertensive rats by diuresis and nephroprotection [On the other hand, the antihypertensive effect of odilator . Neverth pathway . A pilot promise . It is nrtension . In addiotection .Scurrula and Viscum showed evidence of exerting vasodilation effects and are potential antihypertensive drug. However, further clinical trials to ensure the safe use and efficacy of these extracts are still necessary and yet to surface.Thus, both genera of mistletoes Taxillus chinensis exhibited the best activity on both mechanisms of FAS inhibition [Obesity, a metabolic disorder is getting increasingly prevalent globally, leading to various comorbidities and has been linked to mortalities as well . Benefichibition . It was hibition . HoweverScurrula ferruginea Danser has been mentioned to be used after delivery in various indigenous medicines [edicines ,137. HowScurrula ferruginea has been reported for its therapeutic purpose, as a purgative while the haustorium were noted for their effect on ulcer [It is well known that herbal remedies are used worldwide for gastrointestinal disorders. Although there are modern medications available, the herbal remedies are widely used for their efficacy, ease of use and most importantly for lesser side effects. The flowers and leaves of on ulcer .Scurrula ferruginea methanolic extract on gastrointestinal effects exhibited dose-dependent spasmogenic activity [A preliminary study of the activity . Subsequactivity . Althoug50) is calculated as the dose required to kill 50% of a species. This data is essential to identify the optimal therapeutic dose and the highest dose up to which the extract can be given, above which lethality would be expected. The toxicity studies can be acute, sub-acute and chronic, where the former is the most commonly used type to evaluate the dose to be used for test dose for preliminary testing.Lethal dose  lethality test, a bioassay, to assess in vitro toxicity was conducted on water and methanolic extracts of D. pentandra wherein the lethality was observed after a day of exposure and were found to be non-toxic [As observed by Mothana, various doses of talities . While a00 mg/kg . Yet ano00 mg/kg . Brine son-toxic .Viscum album extracts or isolated mistletoe lectins, with the former parasite given at 1400 mg/kg. The isolated mistletoe lectins were administered subcutaneously, nasally and orally, at a dose of 14 μg/kg, 50 μg/kg and 500 μg/kg, respectively. In another study, immunostimulatory response was observed accompanied by substantial increase of cellular and humoral response after antigen stimulation. While there were five studies reporting lethality of animals after high dose in Viscum album, only one study reported death with mistletoe lectin in mice [A systematic review of 48 animal experiments reported about higher doses of  in mice . TherefoHerbal medicines are consumed by cancer patients, both with and without prescription in German-speaking countries and was investigated by National Center for Complementary and Alternative Medicine (NCCAM) in 2003 .Viscum album extracts, administered by different routes, and intravenous isolated mistletoe lectins, 1500 mg/kg and 6.4 μg/kg, respectively. For both, although immunosuppressant activity was not observed, occasional allergic reactions were reported, while for recombinant mistletoe lectins anaphylactic reactions and reversible hepatotoxicity were detected [An investigation through systematic review on the safety of administering extracts in humans was undertaken. There were 69 clinical studies with higher doses of detected .Viscum album extract is commercially available as Iscador®. While, Iscador is a registered homeopathic drug in United Kingdom, France and Italy, the extract preparation is approved in Austria, Germany, Sweden, Switzerland, and Georgia as an adjuvant for palliative cancer treatment by subcutaneous administration [® should be based on patients’ personal adaptation characteristics following personal medicine principles rather than standard dose regime [Fermented stration . This wae regime .® Populi (IP) and Viscummali e planta tota (VM), are the preparations from mistletoe, growing on poplar and apple tree, respectively. A 3-armed randomized, double blind clinical trial was conducted on healthy volunteers, who received increasing doses of either VM  or IP  at 3 different doses for respective groups or placebo administered by subcutaneous route biweekly for 12 weeks. IP strengths higher than 0.1025% caused strong local reaction at injection site and eosinophilia. All IP concentrations increased CD4 counts without IL-6 and CRP increase. However, VM 2% produced mild local reaction and a small increase in eosinophil cell count [Mistletoe lectins are considered to be effective in improving the quality of life during chemotherapy or radiotherapy . In ordell count .Viscum album extracts, which were well tolerated. The extract and its’ compounds showed significant cytotoxic effect on in vitro cancer cells and in animal studies. Likewise, evidence of positive effects on both carcinomas was reported in the controlled studies when high dosage was given locally [Non-randomized (16 studies), randomized (19 studies) controlled studies and single arm cohort studies fit the criteria for the systematic review on breast and gynaecological cancer treatment by  locally .Despite a range of cytotoxic, radiation and surgical therapies available for breast cancer, breast cancer mortality has not reduced significantly. Thus complementary and alternative medicine (CAM) is being considered in various centres to improve QoL and reduce drug side effects . VariousA twelve month phase I/II clinical trial of aqueous mistletoe extract with 6 instillations per week to 30 superficial urothelial bladder cancer patients by intravesical administration followed by transurethral resection, cytology, cystoscopy, and random biopsies was conducted. Tumor-free patients were calculated to be 70%, while the rest had recurrence. There were no reports of side-effects, both local and systemic to extract standardized to mistletoe lectin, which showed good tolerability. Thus the study concluded that this extract is comparable to the standard adjuvant Bacillus Calmette-Guerin treatment, which has high side-effects, in effectiveness .VISCUM® Q, a standardized mistletoe extract was evaluated for its safety and efficacy in 32 postsurgery patients with gastric carcinoma in a randomized controlled pilot study. The patients treated with doxifluridine were randomized either with or without the subcutaneous injection of test extract, triweekly from 1 to 24 weeks in increasing doses. Eosinophil and leukocyte count from lab tests as well global health status from questionnaire increased significantly in the intervention group compared to control, with lesser frequency of diarrhoea in the former [Abnobae former .Viscum album L. extract  [Advance pancreatic carcinoma patients who cannot tolerate first-line treatment or choose to decline main stream treatment, supportive care is available for improvement of quality of life or as palliative therapy, as they weigh the low success probability against side effects of conventional treatment side effects . In addidor® Qu) . The casdor® Qu) .Viscum album (L.) quercus). The dose escalation, given subcutaneously thrice a week, was continued until a local skin reaction accompanied with slight elevation of temperature was observed, the manifestations indicate optimal dose in the body. Patients treated with mistletoe extracts or with standard supportive care, were 96 and 72, respectively. The former group performed better not only in terms of pain, fatigue, loss of appetite and insomnia, with better confidence interval, but also in quality of life parameters [Patients with pancreatic cancer either metastatic or locally advanced, who were only on supportive care and not on specific treatment were included in the randomised phase III trial for mistletoe extract, which was equivalent to the commercial product, Iscador Qu  instillation (10 mg) following paracentesis, to remove malignant peritoneal fluid, in peritoneal cavity of patients reduced the necessity of repeated paracentesis. A total of 23 patients with varying advanced stages, malignancies and histology were recruited for the Phase II study and were checked against self-baseline values for paracentesis requirement. Toxicity was not noticed and the time interval for paracentesis increased from 7 to 13 days, established the efficacy of plant extract in improving malignant ascites. Simple home care administration and feasibility to use in palliative end of life care were the additional advantages. A phase III randomised trial was recommended to validate the promising preliminary results [Management of malignant ascites is a significant challenge in advanced malignancies. Iscador M results .Viscum album. The influence of well-tolerated Viscum album extracts on the impact of quality of life (QoL) in cancer patients was evaluated in the systematic review. Quality of Life for the cancer patients was defined as, “how patients feel and function during the disease and its treatment, including psychosomatic self-regulation, subjective well-being, disease symptoms, performance status , undesirable experiences associated with the use of chemotherapy or radiotherapy (adverse drug reactions), and “treatment symptoms”, by the reviewers of the controlled clinical studies [Viscum album extract were exhaustion, nausea, appetite, anxiety and fatigue. Less consistent results were noticed for diarrhea, pain and general performance. It is beneficial to have controlled trials that are well designed and executed in order to reap benefits for the patients and for conclusive results [The research method quality of the controlled trials was assessed based on several criteria for herbal extract  studies . The ran results .Viscum album L. extract  should evaluate to corroborate the reproducibility of the treatment effect and to investigate whether this approach could be a useful pre-operative intervention for colon adenomas which are too large for endoscopic resection. Phase III randomised trials would be the way to move forward for Iscador M® which was found to be effective in the management of malignant ascites in phase II trials. It would be beneficial to the community to conduct systematic clinical trials.There are many indigenous claims about these genera which have been used in traditional medicine. The claims if supported with scientific evidence backed by clinical trials would be beneficial for the community. Furthermore, in depth studies on pharmacological activity of the plant and its mechanism of action would be an additional advantage. Most of the suggested future studies have been mentioned under the appropriate sections. The plethora of compounds in these mistletoes means that these plants are a huge reservoir of potential medicinal compounds that can be used as leads to drug discovery. Further elucidation of parasitic plant response to host condition is needed. The knowledge of mechanism and biochemistry of each compound will minimise potential side-effects as well as maximize therapeutic potential of the drug. Despite widespread use of the genus for various medicinal purposes, evidence based pharmacological elucidation was conducted for specified extracts particularly for few activities. Moreover, the active phytoconstituent responsible for the biological activity needs to be identified and tested to further authenticate the claim. There is clearly a great need not only for patient but also for doctors to be educated about herbal remedies, which should be substantiated by randomized controlled trials for their safety and efficacy . MoreoveViscum album which has been intensively studied and translated into the drug Iscador, work on the mistletoes of Southeast Asia is still limited to ethnomedicinal uses. Viscum album extract has been studied in clinical trials and is being used in Europe as an adjuvant therapy for cancers of breast, malignant ascites and pancreas. Systematic literature review of 49 publications advocates that cancer patients treated with Iscador survives longer than non-treated patients [Viscum album targeted intratumoral delivery route as seen in clinicaltrials.gov. However, there was a recent article by Von Schoen-Angerer in 2014, which was a case report which described the complete regression of a colon adenoma following intratumoral injection of Viscum album [Scurrula there are no known reports of intratumoral injection. The therapeutic effects of Viscum album infers a huge untapped potential of the Scurrula mistletoes due to the similarities of the plants from both genera. Plants of both genera have shown evidence of anticancer, antimicrobial, antioxidant and antihypertensive properties. As Scurrula research is still in its early stage, phytoconstituents isolation, structure activity relationship of phytoconstituents, mechanism of action of the bioactive compound and clinical trials are in the research pipeline. The abundance of phytoconstituents in plants of Scurrula genus evidently show potential for pharmacological drugs. Both Scurrula oortiana and Viscum album stimulate production of TNFα that assists the immune system to fight cancer. Also, the terpenoids in Scurrula ferruginea, which has been identified as the bioactive compound for its antihypertensive effect and is congruent to the finding as observed in triterpenoids of hyperparasite Viscum articulatum, Economically, Parasitic angiosperms can provide a valuable feedstock for pharmaceutical industry, therefore their medicinal values should be considered in taking account the nature of host species they are parasitizing as well as regional specificity. In conclusion, parasitic plants are important and useful, and future work to develop the Scurrula and Viscum genera mistletoes as reservoir of pharmacological drugs will prove worthwhile.Unlike patients . Currentum album . As for


Although physiologic surgeries for lymphedema  are becoming well established, unpredictable outcomes have still been reported in some studies. Therefore, authors have investigated ways to improve these surgery outcomes. The goal of our study was to conduct a comprehensive systematic review of targeted therapy administration in the surgical treatment of lymphedema. We conducted a comprehensive systematic review of the published literature on targeted therapies associated with lymphedema surgery using the PubMed database. Eligibility criteria excluded papers that reported surgical treatment of lymphedema without the use of targeted therapies and also papers describing targeted therapies in nonsurgical treatment of lymphedema. Abstracts, presentations, reviews, and meta-analyses were also excluded.Extracted data included the year of study, country, lymphedema model, surgical technique, targeted therapy agent, therapy delivery, findings, and outcomes. From 823 potential papers found in the literature, 10 studies fulfilled the eligibility criteria. All papers were experimental, and most of them on small animal model (7/10). Different targeted therapies were proposed, but all of them were associated with lymph node transplantation. The most common targeted therapy proposed mechanism was growth factor delivery (8/10). However, one paper used adipose-stem cell, and one paper proposed the use of sterile inflammation. The pooled publications assessing targeted therapy administration in the surgical treatment of lymphedema demonstrate encouraging data for positive outcomes. To date, all studies were experimental and related to lymph node transfer. Lymphedema is a chronic lymphatic condition frequently related to cancer treatment  in developed countries. It is estimated that 5 to 6 million people have lymphedema in the United States, and the incidences described in the literature are high, such as one in every six patients undergoing solid tumor treatment . HoweverTargeted treatments are of interest in lymphedema treatment literature. Anti-inflammatory treatments targeting Th2-inflammatory responses have been described -7. MoreoLymphedema surgery advanced considerably through the advent of physiologic methods, which aim to restore lymphatic function and continuity. These methods use two microsurgical techniques: 1) lymphovenous bypass (LVB), which connects a lymphatic vessel with a regional vein and is a safe procedure that is effective in early-stage lymphedema -14, and Interestingly, while physiologic surgeries for lymphedema are becoming well established, some studies are still reporting unpredictable outcomes . TherefoSearch strategyTwo reviewers  conducted independently searches using the PubMed database without timeframe limitations, initially through title and abstract screen and then by full-text review. Disagreements regarding article identification and final selection for the inclusion of the literature were resolved by another reviewer (A.J.F). The search was done using the following keywords: ((((Lymphedema) AND Lymphovenous anastomosis)) OR ((Lymph node transfer) AND Lymphedema)) OR ((Lymphedema) AND Growth Factor). The bibliographies of the studies that fulfilled the study eligibility criteria were also examined, looking for articles not present in our initial search. This study followed the guidelines outlined in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flowchart in Figure Selection criteriaEligibility criteria included studies reporting data from the use of targeted therapies in the surgical treatment of lymphedema. Therefore, we excluded papers that reported surgical treatment of lymphedema without the use of targeted therapies and also papers describing targeted therapies in non-surgical treatment of lymphedema. Abstracts, presentations, reviews, and meta-analyses were also excluded. Data extraction and processingExtracted data included the year of study, country, lymphedema model, surgical technique, targeted therapy agent, therapy delivery, findings, and outcomes. Data extraction from articles, tables, and figures was performed by two reviewers , with the accuracy of data entry confirmed by an additional reviewer (A.J.F). Study characteristicsFrom 823 potential papers found in the literature, 10 studies fulfilled the study eligibility criteria as seen in Figure VEGF-C Delivery of VEGF-C was assessed in seven papers, all agreeing that its administration promotes positive results on lymphedema compared to controls. The most common method of VEGF-C delivery was a local injection of adenoviral vectors (6/7). Lahteenvuo et al. demonstrated in pigs that a brief VEGF-C gene expression through adenovirus was enough to promote the formation of stable collecting lymphatic vessels . In theiOther growth factorsSome authors compared VEGF-C with other growth factors , demonstrating that VEGF-C provided the greatest therapeutic results and justifying its further study in combination with surgical treatment of lymphedema. Authors who studied the effects of VEGF-D associated with VLNT demonstrated that it could induce lymphangiogenesis ,20-21. HSterile inflammationTaking into consideration the potential risk of metastasis by using growth factor therapy in lymphedema treatment, Joseph et al. proposed local sterile inflammation inducers, which are used in vaccines to boost its immunization potential . The autMetastasis assessmentExperiments using tumor cells with high potential of lymphatic metastasis are useful to assess lymphatic function. Two authors have assessed metastasis in targeted therapy in lymphedema treatment. Tammela et al. studying VEGF-C and VEGF-D delivery by adenovirus in rats that underwent VLNT, demonstrated through subcutaneous injection of human lung carcinoma cells, that cancer cells were trapped in 80% of VEGF-C-treated lymph nodes (8/10) versus only 17% in the control group (1/6) . They coDiscussionIn this systematic literature review, we have shown that different mechanisms of targeted therapies in association with lymphedema surgery have been proposed with promising experimental results. The literature of lymphedema pathogenesis and treatment has been increasing considerably over the years. VLNT and LVB are considered functional lymphedema surgeries, since they attempt to improve the local lymphatic circulation. While surgeries to treat lymphedema are generally accepted now, some studies still have reported unpredictable outcomes for them, varying from excellent outcomes to no benefit . MoreoveFrom this literature review, we noticed that all efforts to propose targeted therapies in lymphedema surgery were focused on lymph node transplantation. The reason behind this is probably the fact that this procedure is dependent on lymphangiogenesis since it employs microsurgical anastomosis only to reconnect the blood supply. Therefore, its result is dependent on the preservation of the transplanted lymph node architecture and the lymph node’s capacity to reconnect with the local lymphatic circulation through the production of endogenous lymphangiogenesis cytokines -17.Although the first targeted therapy associated with lymphedema surgery was proposed in 2007 by Tammela et al., to date, no clinical studies have been published . Most ofStudies have suggested targeted therapies in lymphedema treatment beyond growth factors. For example, it is well accepted that modulation of Th2 cytokines is useful in lymphedema treatment by promoting anti-inflammatory and antifibrotic action without increasing the risk of tumor metastasis . AvoidinWe do recognize the presence of several limitations to our study, common to systematic reviews. Studies included in this review were published in the English language. Furthermore, there is a potential for bias in interpreting the data reported in each study. We recognize that Lu et al. performed an experimental study in which adenoviral VEGF-C was delivered to a transferred lymph node ; howeverThe pooled publications assessing targeted therapy administration in the surgical treatment of lymphedema demonstrate encouraging data for positive outcomes. To date, all studies have been experimental and related to lymph node transplantation. Most of the studies proposed growth factor therapies, but lymphangiogenesis without delivering cytokines was also possible through sterile inflammation and adipose-derived stem cells.


A severe burn injury is one of the most devastating injuries and is associated with a high risk of mortality  . Hypermeet al. delineated the role of catecholamines and IL-6 in triggering WAT browning after burn injury [et al. provides a detailed review in this context [Increasing evidence suggests that the hypermetabolic response is partly fueled by the fat mass depots or the white adipose tissue (WAT) in burn patients . The burn injury . In addin injury , which i context .IL-6 and other inflammatory mediators acting as ‘messengers’ to activate the nonshivering thermogenesis in hypermetabolic conditions [IL-6-deficient mice with burn injury. Indeed, IL-6-deficient mice demonstrated a protective response against the induction of WAT browning and had better metabolic outcomes after burn injury [IL-6-deficient mice demonstrated the association of enhanced infiltration and migration of type 2 macrophages in WAT after burn injury, implicating the crucial role of IL-6 in WAT browning [IL-6 has reduced macrophage infiltration and reduced WAT browning after burn injury in a murine model [NLRP3 inflammasome after burn injury has demonstrated a crucial need of NLRP3 in WAT remodeling and mitochondrial function [NLRP3 is a multifactor protein complex, which plays a pivotal role in regulating macrophage differentiation and inflammatory response to infections and helps in wound healing [NLRP3 was found activated in the early phase in burn patients. However, when challenged with burn injury, NLRP3-deficient mice had augmented WAT browning response [NLRP3 in WAT remodeling. These studies demonstrate that although macrophages and inflammatory mediators were considered detrimental in initiating WAT browning, NLRP3 murine studies have challenged the notion, warranting the need for detailed mechanistic studies to avoid potential side-effects of future targets. Furthermore, murine studies suggest that NLRP3 has an apparent role in eliciting reactive oxygen species production and is protective in attenuating WAT browning and mitochondrial dysfunction [NLRP3 and reactive oxygen species signaling in the burn-induced hypermetabolic response has yet to be elucidated.The phenomenon of triggering WAT browning was further delineated by following a lead on the plausible role of nditions . It is wnditions . This hyn injury . Also, sbrowning . Althougne model , the mecfunction . NLRP3 i healing . Notablyresponse  and enharesponse , indicatfunction . HoweverIn hypermetabolic conditions, WAT browning (or wasting) not only leads to a decline in body mass reserves, it also substantially enhances the amount of circulating free fatty acids due to WAT lipolysis or breakdown ,5. BeyonCollectively, these studies demonstrate that targeting WAT (or fat) browning is promising yet challenging and complex, as this process drives lipotoxicity when inflicted with burns but also promotes insulin sensitivity in metabolic disorders such as obesity and diabetes. Nevertheless, selective targeting of WAT browning seems to be a promising therapeutic intervention in burn patients to combat the hypermetabolic response after burn injury. Successful clinical drugs include propranolol and metformin, which have shown positive results in burn patients. However, only metformin has shown promising tissue-specific effects in murine studies. In the future, detailed clinical research is required to unveil the specificity, safety and efficacy of these drugs in reducing the WAT browning and associated hypermetabolic response in burn patients. Moreover, the exact mechanistic action of catecholamines, glucocorticoids and other signaling mediators in initiating WAT browning after burn injury is still not understood. Overall, this work highlights the mechanistic and clinical advancement achieved thus far in targeting WAT browning to curtail the hypermetabolic response, which is equally as challenging and important as unlocking its thermogenic potential in reducing the obesity epidemic.


Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. Methods: In a case-control design, 310 adults  were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings , vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. Results: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1β (IL-1β) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. Conclusions: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention. Cardio- and cerebrovascular disorders are recognized worldwide as the most frequent causes for death and major depressive disorder (MDD) for disability . In receCVD is a chronic inflammatory disease  that canHigh CRP seems to reflect also the activity of bipolar disorder: It was associated with high activity of the disorder in both conditions manic and depressed states . WhereasMDD symptoms can be mimicked by excessive secretion of the pro-inflammatory macrophage cytokines  and are Both population based ,24,25 anTherefore, the presented comparative prospective case-control study in both diagnostic groups MDD and CVD which directly compares immunological and clinical cardiovascular risk variables may help to clarify these interdependencies. We prospectively investigated both MDD and CVD patients in comparison to psychiatrically and medically healthy controls. We studied frequency and severity of depression in CVD and compared clinical and immunological cardiovascular risk factors between CVD and MDD in an interdisciplinary study. Moreover, we studied to what extent MDD is related to cardiovascular risk factors and to inflammatory biomarkers in cardiovascularly healthy patients suffering from MDD in relation to healthy controls without CVD in order to identify biomarkers which may be suitable for estimation of the cardiovascular risk in MDD. In addition, we investigated the influence of inflammatory markers on antidepressant treatment outcome.2 = 25.6, d.f. = 6, p < 0.001).Comparison of mean values showed significant differences in a variety of risk markers indicating the elevated cardiovascular risk of MDD patients in comparison to healthy controls . Blood pp = 0.034) and heart rates . Metabolic risk factors included significantly lower total cholesterol  in view of significantly higher triglycerides  and fasting glucose values  in combination with lower high density lipoproteins (HDL) . Lifetime smoking habits did not differ, whereas more MDD patients are current smokers. After correction for age using exact matching all significant differences except for cholesterol (p = 0.24) were confirmed. Moreover, systolic BP was significantly higher in MDD patients at baseline .Post-hoc comparison of depressed patients and controls confirmed the significantly elevated diastolic blood pressure (BP)  and heart rates . Increased body weight , BMI , waist , hip , and waist/hip ratio  were indicators of the higher metabolic risk. We also registered a higher lifetime cigarette consumption with more pack years . The Framingham sum index  and the 10 years risk  were significantly higher in CVD patients. After exact matching for age and sex all statistically significant differences with the exception of systolic BP differences were confirmed.CVD patients in comparison to controls showed significantly higher systolic BP values .Among inflammatory biomarkers, the general inflammatory marker high sensitivity (hs)CRP, the pro-inflammatory cytokines IL-6 and IL-1β as well as the adhesion molecule sICAM-1 were significantly higher in depressed patients in comparison to controls . To ruleTo evaluate putative improvements of cardiovascular risk factors, all inflammatory markers were determined also after remission of depression shortly before discharge of the hospital. Only IL-6 and P selectin declined significantly after treatment with antidepressants .p < 0.001), triglycerides , and fasting glucose levels . Weak, but statistically significant negative correlations could be seen for HDL  and for the Framingham sum score  as well as for the 10-years risk score . The current smoking status (numbers of cigarettes) was correlated with hsCRP levels at the time of admission in MDD patients .There was correlative coherence between classical clinical and inflammatory cardiovascular risk factors and the severity of depressive symptoms: Baseline values showed positive correlations with HAM-D17 scores for heart rate , sICAM-1  and IL-1β . IL-6 showed a positive correlation only before discharge .Baseline values of inflammation biomarkers revealed weak, but statistically significant positive correlations of HAM-D17 sum scores with hsCRP , were younger  and showed a specific inflammatory biomarker profile at baseline. This included higher LDL cholesterol  together with higher IL-1β-  and hsCRP-values  indicating a higher level of chronic inflammation. Also high hsCRP levels >2.0 mg/dL are considered as sign of subclinical inflammation and a biomarker of an enhanced cardiovascular risk [p = 0.025).Surprisingly, a specific combination of psychopathology and inflammatory markers seems to affect the time to complete remission (HAM-D17 scores ≤ 7) from MDD: patients more likely to experience a more rapid relief from depressive symptoms suffered from lesser severe MDD  study CVD patients one month after acute MI, 19.8% suffered from a depressive syndrome and 10.5% fulfilled the criteria for MDD . Also SøEven if depression has been considered as an additional risk factor for CVD independent of classical known risks such as age, gender, vital signs, and blood lipid levels ,34 the pWe detected higher triglycerides and low HDL cholesterol levels in depressed patients in comparison to healthy controls. This profile indicates the considerably enhanced risk for CVD in MDD patients. Differences in fasting glucose levels and waist circumferences as well as a higher rate of smokers in MDD point towards an unhealthy life style  associated with depressive symptoms . Our resHigher inflammatory biomarkers in MDD in comparison to healthy controls support the theory of chronic inflammation and an enhanced cardiovascular risk in MDD. hsCRP represents a stable plasma biomarker for a low-grade systemic inflammation . ElevateIn contrast to other studies , we coulHowever, our data indicate that patients remitted from an acute phase of MDD may still have a persistent elevated cardiovascular risk independently from the state of the depressive disorder, because high IL6 indicates an up to three-fold higher risk of sudden cardiac death and high CRP is associated with nonfatal coronary heart disease . This imMoreover, we provide first evidence in our MDD sample that higher hsCRP levels, which indicate subclinical inflammation and higher risks for CVD, are associated with significantly shorter time to remission during antidepressant treatment. This further fosters the discussion about depression influencing immune dysregulation  or pathoIn a recently published study, patients suffering primarily from hypertension and a metabolic syndrome showed also depressive symptoms, but no significant relationship between depression scores and cardiovascular or metabolic risk factors was detected . In our Summarizing the results, our study revealed elevated inflammatory biomarkers in physically completely healthy MDD patients pointing to an enhanced risk for CVD related to the severity of depression. However, a positive impact of inflammation on outcome after antidepressant treatment could be observed. Thus, the immune system’s inflammatory response may not solely facilitate the symptoms of depression  but, simPatients suffering from MDD are at specific risk for the development of CVD. For the assessment of this risk the observance of classical cardiovascular risk factors including the Framingham index appears not to be sufficient. Our study suggests that the enhanced cardiovascular risk is mediated additionally by non-traditional risk factors including inflammatory biomarkers and a metabolic syndrome. MDD facilitates an unhealthy life style and consequently favors the development of a metabolic syndrome. On the other hand, biomarkers indicating a chronic inflammation, such as hsCRP, interleukins, and others, suggest that MDD patients are a high risk group for CVD. As a consequence a close monitoring of smoking status, vital signs (blood pressure and heart rate), triglycerides, HDL cholesterol, hsCRP, and, if possible, pro-inflammatory cytokines (IL-1β) and adhesion molecules (sICAM-1) is recommended for cardiovascular risk assessment.In patients suffering from stable CVD a relatively high rate of MDD could be detected. Due to the fact that MDD in CVD represents a risk factor for subsequent cardiovascular events sufficient treatment of a putative depressive disorder is warranted. Effective antidepressant treatment supports the relief of depression, whereas an improvement of the prognosis and the reduction of cardiovascular mortality could not be proven sufficiently in prospective studies.For patients suffering from CVD in combination with MDD a cardiac rehabilitation program is recommended, because it was found to increase the levels of physical and mental quality of life and lower also levels of depression .Limitations of our study were the limited case number in comparison to epidemiologic studies. Therefore we were not able to detect small differences in the investigated biomarkers between our three groups. Moreover, up until now, no follow-up investigations to detect longitudinal developments of risk factors and biomarkers and their clinical long-term consequences for the investigated MDD patient group have been performed. Such further investigations are warranted, because they may help to better classify the investigated risk factors and deduce better clinical recommendations.To meet the requirement of an effective prophylaxis of both cardiovascular disorders in MDD and for diminishing the risk for MDD in CVD, more secondary and primary prevention studies are needed. In MDD early assessment of cardiovascular risk and an early induction of preventive arrangements may be useful. These steps may start with nutritional and life style educations, proceed to dietary arrangements and supplements, and, in case of increased cardiovascular risks, may even include cardio-protective medication. In CVD early diagnosis, treatment and prophylaxis of depression is desirable. This may include psychoeducation, psychosocial therapies, psychotherapeutic approaches, and suitable antidepressant medication.Even if evidence from randomized controlled trials RCTs still is lacking, in most cases a combination of the mentioned treatments may be of use. From a clinical point of view only the awareness for the described risks, sufficient diagnostics and adequate treatment may help to go against the predicted worldwide rise of the impact of both disorders, CVD and MDD.A total of 333 subjects were recruited within the funding period of four years, 23 patients and controls were excluded due to somatic or psychiatric diagnoses detected after study inclusion or due to withdrawal of consent. Therefore, a total of 310 patients were investigated in the study. One hyndred unrelated in-patients suffering from unipolar MDD were recruited. Patients were diagnosed by experienced and trained psychiatrists according to DSM-IV  using thOne hundred and six outpatients suffering from CVD were recruited from the Department of Internal Medicine—Preventive Cardiology of the Ludwig-Maximilian-University of Munich (sample 2—CVD). Their psychiatric evaluation included also the SCID for DSM-IV diagnoses together with CGI, HAM-D17, MADRS and BDI evaluation. Criteria for inclusion were evidence of CVD documented by confirmed diagnosis of previous myocardial infarction as per hospital discharge summary, or history of CABG or PCI or evidence of ischemic heart disease based on stress electrocardiography confirmed by diagnostic imaging. Patients had to be in stable conditions defined as at least 3 months from an acute episode, intervention or hospitalization for CVD. Thyroid disease, diabetes, hypertension and other chronic conditions had to be well controlled on a stable medical regimen for a minimum of 3 months. Inflammatory biomarkers were not determined in sample 2 due to ongoing treatments with statins.One hundred and four age- and sex-matched controls of Caucasian ethnicity were recruited at the LMU and screened for psychiatric (SCID) and for medical disorders. A complete medical and social history, a detailed review of systems and complete physical examination were obtained to assess absence of cardiac, cerebral or peripheral vascular disease. Subjects with diabetes were excluded as this is considered a cardiovascular-equivalent disorder. Only healthy individuals negative for both psychiatric and medical disorders entered the study.2) was calculated. Hip and waist circumference were measured to calculate the hip/waist ratio. At least two blood pressure determinations were made after the patient or control subject had been sitting for at least 5 min with the arm at the heart level. Average values were used for further analysis. The calculation of the Framingham index including the risk factors age, gender, total cholesterol, HDL, systolic and diastolic blood pressure, and smoking status was performed as described elsewhere [Height and weight were measured and the body mass index . High sensitivity IL-6 and IL-1β concentrations were measured using ELISA of R&D Systems, Minneapolis according the protocol delivered from the manufacturer. MCP-1, VCAM-1, ICAM-1, E-Selectin, P-Selectin, sCD40-L were determined using ELISAs obtained from IBL , Minneapolis, MN, USA according to standard protocols.U test for comparison of means were performed. In case of normal distributions mean differences in demographic and clinical variables between patients and controls were compared using univariate analyses of variance (ANOVA procedure) or Student’s t-tests in case of continuous variables. In case of categorical variables the frequencies were compared using χ2-tests. In addition, we screened cardiovascular risk factors for correlations with predominantly nonparametric variables using Spearman’s rho coefficient. To test for influence of hsCRP status on treatment outcome in MDD patients Kaplan-Meyer survival analysis including Cox-regression was applied.All analyses were performed using the Statistical Package for the Social Sciences (SPSS) for Windows . The One-Sample Kolmogorov-Smirnov Test was used to test about normal distribution of all variables. In case of a non-normal distribution, the corresponding variables were transformed with the log-transformation to reach a normal distribution before entering parametric testing. In case of persistent deviations from normal distribution non-parametric comparisons of mean values using the Mann-Whitney To rule out significant age and gender effects all comparisons were done after exact matching.The study was approved by the ethics committee of the medical faculty of the Ludwig-Maximilian-University Munich . Written informed consent was obtained from all patients and control subjects. Patients’ data were anonymized.


Formal psychosocial support programs after weight-loss surgery are limited in scope and availability.This randomized pilot study evaluated the feasibility of a postoperative behavioral intervention program.N = 50) were recruited from February 2017–July 2017 and randomized to a four-month behavioral program or usual care wait-list. Outcomes evaluated in addition to feasibility included health-related quality of life (Short Form -36), psychosocial functioning and adherence. Secondary outcomes included within-group changes for each outcome.Postoperative weight-loss surgery patients  were evident between groups.Though participation in a postoperative behavioral intervention varied, the program helped participants to maintain aspects of quality of life and self-reported adherence to dietary recommendations.NCT03092479ClinicalTrials.gov  Weight-loss surgery is an effective treatment for severe obesity , but lonPrevious approaches to postoperative behavioral or psychosocial programs, though limited in number, include acceptance-based , 18, cogTo date, the majority of studies of postoperative behavioral intervention programs focus on the prevention of weight regain , 24 and This study was approved by the Geisinger Institutional Review Board. All participants provided informed consent.Adult (≥ 18 years) weight-loss surgery patients from a large, integrated rural health system were recruited to participate in this prospective, randomized controlled trial from February 2017 to July 2017. The preoperative program for weight-loss surgery candidates is a six to twelve-month multidisciplinary clinical curriculum consisting of medical and psychosocial evaluation, as well as diet, nutritional and lifestyle education with a goal of 10% presurgical body weight loss to promote a reduction in liver fat and greater surgical safety. As part of standard clinical care, patients attend appointments with a psychologist, bariatrician, surgeon, nurse and dietitian, among others. Following the psychosocial evaluation, patients are provided a “light status” indicating clearance status for weight loss surgery from the program’s Behavioral Medicine team . Reasons for delayed clearance (“yellow light”) typically include difficulty making dietary and other behavioral changes, poor understanding of the procedure, risks or associated lifestyle changes, or untreated disordered eating or mental health concerns. Postoperatively, patients are scheduled for follow-up visits at one week, two weeks, two months, five months, eight months, and twelve months after surgery, and then yearly thereafter.Patients were eligible to participate if they were a minimum of 18 years old, completed primary weight-loss surgery  within the past 18 months. The 0–18 month postoperative period was selected for the intervention to impact change in quality of life and adherence before most patients reach their weight-loss nadir. Patients who underwent surgery revisions, were pregnant, or cognitively unable to provide informed consent were excluded. Eligible patients were identified using electronic health records and mailed a recruitment letter in random order. Letters were followed by up to three scripted phone calls by research staff. Participants who expressed interest were then invited for a screening visit and to provide written informed consent.dx.doi.org/10.17504/protocols.io.2bagaie.Patients considering bariatric surgery at the study site undergo preoperative psychological evaluations to evaluate their readiness for surgery. All patients are then given a “traffic light” status  according to their readiness. Patients given a “green” light are cleared for surgery, while “yellow” light patients have preoperative milestones that require further attention before surgery. It is plausible that yellow light patients may experience greater benefit from the intervention. Therefore, participants were stratified by initial psychosocial evaluation status  and then randomized to intervention or usual care (1:1) using a random number generated computer program provided by the study statistician. Recruitment, randomization and treatment occurred in two waves. Recruitment efforts included all eligible patients, regardless of initial light status or whether they previously expressed interested in postoperative behavioral treatment. The authors confirm that all ongoing and related trials for this intervention are registered. Internal review board approval of the trial listing, as well as requested edits by the registry, resulted in a one-month gap between enrollment initiation and registry listing. The protocol is available at The behavioral intervention program consisted of eight, one-hour group sessions that occurred twice monthly and included up to 10 postoperative bariatric surgery patients (8 sessions over 16 weeks). The intervention schedule was selected to allow for adequate time to deliver content while minimizing patient burden of travel to the medical center. Three waves of groups were co-led by a licensed clinical psychologist or doctoral-level psychology trainee. Trainees were provided regular supervision by the attending psychologist to review the previous session, offer ongoing training in leading groups, and to provide guidance regarding delivery of subsequent session content. Intervention content, timing and duration were evidence-based , 21, 24 Usual care patients completed questionnaires only. Upon study completion, usual care patients were offered the behavioral treatment provided to the intervention group after all study data were collected. Usual care participants were reimbursed for time ($50) to complete study visits .Self-report questionnaires were collected at baseline following consent and again four-months later. Intervention patients completed questionnaires following their final group or were mailed surveys if unable to attend the final session. Control patients were offered the option of completing follow-up surveys during a study visit or via mail.The SF-36 –28, deveThe PHQ-9  is a briThe STAI  is a forThe WEL  is an eiThis seven-item measure evaluates loss of control over eating over the past twenty-eight days and is scored on a five-point Likert scale  , 33.The EES  is a tweDietary adherence was measured by nine-point Likert scale (“How well are you following the diet plan given to you by the dietitian?”). This question was used in a previous weight-loss surgery study (range 1–9) .The Paffenbarger Physical Activity Questionnaire (PPAQ) is an eigWeight change was calculated as percentage total body weight change from time of enrollment to end of treatment or waist-list control period (%WL). Weight was obtained using the weight closest to the enrollment and study conclusion available in the medical record.Mean number of group attendees and attendance were tracked to determine treatment tolerability and feasibility.To reduce the chance of data entry errors, the questionnaire responses were manually entered into a database and then visually verified against the source documents by a researcher who did not enter the original data. SAS software  was used to evaluate outliers and electronically score questionnaires with standard scoring algorithms.d  was used to provide a common effect size for change in scores from questionnaires of various scales. To explore whether the initial psychosocial evaluation light status modified the effect of the intervention, change in questionnaire scores was compared between intervention participants with an initial “green light” versus intervention participants with an initial “yellow light.”The demographic and baseline characteristics of the randomized groups were described using percentages and means with standard deviations and were compared between groups using Fisher’s exact tests and two-sample t-tests. A similar analysis was conducted to determine if there were differences between participants that completed study procedures (completers) versus those that did not complete study procedures (non-completers). Change in questionnaire scores was evaluated descriptively within each group. Cohen’s n = 24) or usual care (n = 26). The majority of participants were female (82%), White (94%) and underwent RYGB . Approximately half of participants (n = 28) received psychosocial clearance in one visit  were cleared following completion of behavioral goals (“yellow light”). Intervention and usual care group participants did not differ at baseline (p > 0.05). Patients who declined to participate most frequently cited distance to the Health System and lack of time or conflicting interests as obstacles preventing enrollment . Participant flow through this clinical trial is in Of the 378 eligible weight-loss surgery patients, 50 patients enrolled and were randomized (13.2%) to the intervention  completed study procedures . When comparing completers versus non-completers, there was no difference in race, age, BMI at the time of surgery, weight-loss surgery procedure type, initial psychosocial evaluation light status, and most of the baseline questionnaire summary scores (p > 0.05). However, a higher percentage of females completed study procedures as compared to males  and completers had lower overall mean quality of life score , lower mean anxiety score , and higher physical activity adherence . Although the rate of completion was higher in the usual care group, the difference was not significant . The primary reasons for attrition were travel time to the Health System and competing obligations .Of the 50 randomized participants, 82%  compared to usual care , urges to eat in various places (WEL) or emotional eating (EES) , Table 4d = 0.927, Intervention patients reported stable adherence to the postoperative diet (+0.3±0.8) pre- to post-treatment, while usual care patients reported declines in adherence from baseline , changes in dietary adherence (p = 0.60) or changes in physical activity (p = 0.65).Within the intervention group, the initial psychosocial evaluation light status  was not correlated with change in overall HRQL .Mean attendance per group was 4.2 participants. Participants had a mean of 1.4 missed groups. One make-up session was offered.As hypothesized, participation in a behavioral intervention program following weight-loss surgery resulted in higher improvements in aspects of HRQL compared to usual care. Additionally, participation in a behavioral intervention program helped participants to sustain their adherence to postoperative dietary recommendations.Specifically, weight-loss surgery patients who completed a four-month, group-based intervention program reported better social functioning  compared to usual care controls. Gains in social functioning elevated intervention participants to levels that were comparable to normative populations , 38 and Dietary recommendations after weight-loss surgery typically include promoting consumption of water, protein and low-calorie foods, while limiting or eliminating intake of high calorie foods and beverages, alcohol and caffeine . DietaryPhysical activity did not differ between groups. Notably, however, intervention participants reported a mean of 218 minutes per week of MVPA at the end of treatment versus only 70 minutes per week of MVPA in usual care participants, which is likely clinical meaningful. While no official recommendation exists regarding amount of physical activity recommended following weight-loss surgery, exercise is an important aspect of the postoperative lifestyle .This study’s behavioral program differed from traditional bariatric surgery support groups in modality , target audience (post-surgery patients versus mixed pre- and postoperative patients), frequency (bi-monthly versus monthly) and content . A recent review  of psychFinally, levels of anxiety or depression between intervention and usual care participants were similar. Additionally, participants who experienced greater challenges obtaining psychosocial clearance prior to surgery (“yellow light”) did not benefit more from the intervention than participants cleared in one session (“green light”). The small sample sizes, however, limited the ability to detect differences by initial clearance status.This pragmatic clinical trial had several strengths, including the randomized controlled design, the use of an empirically-supported intervention, and the evaluation of outcomes beyond weight loss or regain. Weight-loss surgery can convey a wide range of benefits beyond weight reduction and requires lifelong behavioral changes for lasting success. Psychosocial interventions such as the program evaluated in the present study emphasize an approach to care that encompassed the “whole” patient.This study has several limitations. First, this was a pilot trial and therefore we were underpowered to detect differences between groups and were limited to presenting effect sizes only. Future studies should include larger samples in more diverse cohorts. Second, our cohort was predominantly White, limiting generalizability of our findings to patients of other races. Timing of enrollment in the study postoperatively varied, which may have influenced the rate of weight loss as well as the degree of psychosocial and quality of life changes. More patients dropped out of the intervention arm than usual care, and intervention participants missed 1–2 sessions on average, which likely relate to the greater burden of time and travel required for participation. Subsequent studies could more comprehensively assess the reasons for missed sessions or attrition; specifically, whether participant burden or dissatisfaction with intervention content related to reductions in engagement. Additionally, most study outcomes were self-reported, which can be subject to bias. The self-report measures selected were chosen to best capture the intent of the intervention, the wide variety in postoperative clinical recommendations of weight-loss surgery programs across the country, and the iterative nature of postoperative clinical guidelines. Subsequent studies could utilize food diaries or standardized 24-hour recalls to obtain greater specificity on dietary adherence. Participants were not blinded to condition and gains may relate to attention given the intervention group had more frequent interaction with the Health System. Finally, study findings were limited by feasibility-related challenges, including reaching expected participation targets, as well as the differential attrition rates in the intervention versus usual care group and the brief intervention period (four months). Reasons cited for treatment refusal or early withdrawal were distance to the Health Center and competing time commitments. Future studies could assess the efficacy and feasibility of minimizing patient burden by delivering behavioral interventions via telephone or online, as was done by ProjectHELP  and KalaIn conclusion, this behavioral intervention resulted in promising potential psychosocial and behavioral benefits for weight-loss surgery patients, particularly in the domains of postoperative lifestyle adherence and HRQL. However, the feasibility of administering postoperative behavioral programs remains unclear. While most weight-loss surgery patients experience improvements in mood and quality of life postoperatively , the potS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.