Evidence from the literature keeps highlighting the impact of mutualistic bacterial communities of the gut microbiota on human health. The gut microbita is a complex ecosystem of symbiotic bacteria which contributes to mammalian host biology by processing, otherwise, indigestible nutrients, supplying essential metabolites, and contributing to modulate its immune system. Advances in sequencing technologies have enabled structural analysis of the human gut microbiota and allowed detection of changes in gut bacterial composition in several common diseases, including cardiometabolic disorders. Biological signals sent by the gut microbiota to the host, including microbial metabolites and pro-inflammatory molecules, mediate microbiome–host genome cross-talk. This rapidly expanding line of research can identify disease-causing and disease-predictive microbial metabolite biomarkers, which can be translated into novel biodiagnostic tests, dietary supplements, and nutritional interventions for personalized therapeutic developments in common diseases. Here, we review results from the most significant studies dealing with the association of products from the gut microbial metabolism with cardiometabolic disorders. We underline the importance of these postbiotic biomarkers in the diagnosis and treatment of human disorders. The human gut microbiota is a complex system of mutualistic microorganisms, hosting an impressive 100 trillion bacteria from 500 to 1000 species representing 1–3% of body mass and encoding for over 4M genes . It funcThe gut microbiota is the central regulator of mammalian fuel intake by processing nutrients into absorbable compounds. It also produces vitamins and essential metabolites that are not synthesised by the host. Changes in the architecture of the gut microbiota are likely to have important repercussion on the regulation of host biochemical pathways and metabolic networks. Many bacterial metabolite end-products of the gut microbiota play crucial roles in the host metabolic homeostasis, immunological processes, and neurobiology, and underline the fundamental importance of this extended genome in human health and disease –15. ThisShort-chain fatty acids (SCFAs) are produced by anaerobic gut bacteria in the caecum and the proximal colon principally through the fermentation of dietary fibers , and to a lesser extent of proteins and peptides . The mosSCFAs have multiple regulatory roles in energy homeostasis, insulin sensitivity, and glucose and lipid metabolism . AssociaExperiments in animal models have confirmed the associations of SCFAs with host metabolism and diseases. Glucose tolerance and insulin sensitivity are significantly improved in rats treated with diet enriched in butyrate or propionate . Diet suData in humans and in experimental models also demonstrated that elevated SCFA can contribute to lowering blood pressure and improving vascular phenotypes. Results from two independent meta-analyses of randomized-controlled trials suggested that increased SCFA induced by probiotics or dietary fiber intake was associated with a reduction in blood pressure in patients with hypertension , 35. MorThe cellular mediators of the effects of SCFAs are partly elucidated. Signaling of SCFAs is mediated by the G protein-coupled receptors GPR41 (FFAR3) and GPR43 (FFAR2), predominantly expressed in adipose tissue, intestine, and immune cells , as welll-carnitine, lecithin, choline, and betaine by microbial enzymes  in the liver predominantly by the enzyme flavin-containing monooxygenase 3 (FMO3) [Results from extensive studies of the metabolism of choline and methylamines in humans and rodent models are, perhaps, the most compelling illustrations played by the role of gut bacterial metabolites in cardiometabolic diseases. Trimethylamine (TMA) is an amine synthesised from dietary components, mes Fig. . TMA is 3 (FMO3) . We have3 (FMO3) .Fig. 2Rel-carnitine treatment in ApoE knock-out mice expressing the cholesteryl-ester transfer protein (CEPT) resulted in a reduction of aortic lesions regardless of plasma lipid and lipoprotein levels, and did not alter the formation of macrophage foam cell [Relationships between TMAO and cardiovascular risk are based on correlative inferences. The multiple detrimental roles of TMAO on human health are still debated –50 and toam cell . The inioam cell . Evidencoam cell . Fat-fed2+ and stimulation of inositol-1,4,5-triphosphate signaling [Subsequent investigations in humans mostly focused on the endpoint of the methylamine pathway (TMAO), which is synthesised by the mammalian metabolism, rather than on its substrate (TMA) synthesised by the gut microbiome. Elevated plasma levels of TMAO have been associated with increased risk of type 2 diabetes mellitus , cardiovignaling .Most recently, a study in HFD-fed mice showed that urinary TMAO prior to the dietary challenge is the most significant predictive marker of future heterogeneity in physiological and behavioral anomalies . Variabll-carnitine, betaine, γ-butyrobetaine, and TMAO) and the wide variety of food sources  that contain TMA or substrates that the gut microbiota can use for TMA biosynthesis, perhaps, prevent systematic nutritional recommendations based on the results obtained until now on methylamines.Despite growing interest in TMAO biology, its cellular ligands remain unknown. Identification of cellular ligands of TMAO is the next milestone to demonstrate causality with diseases. In contrast, a specific ligand for its precursor TMA has been identified . FollowiPrevotella copri provided the evidence of functional relationships between changes in the composition of the gut microbiome and these metabolites, as well as potentially indolelactic acid, in insulin-resistant patients [The branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, are among the nine essential amino acids synthesised by gut bacteria . They arpatients . The dirpatients  and corrpatients  have beepatients , non-obepatients , and nonpatients , 73, 74 patients . Similarpatients  and non-patients , in femapatients , and in patients . Urinarypatients .The impact of BCAAs on cardiometabolic phenotypes has been further explored in rodent models and in humans. Addition of BCAAs to HFD in rats reduced the increase in body growth normally caused by HFD, independently from any to significant changes in insulin resistance, which was associated with increased activity of mTOR and JNK . ConversEvidence for a causal role of BCAAs in human diabetes was suggested in longitudinal and genetic studies. 12-year follow-up and prospective studies in normoglycemic individuals demonstrated that BCAAs individually and in combination predict future development of type 2 diabetes, suggesting that BCAAs may actually assist the identification of individuals at risk of developing the disease . Most reBile acids are steroid molecules produced in the liver from cholesterol and, subsequently, processed into secondary bile acids by the gut microbiota. Knowledge of the relationship between gut microbiota and bile acid homeostasis stems from experiments in germ-free mice , in animPolyphenols are plant metabolites formed by hydroxylated phenolic rings. Fermentation of dietary polyphenols (mainly hydroxycinnamic acids and flavonoids) by the gut microbiota results in the production of small bioactive compounds consisting of phenolic acids, which can be absorbed by the gut. Products of plant polyphenols have been identified experimentally through systems of in vitro fermentation by human colonic microbiota , 99 and Many intestinal bacteria are able to generate phenolic compounds and indoles from dietary amino acids , 103. 4-The role of indole derivatives in cardiovascular and metabolic diseases is emerging from studies in humans. Indole is a signaling molecule produced exclusively by bacterial tryptophanases from the essential amino acid tryptophan supplied in the diet . IndoxylBenzoic acid is an aromatic carboxylic acid synthesised in the gut through fermentation by colonic microbiota of dietary aromatic compounds, including aromatic amino acids present in plants . It is ufa/fa) strain mutant for the leptin receptor gene when compared to lean controls heterozygous for the fa mutation [Biosynthesis and excretion of hippuric acid, the product of benzoic acid degradation, have been reviewed in detail . The impmutation . This obmutation  when commutation . Evidencmutation .Fermentation of dietary fibers by the gut microbiota can produce other metabolites than SCFAs that are also synthesised by the host. The organic acid succinate is an intermediate in the synthesis of propionate by gut bacteria and also an abundant product of microbial metabolism which is used as a substrate for intestinal gluconeogenesis . A metabThe gut microbiome sits at the interface between the host, nutritional, and inflammatory environments, and there is growing evidence of a role of bacterial metabolites as biomarkers of pathophysiological features of cardiometabolic diseases, with applications in disease diagnostics and prognosis in precision medicine. Application of high-density metabolite profiling systems is now essential to broaden the spectrum of microbial metabolites simultaneously detected in biological samples, particularly in biofluids , which can be collected in large populations with minimally invasive methods, as well as in extracts from organ biopsies. Regardless of the biological matrix  and the technology used (nuclear magnetic resonance spectroscopy and mass spectrometry), metabolomics generates high-resolution spectra for hundreds to thousands of metabolite signals , 124, anMapping the genetic control of microbial metabolites to the human genome is an important perspective, which will improve our understanding of transgenomic regulations  and infeTherapeutic applications of microbial metabolites require full characterisation of their cellular receptors and the underlying signaling pathways, which are in many cases unknown. Finally, potential therapeutic solutions of this research lie in the identification of bacterial ecosystems able to synthesise metabolites that play a beneficial role in the host metabolism, for their inoculation in patients.


The use of fiber reinforced polymer (FRP) composites for the rehabilitation of buildings or other infrastructure is increasingly becoming an effective and popular solution, being able to overcome some of the drawbacks experienced with traditional interventions and/or traditional materials. The knowledge of long-term performance and of durability behavior of FRP, in terms of their degradation/aging causes and mechanisms taking place in common as well as in harsh environmental conditions, still represents a critical issue for a safe and advantageous implementation of such advanced materials. The research of new and better performing materials in such fields is somewhat limited by practical and economical constrains and, as a matter of fact, is confined to an academic argument. Fiber reinforced polymers (FRP) are already used in the rehabilitation/strengthening of built infrastructure realized in concrete and masonry, although the lack of fundamental information on their long-term behavior if exposed to different, possibly severe, environments somewhat limits wider implementation of such systems .Their success is due to a variety of different properties, such as high specific strength and specific stiffness, high durability against corrosion, lower weight, ease of installation, and reduced manufacture time. All these latter properties make FRP preferred to traditional construction materials, such as steel and concrete. Furthermore, a wide choice of materials (polymeric resins and fibers) is commercially available: different structures/components can be created from their combination, with tailored anisotropy and geometry able to satisfy the project requirements. Nevertheless, there are several aspects of this relatively new technology that still need further research and development, particularly concerning their durability.Existing data on the durability of FRPs employed in this specific field are still not organically collected and rationalized. Discrepancies between results obtained by different durability studies have been even observed and possibly attributed to different materials, processing, or conditioning conditions employed (for instance: different times elapsed before the execution of durability tests), being all fundamental information for a complete understanding of the effects of the external environment on properties of materials and for an accurate prediction of their behavior over their lifetime. This uncertainty hampers the enormous potential of composites in the rehabilitation of constructions, since the acceptable lifetime of products employed in this field should be in the order of one hundred years .There is a need to find reasonable tools not only for the prediction of change in the properties of these materials with time when hardened  in different but realistic thermo-hygrometric conditions, but also for the determination of the remaining service-life of a structure working in widely variable service conditions. Furthermore, implementation of materials, i.e., the development of long-lasting matrices/adhesives for FRP, is compulsory. For both issues, although the efforts of research are rather active worldwide, no conclusive solutions have been identified yet.The performance and durability of FRPs employed in rehabilitation of civil infrastructure mainly depend on the choice of constituent materials to manufacture the FRP, on the process used to manufacture and to apply the composite, on the load regime, and on the type/level of the environmental exposure. FRP composites for such applications are typically composed of continuous fibers  embedded in a thermosetting resin matrix  that holds together the fibers and transfers the load between them. A thermosetting resin (the same composing the matrix of FRP or a different one) is also employed to act as adhesive between the FRP and the (concrete/masonry) substrate. The chemical nature of the matrix/adhesive for the composite as well as the conditions used to set and harden it will have a decisive influence on the performance and behavior of the FRP and on the effectiveness of the whole intervention.The behavior and integrity of an element reinforced by FRP depend not only on the properties of the individual materials, but also on the performance of the FRP–adhesive and adhesive–substrate interface bonds. Therefore, the reliability of the rehabilitation intervention using externally bonded FRP materials depends to a large extent on the bond between the reinforcement and the substrate and, therefore, on the ability to transfer the stresses at the interface. As an example, experimental tests have proved that composite materials bonded to historic brick joints lose their capacity by brittle delamination failure  Figure .FRP can be applied following two different procedures: (a) the precured FRP prepregs are adhesively bonded as prefabricated elements to the concrete (or masonry) substrate; (b) the composite is applied through a “wet lay-up” of fabrics directly onto the substrate.In the first case, the application of prefabricated (often pultruded) laminates ensures the use of precured materials, produced in factories through industrially controlled processes, thus achieving a high level of uniformity in the final product that will display high properties. On the negative side, prefabricated FRP elements are less flexible and are not adaptable for unpredicted configurations that can be found in field applications . Moreover, the application of a precured FRP element to a concrete/masonry substrate is carried out by means of a thermosetting adhesive applied and hardened on site. This, therefore, implies the introduction of an adhesive interphase between the already cured FRP and the substrate .The use of the wet lay-up technique  provideIn both the described techniques, the weakest link is represented by cold-cured thermosetting resins, often epoxy, used as adhesive in the first case and as matrix/adhesive in the second. While the resin is responsible for the overall integrity of the rehabilitated structure, since it must assure an effective stress transfer among the structure and the FRP reinforcement, it can undergo both chemical and physical degradation by environmental actions and mechanical stresses.Interactions can take place between polymer adhesives and concrete substrates , affectiThe properties and durability of the FRP–substrate bond can be enhanced by surface modification through mechanical treatments ,8 or funAmong the polymers employed in this field, epoxy resins are without a doubt the most used due to their excellent properties. They can be formulated into low viscosity systems which “cure”  at room temperature with a minimal shrinkage; when correctly formulated and cured, they exhibit a good combination of mechanical properties and chemical resistance towards environmental agents; compared to other resins, cured epoxy systems are known to have excellent adhesion to a broad range of substrates and reinforcing materials. For the strengthening/repairing applications through FRPs, epoxies are frequently preferred to both vinyl ester and unsaturated polyester resins, both characterized by an excessive shrinkage during curing, with the possible formation of micro-cracks or micro-gels, resulting in micro inhomogeneity and incomplete polymerization . UnsaturThe polymerization (curing) reactions of an epoxy (part A of the system), giving rise to a rigid network-type structure, occurs in the presence of a suitable curing agent  and is favored by heat/radiations, depending on the ingredients (Part A and B) and on the curing mechanism. In particular, the kind and amount of the hardener are selected on the basis of the resin and on the available curing conditions and have both an appreciable influence on the final performance of the cured epoxy.For economic and practical reasons, the resins used as matrix and/or adhesive for FRP components employed for the rehabilitation of constructions are “cold-cured” types, typically based on bis-phenolic epoxies, cured at ambient temperatures on site with the addition of aliphatic amines . Unlike gT), in practice never greater than 65–70 °C, is attainable by these systems, particularly if the curing of the resin occurs at low winter temperatures [gT of the resin, with consequent negative effects on mechanical and adhesive properties [The main consequences of a cure at ambient (often not-constant and uncontrolled) temperatures of epoxy adhesives are: (i) long curing times (in the order of weeks) are necessary to achieve sufficient mechanical properties, the lower the curing temperature, the longer the curing time; (ii) the curing (cross-linking) reactions taking place at ambient temperatures are often not completed due to kinetic restraints; (iii) a moderate glass transition temperature  is likely to be reduced. Furthermore, the exposure to moderate temperatures (above the gT) of not fully cross-linked thermoset polymers can promote their post-cure. The post-cure is usually reflected in increment of gT, strength, and stiffness of the resin [gT values never exceeding 75 °C are generally found for an epoxy/aliphatic amine couple, even if the cross-linking of the resin has been completed through a post-cure procedure [When the he resin ,24,25. Hrocedure . These sReferring to the fibers, carbon is the most commonly fiber used in FRP systems for rehabilitation applications where exposure to aggressive environments is expected. Carbon fibers are, in fact, considered to be inert to most environments that can be found in civil infrastructure applications. The less expansive glass fibers, on the other hand, are more susceptible to harsh environments, especially moisture/alkaline ones, the latter producing loss in toughness, strength, and embrittlement. Nevertheless, the durability of glass fibers upon exposure to typical outdoor applications is still satisfactory, especially if they are suitably protected against harsh agents by tailored sizing coatings, also acting as a bond-enhancement. The durability of glass fiber reinforced polymers (GFRP) can be even improved by using hybrid glass-carbon fabrics.Other parameters have a crucial influence on the behavior of the FRP-rehabilitated structures, i.e., the number of composite plies, the direction and disposition of fibers in each ply, and their weave pattern. The configuration of FRP components, in fact, must be properly designed taking into account the complex system of forces to which the structure rehabilitated with the FRPs will be subjected over its lifetime.The environmental conditions to which FRPs for rehabilitation of structures are more frequently exposed during their service life are neither constant nor predictable and depend on several parameters, such as: the latitude and the altitude of the site, the season, the distance from sea, and the local weather. Environmental factors can severely affect the performance in service of each element composing the FRP and of the whole FRP, even after a short time from its installation, due to specific processes, either reversible or permanent, taking place between the external agents and the materials composing the FRP. In particular, the role of the matrix/adhesive on the behavior of the FRP system is crucial. Due to the peculiarities of cold-cured epoxy resins, in fact, the environmental conditions most frequently encountered in civil infrastructures may severely affect the performance of wet lay-up type FRP and, more generally, the integrity of FRP-to-FRP and FRP-to-substrate bonds.The service conditions characteristic of the common outdoor applications include atmospheric humidity, rain, solar (UV) radiations, large variations in temperature, freeze-thaw regimes, acid rain, sea-water, deicing chemicals, alkaline environment when in the proximity of Portland cement concrete, and sustained loads. Polymer composites can be also accidentally exposed to extreme environments, such as fire, earthquake, and explosive blasts.gT of the resin and a marked decrease of load-bearing capacity, due to plasticization effects [The presence of humidity in the air, either in the form of moisture or actual water through rain, is probably the most harmful environment that can be encountered by matrices and adhesives employed in FRPs for civil engineering applications. Epoxy resins are able to absorb substantial amounts of water due to the presence of polar groups able to attract water molecules. The ingress of moisture over time is particularly significant if the polymer is permanently immersed in water, or salt or alkaline solutions, or if it is exposed to deicing salt solutions. An excessive penetration of water is generally considered harmful since it leads to a reduction in stiffness  and strength of the resin, with a consequent remarkable reduction of the  effects ,15,16,26gT of the resin, a dramatic decrease (up to 70%) of the  properties of the cold-cured resin occurs: approaching the gT, the behavior of the resin drastically changes from that of a solid adhesive, able to effectively bond two different materials, to that of a soft material, unable to guarantee the stress transfer between the same materials. Even a moderate service temperature, therefore, is able to appreciably reduce the adhesion strength to concrete, i.e., by over 80% at 50 °C, as well as the fatigue resistance [gT; even if the air temperature measured in Mediterranean areas usually does not exceed 40–45 °C even in summer, the temperature of a surface irradiated by sun can be appreciably higher, i.e., even greater than the gT of the matrix/adhesive resin.When the service temperature approaches the sistance . As the sistance ; this trsistance . The serThe detrimental effects of water or moisture and of moderate temperatures on the performance of a cold-cured epoxy resin are also reproduced on its behavior as an adhesive . It was However, satisfactory durability properties of the adhesive/composite do not guarantee proper FRP-to-concrete bond durability . The bongT, attention must be given to the site temperature: the (maximum) environmental temperature under working conditions should be at least 20 °C below the expected glass transition temperature of the resin [As a general conclusion, when using the cold-cured resins, due to their moderate he resin .Referring to the influence of water/moisture on the performance of FRP, apart from the kind of matrix resin and fibers used (carbon vs. glass), it mainly depends on the configuration of fabrics and on the direction of application of the load. In the case of in-plane tensile tests performed on unidirectional single ply wet lay-up FRP, for instance, only a negligible influence from the presence of water was found . On the Severe degradation in FRP properties occurs upon exposure to freeze-thaw regimes due to the stiffening and embrittlement of the matrix, with possible formation of micro-cracks. Fiber-matrix debonding and a local loss of adhesion strength towards substrate may take place due to the difference in coefficients of thermal expansion. Reductions in tensile strength and interlaminar fracture toughness are generally observed after repeated freeze-thaw cycles . The losResearches devoted to investigation of the effects of long-term and field exposure on FRPs are still limited ,42,43 anApart from the degradation of bond performance, as in the previously discussed case of exposure to elevated temperatures, polymer composites display a huge vulnerability against fire since resins are organic materials mainly composed of carbon and hydrogen, both highly flammable. The performance and behavior of a repaired concrete beam under fire depend also on the type of cracks, repaired using epoxy, and on the extent of repair . In addiIn order to reduce the fire hazards in FRP, therefore, it is recommended to: (i) provide thermal protection for structures on site; (ii) to introduce flame retardant agents  into the resin formulations; (iii) or to apply a protective intumescent coating on the surface of the manufactured composite .Although fillers like aluminum or magnesium hydroxides are among the cheapest and most effective fire-retardant agents, they significantly deteriorate the mechanical and electrical properties and the rheology of the pristine resin. Halogen additives, on the other hand, are among the most effective agents for reducing the rate of heat release of phenolic, epoxy, or bismaleimide resins; however, a high loading of such additives is often required, with associated cost, processability, and property penalties.When phosphorous-based flame retardants are purely blended with epoxy resins, they, not being chemically bonded to the network, can migrate toward the surface of components before cross-linking, reducing the glass transition temperature of the cured resin by acting as plasticizer . On the 2 [2O3 [2 [The use of nano-structured polymers as matrix/adhesive for FRP is expected to become a realistic alternative to traditional polymeric products in the civil engineering field due to their superior properties and greater durability against moisture, temperatures, hash environments, and fire. Nano-structured polymers are typically produced as nano-composites, based on preformed nano-sized inorganic particles .gT values are found [Nanoparticles can be used to improve the mechanical properties of the matrix, which comprises both resin and nano-sized filler . The prere found ,56,72,73The main difficulty experienced in the production of such nanocomposites is the non-uniform dispersion of the nanofiller into the resin matrix . MechaniAnother widely practiced way, especially to improve impact properties of the composite and reduce the crack propagation , is the gT [Besides improved mechanical, thermal, and electrical properties, changes in resistance to the damage  and lessTg ,59. HighTg  (Figure Tg .The nanoparticles in FRPs are also able to increase the resistance under fire conditions ,84,85,86More recently, plant-based fibers and recycled materials have been studied as both fibers and fillers for reinforced composites ,92,93,94gT and the elastic modulus in the rubbery region of the resin as well as at improving their performance under different environmental regimes, irrespective of the curing conditions [The efforts of academic and industrial research in this field must be mainly devoted to the development of more durable thermosetting matrix/adhesive resins at affordable costs, also able to achieve a stable thermodynamic state after short curing times in different thermo-hygrometric conditions, with a consequent improvement in the long-term performance of FRPs. The formulation strategy of these systems, then, must be aimed at increasing the nditions .At the present time, however, the production processes of such nano-structured polymers are still too complicated and expensive to be conveniently applied in the construction industry.gT values, lower curing times, and less durability concerns than those commercially available at the present time. Despite the described drawbacks, these resins still represent a viable solution to assemble and/or to apply FRP repairing elements. These latter, in turn, display several advantages over traditional materials in terms of high strength-to-weight and stiffness-to-weight ratios, great versatility, shorter times for the interventions, and, consequently, of activities interruption, with a consequent reduction of the overall costs. Maintenance operations are also cut when polymer composites are applied in substitution of traditional construction materials. The collaboration between experts possessing different scientific background and expertise is, therefore, greatly encouraged for a stronger, deeper comprehension of durability phenomena and a faster successful identification of practicable solutions.Due to the heavy concerns about the durability of FRP materials intended for rehabilitation of constructions, in common as well as in harsh environments, research should be forced to the development of new epoxy resins still able to set and cure at ordinary temperatures and humidity levels but displaying much greater


Endocannabinoids are a group of endogenous lipid mediators that act as ligands of cannabinoid and vanilloid receptors, activating multiple signal transduction pathways. Together with enzymes responsible for their synthesis and degradation, these compounds constitute the endocannabinoid system (ECS), which is involved in different physiological processes in reproduction. The placenta, which is essential for the success of gestation and optimal fetal growth, undergoes constant tissue remodeling. ECS members are expressed in trophoblast cells, and current evidence suggests that this system is involved in placental development, apoptosis, and syncytialization. Impairment of endocannabinoid signaling has been associated with several pathological conditions such as intrauterine growth restriction and preeclampsia. Both clinical entities are characterized by dysregulation on vascular perfusion where nitrergic system performs a pivotal role. Nitric oxide (NO) is a potent local vasodepressor that exerts a critical role in the regulation of hemodynamic flow, contributing to the maintenance of low vascular resistance in the feto-placental circulation. NO production could be affected by different factors and growing evidence suggests that the endocannabinoid mediators may regulate nitrergic signaling. Herein, we review emerging knowledge supporting ECS-mediated regulation of NO production in normal placentation. Finally, we discuss how alterations in these systems could affect homoeostasis and contribute to the occurrence of placental-mediated pregnancy complications. Given the impact on women and perinatal heath, we will focus on current knowledge regarding the effects of ECS on nitrergic system in normal and pathological placentation. The placenta is a specialized transient organ essential for embryo growth and survival. In order to supply the metabolic demands of the developing fetus, this tissue performs numerous physiological functions such as gas exchange and efficient nutrient transfer. These events are crucial for the correct development of the feto-placental unit.The placenta is an organ devoid of nerves; hence communication between mother and fetus takes place through blood-borne as well as locally produced substances. The syncytiotrophoblast (STB) is the main structural and functional epithelial layer that produces a variety of hormones such as human chorionic gonadotropin (hCG), placental lactogen, estrogen, progesterone, aldosterone, cortisol, placental growth hormone, among others. It can also release a large number of growth factors, cytokines, chemokines, and vasoactive compounds that synchronize placental blood flow, which is of outmost importance during gestation for fetal development .Successful pregnancy is coordinated by a complex interplay of maternal, placental, and fetal endocrine signals. Inadequate migration of trophoblast cells and deficient remodeling of uterine spiral arterial walls lead to a reduction of placental blood flow and cause placental ischemia/hypoxia. In this context, vasoactive factors such as inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors (HIFs), and anti-angiogenic factors are the major modulators of the systemic vascular endotheliosis. Both abnormalities in placental formation and function are often associated with human pregnancy complications such as intrauterine growth restriction (IUGR) and preeclampsia (PE).PE is one of the leading causes of maternal and perinatal morbidity and mortality. In fact, it is the first direct cause of maternal death in Latin America . This coEndothelial dysfunction is one of the earliest manifestations of PE. To date, the pathogenesis of PE is complex and not well-understood, but it is accepted that an inappropriate remodeling of spiral uterine arteries leads to restricted supply of oxygen and nutrients to the placenta . VasculaFurthermore, a number of reports also showed differences in the expression and activity of endothelial NO Synthase (eNOS) between normal and unhealthy pregnancies. .Distribution and activity of eNOS are regulated by different mechanisms. Trafficking between caveolar and non-caveolar compartments, protein–protein interaction, and phosphorylation are involved in the modulation and/or release of NO . TherefoThe ECS is expressed in human placenta  and prevHerein, we discuss evidence that supports the role of these endogenous bioactive lipids in the regulation of NO signaling in healthy and pathological pregnancies.Throughout gestation significant circulatory adaptations occur that includes an increase in maternal blood volume and vasodilatation to maintain the fetal demands of oxygen and nutrients. Maternal uterine vascular remodeling is essential for normal fetal growth and NO plays a crucial role in this process .Over the course of gestation the action of NO seems to support a low vascular resistance in the feto-placental circulation , maintaiNitric oxide is a potent gaseous mediator produced in different organs, including placenta .During the third trimester, the growing fetus significantly enhances the metabolic demands on the placenta. Changes in vascular resistance allow the placenta to support fetal development and wellbeing. In this remodeling of placental blood-flow, both maternal and conceptus eNOS increase uterine arterial blood flow in normal pregnancy , and attNitric Oxide acts in multiple pathways. It diffuses into vascular smooth muscle cells, attaches to the receptor soluble guanylyl cyclase (sGC), and catalyzes the formation of cyclic guanosinemonophosphate (cGMP), resulting in vasodilation. Simultaneously, NO prevents the production and action of both endothelium-derived contracting factors and endothelin-1, thus reducing the vasoconstrictor effect. Additionally, NO inhibits platelet aggregation and adherence to endothelial surfaces .L-citrulline are produced from L-arginine through a reaction catalyzed by a family of calcium-calmodulin-dependent enzymes called NO synthases (NOS): Three major NOS isoforms have been identified: neuronal (nNOS or NOS1), inducible, (iNOS or NOS2), and endothelial (eNOS or NOS3). The nNOS and eNOS isoforms are frequently expressed constitutively and their activities are regulated by calcium availability. On the other hand, iNOS is independent of the intracellular calcium concentration and generates a high flow of NO. The tree isoforms of NOS employ flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) as cofactors of the isozymes  and placental growth factor (PlGF). Both induce arterial vasodilation by increasing the endothelial calcium signaling, resulting in the release of endothelial NO. Additionally, endothelial shear stress produced by flowing blood stimulates endothelial NO release through a number of pathways, which involve opening of cation channels like TRPV1, TRPV4, among others . ProteinEndocannabinoids are an emerging group of lipid-signaling molecules that include amides, esters and ethers of long-chain polyunsaturated fatty acids.N-acyltransferase (NAT) and N-acylphospha tidylethanolamine-phospholipase D (NAPE-PLD) in the pathway of Anandamide  synthesis; and phospholipase C (PLC) and diacylglycerol lipases (DAGL) in the case of 2-arachidonoylglycerol (2-AG).Endocannabinoids are produced on demand by cleavage of membrane phospholipids mainly through two-step reaction catalyzed by Both lipid mediators (AEA and 2-AG) are the main endogenous ligands of the cannabinoid receptors (CB1 and CB2) . These rThe action of AEA and 2-AG cease by enzymatic hydrolysis mediated by fatty acid amide hydrolase (FAAH)  and monoIn addition, there are other enzymes that constitute alternative biosynthetic and degradative pathways for this lipid mediators .Altogether, these enzymes and proteins involved in the production and signaling of endocannabinoids, along with these lipid ligands, constitute a complex system called ECS.In the last years, enzymes that participate in AEA and 2-AG synthesis and release have been identified in human placenta , but untThe identification of the different components of the ECS in the placenta promoted the study of ECs in relevant physiological processes such as proliferation, differentiation, apoptosis, and proteins biosynthesis, as well as in the transport of nutrients, oxygen, electrolytes, and other substances to the fetus. The results observed in these studies were extensively reviewed by In addition to the effects of ECs, phytocannabinoids such as delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, may affect the dynamics of placental development . In factA similar mechanism seems to occur when high levels of endocannabinoids are detected during pregnancy. According to this, reports have shown that high plasma levels of AEA seriously interfere in the progression of pregnancy . In agreOther works have described alterations of several components of the ECS in normal and pathological human placentas. It is worth to note the discrepancy in the results observed by different research groups on the altered expression of the ECS components, even when the same type of samples was analyzed. Such differences could be attributed to ethnicity, severity of the disease and/or differences in methodological procedures . These disagreements must be analyzed and requires further elucidation.Our understanding on the interaction between the ECS and nitrergic system has been enriched by several studies that demonstrated a strong influence of ECS on NO production. This regulation is mediated by endocannabinoids like AEA or 2-AG which exert stimulatory or inhibitory effects depending on tissue context, cell type, and/or activation of specific receptors . Also, previous reports have provided evidence that a bidirectional modulation exists between the ECS and NO, and this crosstalk is extremely important since alterations in one or both systems would impact on cellular homeostasis or could trigger a pathological condition. A comprehensive review of these interactions is well described in Regulation of NO production by the ECS was demonstrated in different biological systems such as neurohypophysis , retina The ECS regulates the homeostasis through a wide variety of mechanisms. It facilitates the intracellular communication between different cell types and contributes to maintaining the balance in the body. The placental abnormal expression of the ECS has been associated which serious pregnancy complication such as spontaneous miscarriage  and pretAdditionally, it was demonstrated that uterine deregulation of the ECS increases the levels of prostaglandins contributing to the mechanism by which infection causes preterm birth . In thisEndocannabinoids have also been implicated in blood pressure regulation . These lIn rat placenta, a report from our laboratory demonstrates that AEA exerts a dual effect on NO production depending on which receptor is activated. While activation of TRPV-1 receptor stimulates NO production, the action of AEA on CBs decreases NOS activity, suggesting that AEA acts as a differential fine-tuning regulator of NO during pregnancy .In fact, although AEA activates TRPV-1, the concentration required is higher than that needed for CB1 activation . On the In pathological conditions like PE, a higher basal NOS activity was observed in comparison to healthy normal samples. This observation, together with the altered expression pattern of the ECS metabolic enzymes, could result in higher AEA levels, which positively stimulate NOS activity and NO production  Figure . AdditioAltogether, the results discussed in this review indicate that either the activation or the inhibition of the ECS can alter the production of NO, leading to beneficial or prejudicial biological responses depending on the cell type. Because the ECS and NO signaling are involved in the modulation of relevant aspects of placental physiology such as vasodilatation and placental blood flow, it is crucial for the tissues to keep their levels acutely regulated. Thus, it is expected that a crosstalk between these systems may contribute to the maintenance of the tissue homeostasis.Given the relevance of the nitrergic signaling and the ECS in the development of placenta, this review may contribute to identify novel targets for the treatment of placental diseases such as PE.In order to understand the functionality of the placenta, we must take into account the complexity of the events that occur in this organ. In this review we have focused and discussed about the importance of ECS and NO in the physiological behavior of normal and pathological placentas. The ECS acts as a regulator of nitrergic system, modulating NO levels. Since NO is the main vasodilator in human placenta implicated in modulation of blood flow, alterations in this mediator may modify placental functions and can be associated to pathological conditions of pregnancy like PE. Herein we summarize recent experimental findings that support the importance of a crosstalk between AEA and NO and the contribution of CB1 signaling in placental development in normal and pathological conditions of pregnancy. Altogether this evidence proposes the ECS as a part of a relevant mechanism of the placenta and may serve as a possible pharmacological target given the relevance of this system in the regulation of NO and, consequently, in placental vascular dysfunction.CA and MF have proposed the topic of this revision and designed the figures. All authors have contributed to information recrutment and write the present version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Behavioral science has a long and strong tradition of rigorous experimental and applied methodologies, which have produced several influential and far-reaching theoretical frameworks and have guided countless inquiries of human behavior in various contexts. In cancer care, behavioral scientists have established a firm foundation of research focused on understanding the experience of cancer and using that understanding to design and implement theory- and evidenced-based interventions to help patients cope with the cancer experience. Given the rich behavioral research base in oncology, behavioral scientists are ideally positioned to lead the integration of evidence-based science on behavior and behavior change into the development of smartphone apps supporting patients with cancer. Smartphone apps are being disseminated to patients with cancer with claims of being able to help them negotiate areas of vulnerability in their cancer experience. However, the vast majority of these apps are developed without the rigor and expertise of behavioral scientists.In this article, we have illustrated the importance of behavioral science leading the development and evaluation of apps to support patients with cancer by providing an illustrative scientific process that our team of behavioral scientists, patient stakeholders, medical oncologists, and software developers used to empirically design and evaluate 2 patient-focused apps: the Discussion of Cost App (DISCO App) and MyPatientPal.Using a focused literature review and a descriptive roadmap of our team’s process for designing and evaluating patient-focused behavioral apps for patients with cancer, we have demonstrated how behavioral scientists are integral to the development of empirically sound apps to help support patients with cancer. Specifically, we have illustrated the process by which our multidisciplinary team combined the established user-centered design principles and behavioral science theory and scientific rigor to design and evaluate 2 patient-focused apps.On the basis of initial acceptability and feasibility testing among patients and providers, our team has demonstrated how critical behavioral science is for designing and evaluating app-based interventions for patients with cancer.Behavioral science can and should be coupled with user-centered design principles to provide theoretical guidance and the rigor of the scientific method, thereby adding the much-needed and critical evidence for these types of app-based interventions for patients with cancer. Behavioral scientists seek to understand the interpersonal and contextual motivations, and the limitations and parameters of those motivations, of human behavior. Guided by evidence-based theories and models, behavioral scientists apply the rigor of the scientific method to important areas of human behavior inquiry. For example, behavioral scientists have articulated, tested, and adapted several major theoretical frameworks  [The ossComm)  is a patossComm) -41. The ossComm) ,42 and fossComm) ,42. The ossComm) ,42.The DISCO App advances traditional QPLs in 3 ways. First, it provides patients with a short educational video about treatment costs, about ways to manage those costs, and showing that discussing costs with their oncologist is an important first step. Second, it focuses on specific cost concerns (an emerging problem for many patients with cancer) previously shown to be important to patients with cancer . Third, MyPatientPal (built by CrossComm) is a patient app that is designed to help patients track and manage treatment side effects and medication adherence on a daily basis. The side effects of treatment  can be physically and emotionally debilitating and, when uncontrolled, can cause treatment complications, resulting in unscheduled care costs, patient’s out-of-pocket costs, and delays or discontinuation of treatment. Research shows that patient-reported outcomes (PROs), and in particular daily reporting of PROs, can help to identify significant changes in treatment-related side effects as well as quickly identify new and emerging side effects. On the basis of theories of self-management and self-efficacy [efficacy -45, dailefficacy ) that thbuild) to use in feasibility and effectiveness testing in a clinic setting.In addition to being theoretically guided, both the DISCO App and MyPatientPal were developed using an iterative design-test-redesign process ,48 in coIn summary, smartphone apps are being disseminated to patients with cancer with claims of being able to help them negotiate areas of vulnerability in their cancer experience. However, the vast majority of these apps are developed without the rigor and expertise of behavioral scientists.To be sure, many apps benefit from user-centered design principles, which attend to how users interact with products and ensure they meet user needs. In contrast, behavioral scientists bring an important understanding of the psychological processes underlying the content and how the product can be used to effect behavior change, whether it is focused in health behaviors such as diet and exercise or self-management of diseases such as cancer. Thus, behavioral science has the potential to complement and even significantly augment user-centered design principles by providing theoretical guidance and the rigor of the scientific method, thereby adding the currently lacking but much needed empirical support for these types of apps.Thus, we argue that future apps designed to help patients with cancer should be built by a multidisciplinary team of experts including physicians, survivors, software developers, university technology transfer units, and behavioral scientists, who bring critical theoretical and evidence-based knowledge. This multidisciplinary approach means that app-based interventions will be user-friendly, evidence-based, and theoretically sound, and as such, more likely to be effective sources of support for patients with cancer through the myriad of issues and obstacles they will likely face. Furthermore, this type of team approach can lead to the development of patient-centered apps that meet the needs of stakeholders and improve the experience of cancer diagnosis, treatment, and survivorship for a diverse population of patients.


Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our knowledge of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully elucidated. While initial brain insult involves acute and irreversible primary damage to the parenchyma, the ensuing secondary brain injuries often progress slowly over months to years, hence providing a window for therapeutic interventions. To date, hallmark events during delayed secondary CNS damage include Wallerian degeneration of axons, mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of neurons and glia. Extensive research has been directed to the identification of druggable targets associated with these processes. Furthermore, tremendous effort has been put forth to improve the bioavailability of therapeutics to CNS by devising strategies for efficient, specific and controlled delivery of bioactive agents to cellular targets. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by an update on novel therapeutic targets and agents. Recent development of various approaches of drug delivery to the CNS is also discussed. Traumatic brain injury (TBI) has been one of the leading causes of morbidity, disability and mortality across all ages  closed head; (ii) penetrating; and (iii) explosive blast TBI. Clinical features of TBI include prolonged coma, headache, nausea, aphasia, seizures, amnesia and behavioral abnormalities such as aggression and anxiety, which occur within seconds to minutes after TBI; however, some of these manifestations can persist up to months and years  primary injury, which is directly caused by mechanical forces during the initial insult; and (ii) secondary injury, which refers to further tissue and cellular damages following primary insult.The immediate impact of different mechanical insults to the brain can cause two types of primary injuries: focal and diffuse brain injuries. Studies have demonstrated that the co-existence of both types of injuries is common in patients who suffered from moderate to severe TBI , which aids in the production of NO. The reaction between excessive NO and free radical superoxides results in the formation of peroxynitrite (PN), which induces oxidative damage and can be measured by detecting oxidative markers such as 3-nitrotyrosine (3-NT) and 4-hydroxynonenal , oligodendrocyte myelin glycoprotein (OMgp) and Nogo-A  polymerase-1 and endonuclease G , a non-competitive NMDA receptor antagonist, has been shown to attenuate NMDA receptor-mediated neurotoxicity in neuronal cultures  was found to reduce trauma-induced calcium accumulation by 50–70% in the ipsilateral regions as early as 6 h post-trauma  belongs to type 1 cytokine superfamily. The expression of both EPO and EPO receptor is significantly upregulated in TBI, which plays an important role in neuroprotection though the exact mechanisms remain elusive , brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are capable of determining the post-traumatic fate of neuronal and glial cells. Administration of these growth factors following TBI can improve neurological outcome  on surface, which interacts with the highly upregulated intracellular adhesion molecule 1 (ICAM-1) on endothelial cells of BBB in inflamed brain. Intravenous administration of macrophage exosomes pre-loaded with BDNF has been shown to successfully deliver the protein to the brain  for internalization of the cargo  factor, penetratin, membrane translocating sequences, transportan and Pep-1 , which are capable of traversing biological membranes and act as cellular delivery vehicles (Koren and Torchilin, Research in traumatic injuries in the CNS has significantly expanded our understanding of the underlying pathophysiology and molecular mechanisms. While primary injuries in TBI are largely irreversible, the ensuing secondary damages that develop and progress over months to years are amenable to therapeutical interventions. Since this delayed phase of injury involves a plethora of events, which include excitotoxicity, apoptotic cell death, inhibition of axonal regeneration, neuroinflammation and oxidative stress, the devise of efficacious therapeutic strategies will need to target multiple mechanisms over an extended period. The availability of depot systems for regulated and sustained delivery of therapeutic agents that are capable of entering cells by permeating the plasma membrane will apparently allow further improvement of the bioavailability of existing drugs. More importantly, it will offer the opportunity to explore the therapeutic potential of novel agents against druggable targets. In fact, this therapeutic approach has been applied in the treatment of many neurodegenerative disorders such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease (Popovic and Brundin, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The role of insulin in the brain has been suggested in the late 1950's based on experiments showing that insulin was able to increase glucose uptake in spinal cord tissue, in several brain regions such as the choroid plexus the pineal gland, and in the pituitary  consumption increases hippocampus inflammation associated with the impairment of memory and spatial learning in mice . This group has previously shown that gestational diabetes mellitus (GDM) affects human fetus brain activity measured by magnetoencephalography (fMEG)  . Thus, fy (fMEG) . Thus, tFerreira et al. discuss the mechanisms relating diabetes, obesity, and dementia, focusing on peripheral disturbances related to diabetes and obesity that may trigger AD-like pathology. Based on the purported commonality of pathogenic mechanisms in peripheral and central insulin resistance, a new hallmark of the AD brain, they comment on the potential use of anti-diabetic drugs for AD, emphasizing ongoing intranasal insulin clinical trials. In the second mini-review, Benomar and Taouis describe molecular mechanisms underlying hypothalamus inflammation and insulin resistance. They focus on a new signaling pathway implicating resistin and its receptor TLR-4. Indeed, resistin, an adipokine, has been identified as a potential link between obesity and insulin resistance. The overview presented by these authors report that hypothalamic resistin/TLR-4 signaling is a key signaling pathway implicated in the onset of hypothalamic inflammation and insulin resistance in response to inappropriate diet such as HFD.Finally, the two mini-reviews of this topic cover two aspects associated to the alteration of brain insulin signaling: Alzheimer's disease and mechanisms of diet-induced hypothalamic inflammation. In summary, the articles presented in the Research Topic “Insulin and the Brain” provide a valuable source of information concerning the role of insulin in different brain areas associated to various vital physiological functions.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Herb-herb combinations have been used in Chinese medicine practice for thousands of years, yet scientific evidence of their therapeutic benefits is lacking. With increasing interest in shifting from the one-drug-one-target paradigm to combination therapy or polypharmacy to achieve therapeutic benefits for a number of diseases, there is momentum to explore new knowledge by tapping the past empirical experiences of herb-herb combinations. This review presents an overview of the traditional concept and practice of herb-herb combination in Chinese medicine, and highlights the available scientific and clinical evidence to support the combined use of herbs. It is hoped that such information would provide a lead for developing new approaches for future therapeutic advancement and pharmaceutical product development. Very likely modern technologies combined with innovative research for the quality control of herbal products, identification of active components and understanding of the molecular mechanism, followed by well-designed animal and clinical studies would pave the way in advancing the wealth of empirical knowledge from herb-herb combination to new therapeutic modalities. Yellow Emperor’s Canon of Internal Medicine (HuangdiNeijing) more than 2,000 years ago [Herbal products are of interest to many patients and health care practitioners since about 70% of population worldwide rely on herbal medicines for part of their primary health care . In diffears ago .Currently, combination therapies are employed for the treatment of critical diseases, such as cancer, acquired immunodeficiency syndrome (AIDS) and pulmonary tuberculosis, in order to achieve enhanced therapeutic effects. The modern approach of combination therapy is a renewal of what was advocated in Chinese medicine that started thousands of years ago on the use of herb-herb combination for improvement of therapeutic outcome. Can the past experience of Chinese medicine provide new clue to identifying potential effective combinations for certain conditions that cannot be adequately treated by modern medicine? How can we best tap the wealth of past empirical experience to enhance future therapeutic advancement? Since very little has been written on the subject of herb-herb combination/interaction, we surveyed both English and Chinese literature from databases such as MEDLINE, EMBASE, the Traditional Chinese Medical Database system , and theyin and yang and the interrelationship among the “five elements (wu-xing)” within the body [zang- and fu-organs), and the use of medicaments or other means such as acupuncture and physical manipulation can restore such imbalance so as to re-establish a state of equilibrium (homeostasis).The concept and practice of Chinese medicine is derived from the accumulation of empirical evidence and subsequent deduction to form a series of theories, many of which were borrowed from philosophical thoughts such as the balance between the body ,14,15,16fu-fang). When medications are prescribed, the principles of interactions among the herbs must be taken into consideration by the clinicians so as to compose an optimal prescription for therapeutic benefits. The concept of herb-herb interaction, based on the notions of positive (complementation) or negative (antagonism) outcomes, was therefore developed. Early in the history of use of medicinal agents, it was realized that the presence of one herb may alter the effect of the other when they are co-administered. The combined effect, either complementary or antagonistic, would be manifested in the clinical outcome. Take for example the Decoction of Ephedra (Mahuang Tang), which contains ephedra, cinnamon twig, bitter apricot seed, and licorice root. The prescription is used not only for its diaphoretic effect, but also for the relief of coughing and asthma, as well as reducing headaches and general aching during common cold [Accompanying the above theories of disease, a system of Chinese herbology was also developed to guide the selection of medicaments for the treatment of diseases ,15,16,17mon cold . All of Shengmai San) is another example of herbal combination. The formula consists of ginseng root, Ophiopogon (dwarf lily turf) root, and Schisandra (magnolia vine) fruit. Altogether, they are indicated for the deficiency syndrome of qi, yin, and body fluid, as manifested by profuse sweating, dryness of the mouth, shortness of breath, thirst, and faint pulse [qi, nourish the yin, and promote the production of body fluid. It is “pulse-activating” because it can be used for emergency treatment of severe cases of qi and yin deficiency when the pulses become very weak. More often, the concoction is prescribed to restore qi and yin in patients suffering from chronic diseases. In this formula, ginseng root serves to strengthen qi, dwarf lily turf replenishes yin, whereas magnolia fruit takes up the roles of consolidating qi and yin, and arresting sweating. The traditional usage of the Shengmai formula has led to intensive studies of its cardiovascular pharmacology; and evidence is now emerging to indicate potential clinical applications in the treatment of cardiac diseases such as intradialytic hypotension [The Pulse-Activating Powder  and Curcuma phaeocaulis (er-zhu) in the ancient formula Yanhusuo San, which is useful for improving blood circulation, alleviating blood stasis, and relieving pain. The action of Corydalis rhizome is to promote qi movement in the body so as to reinforce the blood circulation effect of Curcuma phaeocaulis. Another reinforcement pair, honeysuckle (Lonicera japonica) flower and Forsythiasuspense fruit, is often prescribed together to eliminate heat and wind, as well as the toxic components from the body, for the treatment of common cold or influenza. From a modern pharmacological point of view, reinforcement can probably be interpreted to include either an additive effect  or synergistic effect . A similar concept in modern medicine is the use of “cocktail” in antiretroviral therapy (HAART) [Reinforcement refers to situations in which herbs possessing similar medicinal properties are used together to produce a greater efficacy. Taking the Decoction of Ephedra as an example, ephedra and cinnamon twig form a pair of diaphoretic agents; the adrenergic (sweating) effect of the former is strengthened by the latter through an increase of peripheral blood flow. As a result, the febrifugal effect is enhanced. Another example of mutual reinforcement is the combination of the rhizomes of  (HAART) . The usuAconitum carmichaelii) daughter root in an anti-shock remedy, the Decoction of Ginseng and Aconite (Shenfu Tang). In the formula, ginseng is the principal component to strengthen the primary-qi  in order to resuscitate, whereas aconite helps to “warm” the body and raise the yang energy. Working together, they are able to replenish both inborn and postnatal (acquired) essence  in the body and to restore vital physiological functions particularly during the emergency condition of collapse and shock [Paeonialactiflora) and licorice  for the treatment of pain . A recent study in a rat neuropathic pain model has demonstrated the synergistic effect of a combination of paeony glycosides and licorice flavonoids in the ratio of 3:1 [Potentiation refers to situations when two herbs are used in the same prescription, in which one of them serves as the principal herb and the other an adjunct or auxiliary herb. The role of the auxiliary herb is to help strengthen the effect of the principal herb. An example is the combination of ginseng root and aconite , severe infection , and cardiovascular abnormality (cardiotonic and anti-arrhythmic agents) [Tripterygium wilfordii (lei-gong-teng), a toxic plant traditionally used for “dispelling wind”, “removing dampness”, and reliving pain, has now shown promising clinical potential for the treatment of rheumatoid arthritis and other immune diseases [Pinelliaternata) tuber. Pinellia tuber is considered a toxic herb that would cause severe mucosal irritation and inflammation in the throat and the gastrointestinal tract. Calcium oxalate and agglutinin have been suggested to be the toxic principles causing inflammatory responses [2 contents in the inflammatory foot tissue of mice after injection of pinellia [In Chinese medicine, many herbs are considered to possess toxic properties. The concept of toxicity refers to different degrees of adverse or undesirable effects, but not necessarily fatality. Therefore the use of so-called “toxic herbs,”  agents) . For exadiseases . Two of diseases ,31,32,33esponses ,35,36,37pinellia . While tqi), but when used in the presence of turnip, its qi-tonifying effect would be greatly reduced or even eliminated. Interestingly, such counteraction has been observed in a recent study which found turnip juice capable of abolishing the genoprotective effect of ginseng [Counteraction refers to situations in which the therapeutic effect of an herb is diminished by another herb. This can be interpreted as an antagonistic interaction, although in traditional Chinese medicine, the concept of physical, chemical, dispositional, or receptor antagonism is lacking. A well-known example of counteraction is the interaction between turnip root/seed and ginseng root. Ginseng is often used as a tonic drug to elevate the vital energy  [Veratrumnigrum root [Another herb-herb interaction leading to unfavorable outcome is the situation where combination would result in toxic or severe adverse effects, caments” . While t CYP2E1) ,41,42,43rum root . FurtherIn Chinese medicine practice, a special concept of herb-herb interaction is utilized when multi-item prescriptions are formulated. Although each individual herb included in a prescription is indicated for certain symptom(s), when multiple herbs are administered together, the mixture is more than a random group of herbs. Rather, they work in unison through mutual interaction resembling different roles of the government official hierarchy, with each herb figuratively designated as either “emperor”, “minister”, “assistant”, or “servant” . The folThe “Emperor” Herb: In ancient Chinese government structure, the emperor is the most important and authoritative figure at the top of hierarchy. An analogy for the emperor herb in a multi-item prescription is its designated role to handle the main course of disease or deal with major symptoms. An emperor herb is sometimes translated as the King or Monarch. Take the Decoction of Ephedra as an example for treating common cold , ephedra plays the leading role as an emperor to induce perspiration, relieve coughs, and smooth the flow of qi. Its pharmacological effects can be attributed to ephedrine and related alkaloids, which possess adrenalin-like and sympathomimetic properties. The “Minister” Herb: The minister herb serves two roles -it is either an adjunct to the emperor herb to reinforce and support, and/or it is used to deal with certain minor symptoms of the disease. In the Decoction of Ephedra, the cinnamon twig takes up the role of a minister. This herb is thought to have the ability to “warm the channel”so as to dispel excessive “coldness” from the body, and expel “evils” (the pathogenic factors) from the muscles and skin so as to relieve common cold symptoms. Pharmacological studies have revealed that cinnamon twigs can increase sweating by dilating peripheral blood vessels and ease pains in the limbs during common cold.The “Assistant” Herb: Assistant herb, also known as the Clerical, Adjuvant, or Auxiliary herb, may play three roles. First, it can help to optimize the therapeutic effects of the emperor and minister. Second, it can be used to diminish or counteract the toxicity caused by the emperor or minister, thereby reducing the undesirable effects of the entire prescription and tempering the drastic action of the principal herbs. Third, it can serve to maintain a balance such as the warm-cold effect. While the assistant herb plays a relatively minor role itself, it is an essential component in a multi-herb concoction. To cite the example of the Decoction of Ephedra, apricot seed acts as the assistant, helping to ventilate the lungs and stopping cough during common cold. The “Servant” Herb: The servant herb, sometimes referred to as the Convoy, Dispatcher, Guide, or Emissary drug, is perceived to play the role of a guide or courier so as to direct the essence of the entire prescription to the target organ/tissue or meridian. It may also serve as a harmonizer or moderator to “bind” the formula together. Licorice root plays the role of a servant in the Decoction of Ephedra to regulate the overall medicinal property of the prescription. From a modern pharmacological point of view, interactions among herbs in a multi-item prescription can occur either pharmacokinetically or pharmacodynamically. Furthermore, Chinese medicine often provides multi-target  treatment with individual components affecting different symptoms and at different target organs. Such a multi-target interaction is consistent with the modern concept of polypharmacy.In summary, the concept and practice of herb-herb combination has been recognized in Chinese medicine for thousands of years. The rationale of the multi-item prescription appears to be contrived when judging from scientific perspective, but their empirical effects are obvious. While the exact pharmacological mechanisms are not clearly understood, pharmacokinetic, pharmacodynamic, and/or polyvalent effects are likely involved.Despite the wealth of experience with multi-herb prescription in Chinese medicine practice, scientific efforts to understand herb-herb interaction or proof of clinical benefit of many such combinations have been slow and weak. One reason may be due to the immense undertaking and high cost involved in conducting clinical trials on herbal products. The most important reason, perhaps, is because the medical and pharmaceutical communities have adopted the concept and philosophy of the “silver bullet” approach of therapy , and druin vitro and animal models as well as clinical observations were highlighted [etc.; (2) Pharmacokinetic or physiochemical effects based on improved solubility, resorption rate, and enhanced bioavailability; (3) Antagonistic interactions with resistance mechanisms of pathogenic microorganisms; and (4) Elimination or neutralization of adverse effects caused by other substances present in the mixture.With increasing acceptance of combination therapy for the treatment of diseases such as cancer, AIDS and others ,47,48, shlighted . Such inhlighted . Accordihlighted . Four me(1)More potent antispastical effect was observed from cannabis extract (containing equimolar tetrahydrocannabinol content) than from tetrahydrocannabinol alone, suggesting involvement of other chemical ingredients present in the plant extract ;(2)Paeonia root and total flavonoids of Glycyrrhiza root on neuropathic pain was demonstrated in rats using isobolographic analysis [Synergistic interaction between total glycosides of analysis ;(3)Angelica sinensis extract than the corresponding mixture of three main phthalide constituents, n-butylidenephthalide, senkyunolide A, and z-ligustilide, suggesting some other ingredients were involved in enhancing the efficacy of the crude extract [Significantly higher anti-proliferative effect in HT-29 and CCD-18Co cell lines was found from  extract ;(4)Rhodiolarosea  was observed than from each individual component when evaluated in a forced swimming rat model [More potent antidepressant activity from a combination of the active ingredients of at model ;(5)Corydalis yanhuosuo and Curcuma phaeocaulis at a ratio of 3:2 exhibited the strongest anti-proliferative effect on the MDA-MB-231 human breast cancer cell line [A combination of the rhizomes of ell line ;(6)Astragalusmembranaceus and Rehmanniaglutinosa (in 2:1 ratio) significantly reduced the wound area of rats in a foot ulcer animal model, whereas no wound-healing effect was observed when individual herb was applied to the wound [A combination of the roots of he wound ;(7)Citrus aurantium and Magnolia officinalis, suggesting that herb-herb interaction may have led to a better bioavailability of the active ingredient [The oral bioavailability of geniposide in rats was dramatically enhanced in the presence of gredient ;(8)Artemisia tea, the active ingredient artemisinin was found to be more rapidly absorbed than when it was given in the form of pure compound [When administered in the form of compound .Further examples of scientific studies demonstrating synergistic effects include:Piper methysticum); after an intervening wash-out period of two weeks, the trial continued with valerian  for six weeks. After another two-week washout, the patients further received a combination of kava-kava and valerian for six weeks. The trial showed that the combination treatment during the last six weeks significantly improved sleep. In another example, Scholey and Kennedy conducted a double-blind, placebo-controlled study on the performance of healthy adults following single dose of Ginkgo biloba or ginseng, as well as their combination using a computerized test of serial subtraction tasks  [Besides the above pharmacological studies, at least two clinical studies demonstrating the therapeutic benefits of herb-herb combination are available. Wheatley reported positive results of an herbal combination in a small-scale, open, cross-over trial in patients suffering from stress-induced insomnia . The pat Seven”) . SpecifiIn summary, in the last decade or so, an encouraging number of scientific and clinical studies have begun to provide preliminary understanding and evidence of enhanced efficacy of herb-herb combination.The wealth of knowledge from empirical use of herb-herb combination according to Chinese medicine concepts described above has not been systematically explored to benefit modern pharmacotherapy. Since only limited scientific and clinical studies have been carried out so far, a great potential exists to probe the potential therapeutic benefit from the herb-herb combinations used in Chinese medicine practice. For reaping such benefit, we believe that improving future herbal research in the following areas is essential.One of the fundamental requirements for medicinal products is quality assurance/control (QA/QC), without which scientific and clinical studies would be greatly hampered and less likely to yield valid results. At present the QA/QC of herbal products are inadequate. The current approaches to standardize herbal preparations include botanical verification, chromatographic profiling of chemical components, as well as quantification of selected marker components  . DNA finin vivo validation [A recent proposed method of quality control for botanical formulation is the technique of PhytomicsQC, which integrates the use of liquid chromatography/mass spectrometry (LC/MS) for chemical characterization and chemical fingerprinting, differential cellular gene expression for bioresponse fingerprinting, and animal pharmacology for lidation . Procedulidation . The explidation . Such teIn Chinese medicine practice, while many multi-item prescriptions have been used clinically for thousands of years, their exact pharmacological actions remain unclear and should be determined in order to validate and better understand the empirical observations. However, the routine pharmacological protocols are likely to be inadequate to demonstrate the unique composite effect of herb-herb combination. The use of systems biology and the “omic” technologies may provide a new approach to evaluate the synergistic effects of phytopharmaceuticals ,69,70,71Indigo naturalis, and Salvia miltiorrhiza for treating promyelocytic leukemia was rationalized by a systems biology approach [Salvia), were combined and tested for in vivo and in vitro activities. The mixture was found to yield synergy in the treatment of leukemia in mice and in the induction of promyelocytic leukemia cell differentiation both in vivo and in vitro. There was also involvement of a number of cell cycle modulators, oncoproteins, and cell differentiation regulators in a concerted manner.Combination of molecular, cellular and analytical techniques may be utilized to explore and better describe the effects of multi-item prescriptions. For example, the design of a Chinese medicinal formula containing realgar, approach . In thisThere is also a need to analyze large volumes of research data generated from the evaluation of multi-component herbs and synergistic effects ,75,76. Ai.e., with sufficient power). Unfortunately, such rigorous clinical studies are seldom performed due to high cost and other reasons. Small clinical studies are less costly but often yield negative or equivocal results, since the QC, mechanisms, and dose response are seldom considered in designing such studies. In the future, studies with questionable quality, small sample size, low level of evidence, and/or methodological weakness, all of which can lead to unreliable and inconclusive outcomes, should be avoided [Once the components and mechanism of a given herb-herb-combination are identified, a quality product can then be prepared for testing the therapeutic effect of the product. The therapeutic effect must be carefully evaluated by a well-designed, randomized, double-blinded, placebo-controlled clinical trial involving a significant number of subjects ( avoided ,80,81,82Despite vast experience from empirical use of herb-herb combination in Chinese medicine practice over two thousand years, well documented beneficial outcomes are lacking, and the six basic modes of Chinese medicine theory of interaction have not been adequately proven or confirmed by modern scientific studies. Nevertheless, the huge experience accumulated from clinical observations of herb-herb combination may provide a lead for future exploration of new therapeutic benefits and product development. Innovative research for better quality control of herbs, identification of active components, and understanding of the molecular mechanism, followed by well-designed animal and clinical studies will be needed to harness such benefits.


The importance of classifying cancer patients into high- or low-risk groups has led many research teams, from the biomedical and bioinformatics fields, to study the application of machine learning (ML) algorithms. The International Society of Geriatric Oncology recommends the use of the comprehensive geriatric assessment (CGA), a multidisciplinary tool to evaluate health domains, for the follow-up of elderly cancer patients. However, no applications of ML have been proposed using CGA to classify elderly cancer patients.The aim of this study was to propose and develop predictive models, using ML and CGA, to estimate the risk of early death in elderly cancer patients.The ability of ML algorithms to predict early mortality in a cohort involving 608 elderly cancer patients was evaluated. The CGA was conducted during admission by a multidisciplinary team and included the following questionnaires: mini-mental state examination (MMSE), geriatric depression scale-short form, international physical activity questionnaire-short form, timed up and go, Katz index of independence in activities of daily living, Charlson comorbidity index, Karnofsky performance scale (KPS), polypharmacy, and mini nutritional assessment-short form (MNA-SF). The 10-fold cross-validation algorithm was used to evaluate all possible combinations of these questionnaires to estimate the risk of early death, considered when occurring within 6 months of diagnosis, in a variety of ML classifiers, including Naive Bayes (NB), decision tree algorithm J48 (J48), and multilayer perceptron (MLP). On each fold of evaluation, tiebreaking is handled by choosing the smallest set of questionnaires.It was possible to select CGA questionnaire subsets with high predictive capacity for early death, which were either statistically similar (NB) or higher (J48 and MLP) when compared with the use of all questionnaires investigated. These results show that CGA questionnaire selection can improve accuracy rates and decrease the time spent to evaluate elderly cancer patients.A simplified predictive model aiming to estimate the risk of early death in elderly cancer patients is proposed herein, minimally composed by the MNA-SF and KPS. We strongly recommend that these questionnaires be incorporated into regular geriatric assessment of older patients with cancer. Aging is a complex and personal, cumulative, and irreversible phenomenon that goes well beyond chronological age . It invoThe International Society of Geriatric Oncology has recommended the use of the Comprehensive Geriatric Assessment (CGA) for the evaluation and follow-up of elderly cancer patients . The CGAThe accurate prediction of a disease outcome is one of the most interesting and challenging tasks for physicians. As a result, a growing trend was noted in the studies published during the past years that applied machine learning (ML) algorithms for modeling cancer survival. This type of algorithms can discover and identify patterns and relationships between them, from complex databases, while they are able to effectively predict future outcomes of a cancer type . On the A study combining data from 4 cohorts involving the elderly, 1 including elderly people with neoplasms, proposed to explore the performance of various ML classifiers  regarding death prediction in 6 months . AnotherThus, the primary aim of this study was to propose and develop predictive models, using ML and CGA, to estimate the risk of early death in elderly cancer patients. The secondary aims were to optimize the CGA through the selection of the most appropriate instruments.The ability of ML techniques to predict early mortality in a heterogeneous cohort was tested in 608 elderly cancer patients (aged over 60 years), admitted to the oncogeriatrics sector of the Instituto de Medicina Integral Prof. Fernando Figueira - IMIP, from January 2015 to July 2016. The IMIP is a teaching hospital and cancer center located in Recife, Pernambuco, Brazil. On admission to the cohort database, the patients were evaluated by CGA questionnaires presented in v′ is the value normalized, v is the original value, minv is the minimum value of corresponding feature, and maxv is the maximum value of corresponding feature: v’=(v−vmin)/(vmax−vmin).The first step was to remove patients presenting redundancies and/or incomplete questionnaires/features. A total of 543 patients remained after that. Data normalization technique for equalizing the range of features, usually employed in the database before feature selection and learning phase, is of important concern in pattern recognition and computer-aided diagnosis . The mosPredictive modeling is the general concept of building a model that can make predictions. Typically, such a model includes an ML algorithm that learns certain properties from a database to make those predictions. We have presented below a brief summary of the commonly used supervised learning algorithms:Decision tree J48 (J48) : They arMultilayer perceptron (MLP) : They arNaïve Bayes (NB) : They arThe purpose of this work was not to introduce the highest accuracy prediction model. The goal was to designate the most relevant questionnaires to evaluate elderly health condition domains in CGA. Therefore, in the experiments, we always used the same configuration with the default parameter values in Weka  from The University of Waikato, version 3.8.3. The advantage of using default parameters is that it does not introduce optimistic bias by tuning the parameter to maximize performance on the test data. Cross-validation (CV)  is one oThe learning procedure and the subsequent prediction of predictive models can be affected by the problem of imbalanced database . The balThe area under receiver operating characteristics curve, or simply area under curve (AUC), has recently been proposed as an alternative single-number measure for evaluating the generalization of learning algorithms . This meSensitivity is the true positive rate, and for this study, it is the percentage of patients with early death that are predicted correctly.Specificity is also called the true negative rate, for example, the percentage of patients without early death that are predicted correctly.Feature selection is an important and frequently used technique for dimension reduction by removing irrelevant and/or redundant information from the database to obtain an optimal feature subset. A 10-fold CV was used to evaluate all possible combinations of CGA questionnaires, presented in t test, the P value is calculated considering the subset of questionnaires with occurrence ≥0. The experimental results demonstrate that the feature selection can discard questionnaires and finally find out subsets that reduce the dimensionality of data to make the predictive models more efficient and the results more accurate. Thus, a simplified predictive model aiming to estimate the risk of early death in elderly cancer patients is proposed herein, minimally composed by the Mini Nutritional Assessment-Short Form (MNA-SF), accompanied or not by the Karnofsky performance scale (KPS) and/or the Mini-Mental State Examination.Results indicate that the MNA-SF has greater predictive power to estimate the risk of early death in elderly cancer patients as it was selected on the 10-folds. MNA-SF is a rapid test validated for screening for nutritional risk and malnutrition in the elderly population. The predictive value of MNA-SF for early death may be related to the fact that the 6 MNA-SF questions cover areas other than just nutrition, which are frequently included in the CGA, such as mobility, neuropsychological disorders, and self-reported health, in addition to nutrition aspects, including weight loss, reduced food intake, and body mass index. In fact, low MNA-SF may reveal the effects of advanced disease in the overall health of patients, which also affects cancer-related mortality. A Brazilian study showed that abnormal nutritional status was an independent factor associated with hospital death among older patients with various chronic diseases, including cancer . A similThe results also indicated that KPS questionnaire has proven itself a valuable tool to estimate the risk of early death in elderly cancer patients. In the past decades, various studies have demonstrated the prognostic value of the KPS not only primarily for various cancers -40 but aThe efforts of this paper are a starting point. They provide solid evidences and some clinical recommendations. We proposed and developed simple ML models for the prediction of early death in elderly cancer patients. These models are accurate and precise and could be possibly used by clinicians to make proper treatment plans. However, additional research is needed to continue to strengthen the evidence base.The results showed that the MNA-SF and KPS have the highest predictive power to identify elderly patients at risk for early death. We strongly recommend that these questionnaires be incorporated into regular geriatric assessment of older patients with cancer.The MNA-SF and the KPS requires only a few minutes to be completed. In addition, both can be easily managed by any member of the multidisciplinary team to help in the early identification of patients at risk, providing information that assists in the planning of interventions and improving the adherence to CGA in daily clinical oncology practice.This study also has limitations that should be considered. This is a nonrandomized, single-center, exploratory study of a heterogeneous patient population similar to a real-life population of older patients with cancer. Conversely, some of its weaknesses could be considered the main strengths of the study: this is one of the few studies in Brazil that, in the clinical practice context of a Unified Health System oncology unit, investigated the use of ML algorithms in the prediction of early death in elderly cancer patients.


Circumcision is one of the most frequently used surgical procedures worldwide. Extensive penile skin defects, which can occur as a rare but severe complication of circumcision, are serious and frustrating problems for patients who experience them. Procedures for correcting these problems can pose a challenge to plastic surgeons in the clinic.A 31-year-old man was admitted to our care with an extensive defect of the penile skin caused by a circumcision performed 20 days previously.Infection, necrosis, and defects of the penile skin.A reverse bilateral anterior scrotal flap was used to correct complete penile skin loss following debridement of the infected and necrotic tissue.The patient experienced no complications during the 10-year follow-up period. The patient reported normal erectile function and the ability to perform intercourse.The reverse bilateral anterior scrotal artery flap is suitable for repairing skin defects of the penis and allows for satisfactory cosmetic and functional improvement following defects of the penile skin. When complications do occur, the majority of them are minor and can be corrected easily. However, on rare occasions, more serious complications can arise, including extensive defects of the penile skin. These defects often require surgical correction, resulting in a significant financial burden on the health care system and risk to the patient. Due to the complexity of the penis, repair and reconstruction present a formidable challenge anatomically, functionally and cosmetically. The aim of penile reconstructive surgery is to improve the cosmetic appearance of the penis to a point that is acceptable for the patient and to restore functionality of the penis, allowing the patient to recover normal erectile function and the ability to perform intercourse. The full-thickness skin graft (FTSG) is a commonly used and effective tool in the management of severe penile skin defects; however, the use of FTSG can lead to contracture of the penile skin and extensive scarring.,6 Few studies in the available literature have reported on the durability and viability of the local flaps used to treat defects of the penile skin. The key to reconstruction is to choose tissue for a flap that has properties similar to the tissue of the repair site to achieve acceptable cosmetic and functional results. A scrotal skin flap, with sufficient blood supply and plenty of nerve endings, could, therefore, provide excellent therapeutic effects when used in cases of penile skin defects. Here, we demonstrate the use of a reliable and effective reconstruction method using a reverse bilateral scrotal flap to repair extensive defects of the penile skin through a one-stage operation.Circumcision is one of the most commonly applied surgical procedures.2A 31-year-old man was admitted to our care presenting with extensive defects of the penile skin Fig. A. The paThe scrotal skin flap tissue survived well. The patient healed without adverse events and was able to have normal intercourse 2 months after the operation. A 2-year follow-up showed favorable aesthetic and functional results Fig. . Excelle3,8 Defects of the entirety of the penile skin, a rare complication of circumcision, can cause severe physiological disorders and psychologic distress.,10 Complete resurfacing of the penile shaft has proved difficult. Penile resurfacing not only requires adequate cosmetic results, but also requires the maintenance or restoration of erectile function, tactile sensibility, and sexual satisfaction. A wide range of medical treatments has been employed to repair defects of the penis. Repair for disorders such as adult-acquired buried penis, where the penis is buried in the scrotum or in the suprapubic region, can be performed, but treatments can cause prolonged aesthetic issues and issues relating to hygiene and sexual function. The results of skin grafting, the most commonly performed penile surgery, can cause trauma during sexual intercourse, and contracture of the graft commonly occurs as a delayed complication.,13 Axial pattern skin flaps, such as the deep inferior epigastric perforator (DIEP) flap, the groin flap, the lower abdominal flap, and the tensor fascia lata flap, all present the problem of giving the penis a bulky appearance. By contrast, the advantages of using the scrotal skin as a flap include its lack of subcutaneous fat, high elasticity, similar thickness to penile skin, and rich blood supply.,16 The use of scrotal flaps for the coverage of extensive penile defects has not been extensively reported. Fakin et al reported that a bipedicled anterior scrotal flap can cover to 65% of the penile shaft during reconstruction of the penile skin. In this case report, we describe the successful reconstruction of the entire penile shaft using a reverse bilateral scrotal anterior flap. Furthermore, local 1-stage reconstruction minimized the number of surgical procedures required to achieve a suitable aesthetic outcome. The Z-suture on the ventral side was scarcely visible and secondary contraction and scarring could be avoided with the use of the Z-suture. No complications were encountered during the 2-year follow-up period. The patient reported normal erectile function and the ability to perform intercourse, which shows the feasibility and effectiveness of this method.Circumcision is one of the most commonly practiced surgeries in history. Nearly 30% of the world's male population aged 15 years or older are circumcised. Anatomical findings and clinical applications have shown that the scrotal flap is thin, versatile, easy to harvest and is generally anatomically consistent between patients. This relatively simple and timesaving procedure is performed in 1 stage; thus, high economic, social, and personal costs are avoided. Moreover, as the scrotal flap contains sensory branches from the ilioinguinal nerve, the use of this tissue appears to contribute markedly to long-term erectile function and sexual satisfaction. Therefore, the advantages of this surgical technique include: the use of easily obtainable tissue from the scrotum, with a similar color, thickness, and texture as the penile skin; the need to perform only a single procedure for full reconstruction; a higher degree of tissue survivability; and the preservation of the sensitivity and function of the penis.The scrotal anterior flap has a dual blood supply. Branches of the external and internal pudendal arteries connect with each other and form the blood supply system of the scrotal wall.4In conclusion, our report suggests that the reverse bilateral anterior scrotal artery flap is suitable for the repair of complete skin defects of the penis and provides substantial benefits to the patient due to satisfactory cosmetic and final functional results. Further studies will be required to confirm the reliability of this method across a larger cohort of patients.Conceptualization: Wenrui QuInvestigation: Qing-Guo GaoMethodology: Wenrui QuWriting – original draft: Qing-Guo GaoWriting – review & editing: Wenrui QuWenrui Qu ORCID: 0000-0002-0178-3698