This review describes the current understanding of the mechanisms by which ginseng alleviates CHD, and provides a reference for the clinical development and application of ginseng as an alternative therapy for CHD.Coronary heart disease (CHD) is the most common clinical manifestation of cardiovascular disease. It is characterized by myocardial ischemia, which is caused by coronary atherosclerosis. CHD is a significant global health problem with increasing prevalence every year because of significant changes in the lifestyles and diets. Ginseng is a traditional Chinese medicinal herb that has been used in food preparations and traditional medicine for several centuries. Several studies have demonstrated that ginseng improved cardiac function by normalizing blood glucose levels and decreasing blood pressure, oxidative stress, platelet aggregation, and lipid dysregulation  Coronary heart disease (CHD) is a cardiovascular disease caused by gradual narrowing of the coronary artery because of plaque buildup or atherosclerosis. Eventually, significant blockage of the vascular lumen causes myocardial ischemia, hypoxia, and necrosis of the cardiomyocytes. CHD is manifested in the form of heart failure, arrhythmia, and sudden death in severe cases . The maiSeveral types of drugs are available for the clinical treatment of CHD. These include statins , aspirinPanax ginseng. The clinical safety of ginseng is higher than several chemically synthesized drugs. Therefore, ginseng is a promising candidate drug for the treatment of CHD.Ginseng is a commonly used Chinese medicinal herb with a variety of pharmacological effects, including management of blood sugar levels and cardiovascular protection by lowering cholesterol levels and blood pressure . In the A search of the literature was performed based on the methodology of the preferred reporting items for systematic review and meta-analysis (PRISMA)  in Web oTo date, more than 200 ginsenoside and non-saponin components have been isolated and characterized from ginseng , includiCoronary heart disease is caused by stenosis or obstruction of the coronary artery. Patients with CHD demonstrate abnormal cardiac function because of myocardial ischemia, hypoxia, and necrosis . MyocardPanax ginseng. They improved myocardial blood supply and pumping action of the heart by significantly increasing myocardial contractility, myocardial vasodilatation, and the myocardial blood flow  injury; it also decreased in vitro H2O2-induced stress in the H9c2 cardiomyocytes  by increasing intracellular cAMP levels in a concentration-dependent manner and subsequently reduced platelet coagulation (Anti-platelet and anti-coagulant drugs reduce the development and progression of cardiovascular diseases by inhibiting the formation of blood clots . Many cagulation .Dyslipidemia is closely related with the pathogenesis of CHD  and is c−/−) mice with ginsenoside Rc through tube feeding significantly reduced the abundance of Bacteroides thicketi and Bacteroides mimosus, thereby partially restoring balance of the intestinal flora and reversing the effects of HFD by altering the bacterial flora composition at the genus level (Several studies have demonstrated that dysregulation of gut microbiota is involved in the development of atherosclerosis and coronary heart diseases . The hosus level .In Asian countries, ginseng has been used in foods and therapeutic supplements for more than 2000 years. A low incidence of toxicity has been observed in human studies in ginseng preparations. However, ginseng is rarely associated with toxic side effects, adverse events, or interactions with prescription drugs . MoreoveCHD is the leading cause of death in most developed and developing countries . ClinicaChinese herbal medicine is a traditional and mild treatment for CHD and has multiple advantages. Firstly, compared with western medicine, treatment with Chinese herbal medicine is milder with fewer side effects. Secondly, treatment with Chinese herbal medicine is multifaceted and involves disease maintenance or alleviation, improvement in the overall health status, and enhanced immunity. Furthermore, Chinese herbal medicine can eliminate cardiac lesions, relieve symptoms, delay disease progression, and effectively prevent recurrence of the disease. Finally, Chinese herbal medicine can treat a variety of diseases, including CHD, hepatitis, diabetes, and hypertension. In conclusion, treatment with Chinese herbal medicine is mild, personalized, and comprehensive, and can prevent disease recurrence and improve the overall health status of the patient . However


The capacity for autonomous functionality serves as the fundamental ability and driving force for the cross-generational upgrading of unmanned aerial vehicles (UAVs). With the disruptive transformation of artificial intelligence technology, autonomous trajectory planning based on intelligent algorithms has emerged as a key technique for enhancing UAVs’ capacity for autonomous behavior, thus holding significant research value. To address the challenges of UAV trajectory planning in complex 3D environments, this paper proposes a multi-UAV cooperative trajectory-planning method based on a Modified Cheetah Optimization (MCO) algorithm. Firstly, a spatiotemporal cooperative trajectory planning model is established, incorporating UAV-cooperative constraints and performance constraints. Evaluation criteria, including fuel consumption, altitude, and threat distribution field cost functions, are introduced. Then, based on its parent Cheetah Optimization (CO) algorithm, the MCO algorithm incorporates a logistic chaotic mapping strategy and an adaptive search agent strategy, thereby improving the home-returning mechanism. Finally, extensive simulation experiments are conducted using a considerably large test dataset containing functions with the following four characteristics: unimodal, multimodal, separable, and inseparable. Meanwhile, a strategy for dimensionality reduction searching is employed to solve the problem of autonomous trajectory planning in real-world scenarios. The results of a conducted simulation demonstrate that the MCO algorithm outperforms several other related algorithms, showcasing smaller trajectory costs, a faster convergence speed, and stabler performance. The proposed algorithm exhibits a certain degree of correctness, effectiveness, and advancement in solving the problem of multi-UAV cooperative trajectory planning. Unmanned aerial vehicles (UAVs) have gained increasing prominence on the battlefield, and enhancing their autonomous combat capabilities in high-threat environments has become a key research focus . UAV traConsiderable research has been conducted in the field of cooperative trajectory planning for UAVs. Presently, the research on trajectory-planning problems for single vehicles is more developed. However, in the execution of cooperative missions involving multiple UCAVs, the complexity of combat tasks often gives rise to various collaborative and performance constraints . To addrBecause of the intricate nature of multi-constraint conditions and diverse task demands in the problem of collaborative path planning and allocation for multi-UCAV combat, researchers frequently employ meta-heuristics, such as Particle Swarm Optimization (PSO) ,15,16, GPredicting Rock-Physics Parameters of Gas-Bearing Reservoirs in the Eastern Mediterranean Sea, Egypt. Vijay et al. [The Cheetah Optimizer (CO)  is a recy et al.  proposed(1)We analyze the cooperative constraints and performance constraints among multiple UCAVs. We establish a comprehensive set of trajectory-cooperative constraints that take into account spatio-temporal coordination, range, speed, angles, flight altitude, and three-dimensional threat distribution. Additionally, we propose evaluation criteria in the form of a cost function to measure the level of satisfaction of multi-type cooperative constraints among UCAV trajectories.(2)Building upon the CO algorithm, we propose the Modified Cheetah Optimization (MCO) algorithm. This algorithm incorporates an adaptive search agent strategy, the Cheetah returning home mechanism, and the Logistic chaotic mapping strategy.(3)The performance of the proposed approach is evaluated through testing with nine shifted CEC2005 functions and fifty test functions that cover single-peaked, multi-peaked, separable, and non-separable characteristics. The MCO algorithm is compared with other algorithms such as CO, PSO, GWO, and FA.(4)We use the MCO algorithm in combination with a dimensionality reduction search strategy to address the problem of autonomous trajectory planning in real-world scenarios.So far, many scholars have proposed the use of various meta-heuristic algorithms to execute the path planning of UCAVs. Xiong et al.  used a pThis paper is outlined as follows. In Multi-UAV collaborative trajectory planning aims to optimize the trajectories of multiple UAVs to achieve collective objectives while considering various constraints and uncertainties. Let each UAV . In thisCollaborative constraints refer to ensuring that the trajectory of each UAV in a formation can successfully complete the mission as required while meeting the individual trajectory constraints .Spatial collaborative constraints, also known as non-collision constraints, require that the distance between any two UAVs at any given time should not be less than the minimum safe flight distance.During the collaborative execution of tasks by multiple UAVs, due to the complexity of the mission, multiple UAVs often need to arrive at their respective targets and perform tasks in a specific order . This paDuring the execution of a mission by a drone, factors such as fuel consumption and task efficiency need to be taken into consideration. Thus, it is essential to establish the maximum range of the drone. Assuming that the maximum range In the constraint of the shortest trajectory segment, the maneuverability of the UAV influences the existence of a minimum straight-line distance before changing its heading. Therefore, this constraint can be expressed as:During the flight process of a UAV, the flight speed needs to be maintained within a certain range. This range should take into account various factors such as local weather conditions, wind speed, the number of restricted flight zones, and more. It is essential to control the speed of the unmanned aircraft within this range.The angle constraint includes two parts: the yaw angle constraint and the pitch angle constraint. The yaw angle constraint refers to the limitation on the turning angle of the UAV during flight between two consecutive waypoints. Similarly, the pitch angle constraint specifies that the vertical angle of the UAV can only vary within a certain range between two consecutive waypoints. The yaw and pitch angles of the UAV are affected by its thrust and maneuverability. If the angles exceed this range, there is a risk of crashing. The UAV angle constraint is as follows:ith waypoint of an individual unmanned aerial vehicle (UAV).In the spatial planning of UAVs, the flight altitude should not be lower than the minimum flight altitude to prevent the risk of crashing into the ground due to excessively low altitude. Additionally, the waypoints of the UAV trajectory should be within the planned airspace. Therefore, the flight altitude should be maintained below the maximum flight altitude. The flight altitude constraint is expressed as follows:In the airspace of unmanned aerial vehicle (UAV) operations, there are often three-dimensional threat distributions, such as radar systems, missiles, and anti-aircraft artillery. During the collaborative mission execution of multiple UAVs, it is crucial to avoid entering these threat areas. The model of three-dimensional threat distribution can be described as:The evaluation of the quality of UAV trajectories is composed of various indicators. The evaluation indicators of the trajectory cost mainly include fuel cost, altitude cost, and threat cost. These cost functions serve as standards for assessing the superiority or inferiority of trajectories. Therefore, the cost function can be defined as:Fuel consumption is one of the important evaluation indicators for mission allocation. The duration of a drone’s flight indirectly reflects the amount of fuel consumed. The expression for calculating the cost of the trajectory length is as follows:When the flight altitude of unmanned aerial vehicles exceeds the designated height range, a height cost is incurred, which can be expressed as follows:Due to the presence of various spatial threats such as radar, missiles, and anti-aircraft artillery in UAV flight space, the cost of threats includes radar, missiles, anti-aircraft artillery, and atmospheric threats. This article defines the threat cost for different threats as follows:The detection probability of radar for unmanned aerial vehicles (UAVs) can be approximately represented asThe detection probability of other threats such as missiles and anti-aircraft artillery for the UAV can be approximately represented asThe expression for the threat cost is as follows:After obtaining the trajectory planning results for multiple UAVs, collision checking is performed on the trajectories. Let Assuming that UAVs maintain a constant speed during the flight process, the temporal collaboration cost can be computed by calculating the time taken for UAVs to reach their respective targets. The expression for the temporal collaboration cost is as follows:The cheetah optimization (CO) algorithm is a novel heuristic intelligent optimization algorithm based on the hunting strategies of cheetahs in nature. By simulating three main hunting strategies commonly used by cheetahs, searching, waiting, and attacking, and introducing a strategy of returning home after leaving the prey during the hunting process, CO aims to solve optimization problems and improve the algorithm’s population diversity, convergence performance, and robustness .One of the main hunting strategies employed by the CO algorithm is the searching strategy. The following equation presents the random search equation that updates the new position of the cheetah based on its current position within each permutation:In the waiting strategy, the cheetah remains stationary and waits for the prey to approach. This behavior can be modeled as follows:The attacking strategy of cheetahs can be defined mathematically as:Due to the limitation of energy, the hunting time of each group of cheetahs is finite. Therefore, if a group fails to succeed within a certain hunting time, the current prey is left behind, and the group returns to its activity range for rest before starting another hunting session. In fact, if the energy of the cheetahs (modeled by hunting time) decreases while the position of the leader remains unchanged, a group of cheetahs will return home. At this point, the position of the leader is also updated. The result of this strategy is to avoid becoming trapped in local optima.The quality of the initial population significantly affects the accuracy and convergence speed of an algorithm, and an initial population with good diversity can greatly improve the performance of the algorithm . HoweverIn After initialization of the population according to Equation (25), it needs to be mapped to the solution space as follows:In each iteration, a subset of individuals participates in the evolution process, which is referred to as the search agent. In the CO algorithm, the number of search agents remains fixed throughout the entire iteration process. When the number of search agents is small, the algorithm is prone to becoming trapped in local optima and has poor global search ability. On the other hand, when the number of search agents is large, the convergence speed of the algorithm becomes slow. To achieve a better balance between the global and local search abilities, this paper proposes a new formula for calculating the number of search agents which decreases non-linearly with iteration count. The specific expression is as follows:During the search process, the CO algorithm utilizes the dual-mirror-reflection theory for boundary optimization . When inThe formula for the dual-mirror-reflection boundary handling approach is as follows: In the later stages of the CO algorithm evolution, the probability of cheetahs leaving their prey and returning to their home increases, and the leader’s position is updated. Therefore, an efficient method of updating the leader’s position is particularly important. In contrast to the random updating method employed in the original algorithm, this study introduces the Cauchy mutation operator  to updatAfter some cheetahs return to their home, the cheetah population will engage in a reverse search in order to locate their prey more quickly. The reverse search strategy  is basedAlgorithm 1: The MCO Algorithm1:Define the problem data, dimension  solution38:endBased on the above considerations, the pseudocode for the MCO algorithm is as follows (Algorithm 1):In establishing a three-dimensional UAV trajectory planning model, if the problem dimension is set too high, intelligent optimization algorithms exhibit instability, especially in complex situations where the algorithms struggle to converge within a reasonable time . TherefoProjecting the start and end points onto the plane The encoding rules are as follows: assuming we have To substantiate the efficacy of the proposed MCO algorithm, we conducted preliminary tests on this method using publicly accessible benchmark functions. Subsequently, we implemented the MCO algorithm to address multi-UCAV trajectory-planning challenges. The experiments were conducted using MATLAB_ R2018a and performed on a computer equipped with a 1.1 GHz dual-core Intel Core i3 processor, 8GB of memory, and an Intel Iris Plus Graphics 1536 MB graphics card. The experiment utilized macOS Big Sur 11.7.6 as the operating system.In this section, we tested nine CEC2005 functions with shifts  and fiftBased on the data presented in The experimental framework for UAV path planning based on the MCO algorithm proposed in this study is illustrated in In this section, the proposed MCO algorithm is evaluated in four distinct scenarios, namely, PSO, GWO, FA, MCO, and CO. Among these algorithms, the parameters of the search agents are as follows: in the CO algorithm, m=2; in the PSO algorithm, c1 = c2 = 2.0, w = 0.9; in FA algorithm, beta0 = 2.0, gamma = 1.0, alpha = 0.2, and alpha damp = 0.98. The starting and target positions of the UAVs, the stereoscopic threat distribution field position and the effective operating distance are presented in The MCO algorithm was employed to perform path planning for UAVs in four different scenarios, with a population size of 50 and a total of 2000 iterations. In Scenario 1, all the UAVs had the same initial positions and corresponding target coordinates. In Scenario 2, all the UAVs had the same initial positions, but their target coordinates were different. In Scenario 3, the initial positions of all the UAVs were diverse, while their target coordinates remained the same. In Scenario 4, both the initial positions and target coordinates of all the UAVs were distinct. The result of multi-drone trajectory cooperative planning based on the multi-objective optimization (MCO) algorithm is shown in To further compare the effectiveness of the four algorithms, namely MCO, CO, PSO, and GWO, they were individually run 50 times in each of the four scenarios. In all cases, the population size was set to 50, and the number of iterations was set to 1000. The convergence comparison curves are shown in This study proposes a new algorithm named MCO that integrates a mixed strategy consisting of three improved techniques for solving the problem of multi-UAV collaborative trajectory planning in a three-dimensional environment. By introducing logistic chaotic mapping, the algorithm improves the initialization of population positions. By employing an adaptive search agent strategy, the algorithm effectively balances global and local search capabilities and utilizes the bidirectional mirror-reflection theory for boundary optimization to effectively address the problem of uneven distribution when handling boundaries. By introducing the Cauchy mutation operator to update leader positions, the diversity of the population was increased, effectively enhancing the algorithm’s ability to escape local optima. The proposed MCO algorithm has been tested on 59 benchmark functions, and we conducted a Friedman test on the result. The experimental results show that the performance of the MCO algorithm is significantly better than that of the other algorithms, showing advantages in terms of optimizing extremum values, means, and stability. Finally, the proposed MCO algorithm was applied to the problem of multi-UAV collaborative trajectory planning along with the CO, PSO, and GWO algorithms. Simulation experiments demonstrated that the MCO achieved more stable application effects and higher-quality planned paths, exhibiting improvements in both speed and stability. In future work, techniques such as crossover operators can be introduced to further enhance the performance of the MCO algorithm. Additionally, consideration can be given to collision risk costs and communication costs under signal denial conditions in relation to the problem of multi-UAV collaborative trajectory planning.


Metal additive manufacturing (AM) is capable of producing complex parts, using a wide range of functional metals that are otherwise very difficult to make and involve multiple manufacturing processes. However, because of the involvement of thermal energy in the fabrication of metallic AM parts, residual stress remains one of the major concerns in metal AM. This residual stress has negative effects on part quality, dimensional accuracy, and part performance. This study aims to carry out a comprehensive review and analysis of different aspects of residual stress, including the causes and mechanisms behind the generation of residual stress during metal AM, the state-of-the-art measurement techniques for measuring residual stress, various factors influencing residual stress, its effect on part quality and performance, and ways of minimizing or overcoming residual stress in metal AM parts. Residual stress formation mechanisms vary, based on the layer-by-layer deposition mechanism of the 3D printing process. For example, the residual stress formation for wire-arc additive manufacturing is different from that of selective laser sintering, direct energy deposition, and powder bed fusion processes. Residual stress formation mechanisms also vary based on the scale  at which the printing is performed. In addition, there are correlations between printing parameters and the formation of residual stress. For example, the printing direction, layer thickness, internal structure, etc., influence both the formation mechanism and quantitative values of residual stress. The major effect residual stress has on the quality of a printed part is in the distortion of the part. In addition, the dimensional accuracy, surface finish, and fatigue performance of printed parts are influenced by residual stress. This review paper provides a qualitative and quantitative analysis of the formation, distribution, and evolution of residual stress for different metal AM processes. This paper also discusses and analyzes both in situ and ex situ measurement techniques for measuring residual stress. Microstructural evolution and its effect on the formation of residual stress are analyzed. Various pre- and post-processing techniques used to countermeasure residual stress are discussed in detail. Finally, this study aims to present both a qualitative and quantitative analysis of the existing data and techniques in the literature related to residual stress, as well as to provide a critical analysis and guidelines for future research directions, to prevent or overcome residual stress formation in metal AM processes. Additive manufacturing (AM) or three-dimensional 3D) printing is a type of manufacturing technology in which feedstock materials are joined in layer-by-layer fashion to create parts from 3D CAD data ,2. AM enD printinThe classification of AM technologies for metal 3D printing uses their heat source and feedstock. Powder bed fusion (PBF) and directed energy deposition (DED) are the two primary categories of AM technologies. PBF includes AM techniques that use a bed of powder particles. A roller or rake is used to spread a thin layer of powder across the baseplate, and an electron beam or laser is used to scan the layer geometry, which melts the powder particles into a solid structured layer . SelectiIn addition to PBF and DED technologies, binder jetting and sheet lamentation are also utilized for metal additive manufacturing. Binder jetting utilizes a polymeric liquid (binder) to bond layers of powder material into the desired layer shape. The main advantage of binder jetting over other AM technologies is the compatibility of the process with any powdered material. The shaping process in binder jetting is completed at room temperature, which reduces issues of oxidation, phase change, and formation of residual stress. The main disadvantage of binder jetting is the requirement for post-processing, such as curing and densification. A schematic diagram of binder jetting is presented in Fast-paced research and development in metal-additive manufacturing, which uses powder metals ranging from steel, aluminum, and titanium alloys, to Ni-based super alloys for high temperatures, has been a major factor in the increasing acceptance of AM in recent years. Despite the wide range of applications of AM technology in various scientific fields, wider adoption of these technologies is limited, due to challenges associated with the design and manufacturing of parts. The high-intensity laser beam used to melt the metal materials can locally increase the temperature distribution of the metal to thousands of degrees. The laser melting in the AM process leads to the formation of high residual stress in parts fabricated through this process compared to in the traditional manufacturing process . SimilarAmong the various challenges associated with AM of metals, residual stress and part distortion have been the major obstacles encountered by researchers. These two factors are particularly important to resolve, because of their direct association with the dimensional accuracy and mechanical performance of the fabricated parts . While tResidual stress in AM metals directly affects the part quality and performance under various mechanical loadings and applications, resulting in part failure. Residual stress in metal parts has the tendency to either pull or push the materials and deform the parts, depending on the direction of residual stress. As a result, AM metal parts are susceptible to distortion in the presence of residual stress. The structural reliability of a part under cyclic loading is negatively impacted by residual stress, in terms of the performance of the part. The characteristics of the residual stress  depend, not only on the features of AM technologies, such as the heat source, material feedstocks, and the ambient conditions, but also on the input process parameters, including the scanning speed, laser power, scanning strategy, and build orientation . The proRapid heating, cooling, and melt-back, which involves simultaneously melting the top material layer and remelting the lower, previously hardened layers, are characteristics of the special thermal cycle of metal AM. For additive manufacturing of alloy elements such as magnesium alloys or aluminum alloys, in addition to rapid cooling, which acts as the transformation kinetic, selective dealloying can influence the nucleation of the new phase. Additive manufacturing of Mg powder is difficult, because it readily oxidizes in air under the influence of heat. Thus, alloying is conducted by adding elements such as calcium, zinc, and manganese, in order to slow the degradation. The addition of these elements affects the integrity, grain structure, and heat resistance of manufactured components. The low presence of alloying elements in magnesium powder can result in a loss of relative density in the deposit, whereas increasing the content of alloying elements can result in micro-cracks in a deposit . Due to A wide range of difficulties related to the metal additive manufacturing process have been the subject of numerous published or continuing investigations, including processability, functionality, and surface integrity. The issue of residual stress in the AM process has gained much importance in recent years, as AM processes are finding industrial applications. Therefore, this study aims to provide a comprehensive overview of various aspects of residual stress generation in AM, including the mechanism, cause, effect, measurement techniques, and post-processing techniques used to alleviate the negative effects of residual stress on part quality and application.Residual stresses (RS) are classified based on different length scales. Depending on the length, the residual stress can be type I, type II, or type III . Type I The formation of RS In metal AM Is Induced by the Input thermal energy, which creates a differential heating of solid and differential cooling during the solidification process. Contraction tensile stresses are generated during the melting process, due to the change in volume. Similarly, tensile stresses are generated during the solidification process of AM. In some metals and alloys, phase transformation causes volume change during the melting process, resulting in the formation of tensile stresses . Non-uniMercelis et al.  explaineThe second mechanism that explains the formation of residual stress in AM processes is the cool-down phase mechanism. AM processes are characterized by the layer-by-layer deposition of materials. A recently deposited layer tends to shrink during the cooling process; however, the shrinkage process is restricted by the layer below the recently added layer. This results in the formation of tensile stress in the newly deposited later, and the lower layer develops compressive stress. When a material is deposited layer-by-layer, compressive stress is continuously developed in the lower layer. In order to create a moment equilibrium, the bottom layer of the part develops a tensile stress zone, forming a tensile–compressive–tensile stress distribution from the top to the bottom of the part.The fatigue life of fabricated metal parts is reduced in the presence of tensile residual stresses, because they act as a driving force for the formation and propagation of cracks under cyclic loading . Figure AM technologies lack product quality control compared to subtractive manufacturing processes, because of the undesired distortion and fatigue-induced cracking caused by the formation of RS during manufacturing; however, it should be emphasized that a material’s performance is not always harmed by residual stress. For example, shot peening introduces residual compressive stress on the surface of parts to enhance fatigue performance . HoweverMeasurement methods for residual stress are classified into three major groups, depending on whether the sample is destroyed or not. Based on the destruction of samples, measurement techniques are categorized as non-destructive, destructive, and semi-destructive. A classification of these measurement techniques, with some examples under each type, is presented in Destructive and semi-destructive measurement techniques destroy the specimen part, to release the residual stress in the sample. Destructive techniques are also defined as stress-relaxing methods. The deformation (strain) created by the stress-relaxation when the sample is destroyed is measured, and the measured strain is utilized to calculate the residual stress of the sample based on the general principle of Hooke’s law. Therefore, the accuracy of this method depends on the accuracy of the strain measurement. Despite the harm they do to the specimens, making them appear less desirable than non-destructive procedures, mechanical release methods are frequently the best option, due to their adaptability and dependability. Non-destructive methods for measuring residual stress in metals are considered relatively expensive compared to destructive methods.Semi-destructive methods involve fewer modifications in the properties of the specimen compared to destructive methods; hence, they are an intermediary case. The majority of destructive measurement techniques that are frequently applied to calculate residual stress involve hole drilling, ring core, deep-hole drilling, sectioning, and contour techniques. Among the different types of destructive measurement techniques, hole drilling is the most commonly used. In the hole drilling process, a small hole, with typical dimensions of 1.8 mm in diameter and 2 mm in depth, is drilled at the location where the residual stress of the specimen is to be measured. Strain gauges are installed on the surface of the specimen prior to the drilling process. When the material is removed via the orbital drilling process, the specimen undergoes strain relaxation, and the amount of strain is noted using a strain gauge rosette. The measured strain values are used to calculate the residual stress . The holDestructive techniques are not viable for parts that are fabricated for application purposes, because the process induces damage to the parts, degrading the integrity and quality of the parts. Therefore, non-destructive techniques are particularly important for expensive specimens, because they do not alter the part integrity significantly. X-ray diffraction, neutron diffraction, the Barkhausen noise method, ultrasonic method, and thermoelastic method are the most commonly applied non-destructive techniques for measuring RS. A survey of 42 papers related to residual stress in AM showed the most frequently used measurement techniques by researchers, and this is presented in In non-destructive methods, the crystal lattice strain is assessed using non-destructive techniques (NDT), such as neutron diffraction and XRD. After that, assuming linear elastic deformation of the crystal lattice, the RS is determined using elastic constants. A number of material attributes, including tensile modulus, fracture toughness, microstructure, and flaws, can be revealed using NDT techniques. A schematic diagram of the Barkhauser noise method is presented in Although NDT techniques are quick, flexible, and repeatable with high accuracy, there are some limitations associated with NDT methods. Only certain crystalline materials can be measured using X-ray diffraction, depending on how well the surface has been prepared. Only magnetic materials may be tested using magnetic methods, based on how the stress–magnetization curve relationship changes during ferromagnetic saturation. Additionally, ultrasonic testing is suited for depth-varying residual stress measurements and is straightforward in theory, while there are still some challenges to be solved, such as differentiating sound velocity changes brought about by material defects or stress . Table 1The temperature gradient mechanism (TGM) model and the cool-down phase model provide a simplified explanation of how residual stress is formed in metals; however, AM processes are very complex in nature, and the formation of residual stress is, not only affected by the unique thermal cycle of the AM process, but also by the various process parameters. The characterization of residual stress in the AM of metals depends on numerous factors, including beam/laser parameters , process conditions and geometry , and scan strategy . Researchers have conducted various studies to outline the relationship between processing parameter control and the formation of residual stress. T. Mukherjee et al.  investigYu Zhan et al.  measuredIn addition to varying scan speed and beam power density, G. Vastola et al.  investigAmanda et al.  investigIn-plane strain components were affected by varying the island orientation/power/speed; however, the axial strain was unaffected. When the build parameters were set to 250 W and 1800 mm/s, the tensile residual stress the in y-direction was significantly reduced, compared to specimens with build parameters of 400 W and 1800 mm/s. This phenomenon was attributed to an increase in island rotation from 0 to 45 degrees, rather than attributing it to an increase in laser power. The use of 45 degree off-axis scanning reduced the residual stresses, which resulted in a useful misalignment between the largest part dimension and the maximum thermal stresses (scan direction). The results of the interaction between the laser power and speed showed that the amount of residual tension caused deflection during sectioning decreased as the energy per unit length increased.In a similar study conducted by J. Robinson et al. , the resThe results obtained in the study showed that the all Y scanning strategy showed lower stress values in the measurement direction compared to all X. This was attributed to the fact that the residual stress was primarily in the direction parallel to the scanning direction ,26,66. TKaran et al.  investigN.C. Levkulich et al.  investigA dependable and well-tested distortion and the residual stress prediction model would be of considerable use for improving the process optimization of AM technologies. It could save time and money compared to experimental methodologies and help researchers gain insight into the development and parameter dependency of residual stress in the additive manufacturing process ,71,72. TA simulated model of the AM process can be at the micro-level or macro-level. The interaction between the heat source and feedstock is included in micro-scale models of AM processes. While macro-scale models employ the dimensions of the heat-affected zone and the thermal cycle to compute the residual stress in components, micro-scale models provide information about the size of the melt pool, temperature distribution, and material consolidation quality. Usually, the residual stress modelling of AM is carried out at macro scale, with the assumption of heat distribution from a source. However, for accurate measurement of RS, it is recommended to model the interaction of the heat source and feed-stock at the micro-level and to model the interaction of fluid flow to develop the temperature distribution of the system. The obtained temperature distribution of the system can be utilized using macro-modeling, to reveal the residual stress and distortion present in the system . Once thXu Song et al.  utilizedThe local temperature profile was successfully predicted using the ABAQUS AM module and validated using fine mesh approaches with Goldak heating and coarser mesh resolutions. The results showed that the simulation time could be reduced if the time step resolution was increased; however, this could negatively affect the prediction of the local peak temperature profile.Jinqiang et al.  utilizedElham et al.  utilizedXinran et al.  developeApart from the process parameters of the control and pre-heating of the substrate or feedstock material, several post-processing techniques can be applied to mitigate the residual stress present in the MAM process. The most commonly applied post-processing techniques for metal additive manufacturing include post-heat treatment, laser shock peening (LSP), shot peening (SP), ultrasonic shot peening (USP), ultrasonic impact treatment (UIT), inter-pass rolling, machining, laser polishing, and chemical and electrochemical polishing. Among the mentioned post-processing techniques, heat treatment and the LSP process have been studied the most for reducing the RS in the MAM process.The fatigue performance of parts can be improved using stress relief heat treatment, because this helps to decrease the tensile residual stresses. Through a carefully regulated heat treatment process, the brittle microstructures in as-built AM metals can be made stable. Heat treatment can alter the microstructure of metals, improving their ductility and strength. Pengfei et al.  investigYeong Kim et al.  investigLaser shock peening (LSP) is a surface treatment process in which compressive stresses are developed in the specimen. The LSP process is beneficial, because it modifies the residual stress profile of AM components ,86. The Guru et al.  investigIn a similar study conducted by Rujian et al. , researcRolling is a post-processing technique that is applied to eliminate residual stress and distortion present in AM metal components. Rolling can be performed in normal ambient conditions (cold rolling), as well as under the influence of high temperature and pressure. Rolling introduces plastic deformation in AM metal parts, resulting in lower porosity and microstructural anisotropy. However, rolling is limited to parts that have simple geometries, such as straight walls or flat surfaces. For parts with complex geometries, the rolling process can be complicated and may require specific flexible tools .F. Martina et al.  investigLuis et al.  applied Ultrasonic impact treatment (UIT) is a post-weld technique in which a mechanical impact is applied in combination with ultrasonic oscillation in welded joints, to introduce plastic deformation and compressive residual stress in components. A schematic diagram of the UIT process is presented in Jianfei et al.  investigLanqing et al.  investigMetal additive manufacturing (MAM) has several advantages over subtractive and traditional manufacturing processes. The ability to fabricate complex shaped geometries with reductions in material waste, energy, cost, and time makes the MAM process a growing industry, and applications have been realized in the medical, automotive, and aerospace fields. However, the sustainable development of MAM technologies is restricted by inherent problems associated with the manufacturing of high-quality parts. The staircase effect and dependency on various process parameters restricts AM technologies from reliably producing high-quality parts, hence its application is limited. Residual stresses in AM metals have been identified as a key factor opposing the production of high-quality parts. Scientific communities have made various attempts to characterize the evolution, mechanism, and development of residual stress in the MAM process. Characterization of residual stress based on varying process parameters is a key necessary step that ensures the reliability of the MAM process.In this paper, the current state of AM technologies was thoroughly investigated. Several AM technologies were identified, and the problems existing in AM process were outlined. Residual stress was determined as the key factor for reducing the fatigue life and mechanical performance of fabricated AM parts. Measurement techniques for measuring the RS in metal were classified, and the advantages and disadvantages of each measuring technique were established. The characterization of RS based on varying the process parameters was identified. The proper control of these process parameters is essential for in situ control of residual stress. Similarly, numerical simulation was identified as an important technique for measuring and predicting the evolution of RS in metal AM with varying process parameters.Post-processing of metal additively manufactured parts is recommended to improve the surface integrity, including the surface roughness, sub surface residual stresses, and microstructure. Post-processing methods to improve surface integrity are well established in conventional manufacturing processes, such as machining, grinding, chemical etching, etc. Research on using conventional material removal processes to improve metal additive manufactured part surface integrity is essential for improved part quality and life. However, machining may induce additional residual stresses on metal AM parts. As a result, specific post-processing methods targeted towards the improvement of residual stress need to be developed.Sustainable post-processing and sustainable machining of metal AM parts have become important areas of research in recent years. Sustainable post-processing using MQL and cryogenic coolant was found to provide an improved surface finish and reduced burr formation ,101. HowResidual stress generation in metal AM processes, especially in AM processes associated with melting and solidification, is an inevitable phenomenon. Therefore, our understanding of the mechanism of residual stress formation is of prime importance. Physics-based models for understanding the residual stress generation and the influence of post-processing can be used to better understand and optimize the AM process parameters.Most of the current techniques for the measurement of residual stress  require expensive equipment and/or technical expertise. In many cases, these two methods are difficult to apply in an industrial setting. Future research should focus on the design and development of innovative experimental techniques to measure the residual stress of metal AM parts in a simple and inexpensive way. A dependable and well-tested distortion and residual stress prediction model would be of considerable use for improving the process optimization of AM technologies. This could save time and money compared to experimental methodologies and help researchers gain insight into the development and parameter dependency of residual stress in the additive manufacturing process.It is now obvious that the same complex metal 3D part can be manufactured using different metal 3D printing processes. Metal 3D printing processes not only vary in terms of process mechanisms, capabilities, and part qualities, but also vary in the amount and type of residual stress generated during the 3D printing processes. It is important to carry out comparative analysis of the residual stress generated by different AM processes when making a single part and to consider that analysis in the selection of a particular metal AM process.Designs for residual stress in metal AM should be an area of focus of future research. Currently, design for additive manufacturing is an important area of research. As the additive manufacturing field grows, individual design criteria become an important topic to consider. Residual stress remains one of the major challenges in metal AM processes that has to be considered when designing a part. Therefore, it is expected that design for residual stress in metal AM will become an important research area for future researchers. Although, methods for mitigating residual stress were discussed at the end of this review paper, many opportunities remain to work on this area of research. Currently, the majority of researches are focusing on the measurement of residual stress in already printed parts and applying post-processing techniques for relieving the residual stress in a 3D printed part. Post-processing methods are particularly important, because these processes further enhance the qualities and properties of components, which is impossible to achieve via 3D printing alone. However, future research should also consider relieving residual stress in situ, as the part is built layer-by-layer.The residual stress that remains in the part also influence the post-process machining performance of metal AM parts. The challenges in maintaining the dimensions and part quality after post-processing due to residual stress has been discussed in various research studies. However, the influence of residual stress on the machinability aspects of metal AM parts has not been studied in depth in the literature. For example, the effects of residual stress on cutting forces, tool wear, surface integrity, and burr formation when post-processing metal AM parts need further attention. The tool wear mechanisms for the machining of traditional cast or forged metal will be different from the machining of AM metal parts, and residual stress may have a significant influence on that difference. However, the basic knowledge of tool wear mechanisms  and burrIn addition, post-process machining of 3D printed polymer or metal parts imposes other challenges, such as delamination, decohesion, and debonding of layers . NumericIn recent years, various thermal material removal processes  have been used for the post-processing of metal AM parts . EDM andThe application of machine learning (ML) and artificial intelligence (AI) to optimizing the process performance of additive manufacturing has received much attention in recent years and will remain a major focus of manufacturing research in the next decade . As a re


Paxillin is a multi-domain adaptor protein. As an important member of focal adhesion (FA) and a participant in regulating cell movement, paxillin plays an important role in physiological processes such as nervous system development, embryonic development, and vascular development. However, increasing evidence suggests that paxillin is aberrantly expressed in many cancers. Many scholars have also recognized that the abnormal expression of paxillin is related to the prognosis, metastases, invasion, survival, angiogenesis, and other aspects of malignant tumors, suggesting that paxillin may be a potential cancer therapeutic target. Therefore, the study of how aberrant paxillin expression affects the process of tumorigenesis and metastasis will help to develop more efficacious antitumor drugs. Herein, we review the structure of paxillin and its function and expression in tumors, paying special attention to the multifaceted effects of paxillin on tumors, the mechanism of tumorigenesis and progression, and its potential role in tumor therapy. We also hope to provide a reference for the clinical prognosis and development of new tumor therapeutic targets. Paxillin is a 68 kDa multi-domain adaptor protein that is a major constituent of focal adhesions (FAs) and is expressed in virtually all tissues . As a siHowever, the special structure and function of paxillin make it play an indispensable role in the development of cancer. Growing evidence has shown that paxillin is aberrantly expressed in a variety of human malignancies, such as melanoma , breast Paxillin mainly consists of five leucine–aspartic acid (LD) domains at the N-terminal, four cysteine–histidine-rich Lin11, Isl-1, and Mec-3 (LIM) domains at the C-terminal, and a proline-rich sequence and some serine and tyrosine residues, in which the N-terminal LD domain controls most of its signaling activities . LD motiStudies have shown that p21-activated kinase can phosphorylate paxillin at tyrosine residue 273, which increases the cell migration ability and neurite activity and makes paxillin a regulator of cell adhesion . The phoDespite the fact that the LD domain can bind to a variety of FA-related proteins, the real targeting of paxillin to FA is the four cysteine–histidine-rich LIM domains at the C-terminal of paxillin. All four LIM domains are double zinc finger motifs that anchor paxillin to the plasma membrane and can mediate protein–protein interactions ,20. AmonThe expression of paxillin plays an important role in the human body both in the process of physiological development and in the process of disease development. Although paxillin mutations in somatic cells are rare, studies have also shown that paxillin mutations are associated with tumor progression. In a study of lung cancer, the expression of paxillin in cancer tissue was higher than in normal lung tissue, and the somatic mutation rate was 9.4%, of which the most common point mutation A127T) enhanced the growth and invasion ability of lung cancer cells . Later, T enhancePaxillin is phosphorylated at the tyrosine-88 residue (Y88-paxillin) by the oncogenic kinase Src to form pY88-paxillin, which is highly expressed in most human colon cancer tissues, and pY88-paxillin plays an oncogenic role in colorectal tumorigenesis . AdditioAs paxillin expression is more widely studied in cancer, the clinical significance of paxillin has received increased amounts of attention. The aberrant expression of paxillin is often associated with carcinogenesis and is associated with poor tumor prognosis , so the Abnormal paxillin expression is associated with many clinicopathological parameters such as aggressiveness, distant metastasis, and clinical stage in various tumors, including colorectal cancer , prostatAs a highly expressed central gene in glioblastoma (GBM), paxillin expression is negatively correlated with the overall survival, progression-free survival, and disease-free survival of GBM patients, which can be used as an independent prognostic factor and an independent prognostic biomarker in GBM patients ,41. The Despite the fact that the role of paxillin in cancer has been studied for many years, many studies have also demonstrated its value as a prognostic factor in cancer patients, and this topic remains controversial. For example, paxillin overexpression is associated with tumor aggressiveness, poor tumor differentiation, and lymph node metastasis in LSCC, and paxillin is a predictor of poor survival and recurrence-free survival. However, it is not an independent predictor factor of LSCC . SimilarHence, the correlation between paxillin and clinicopathological features is not completely consistent between different tumors, suggesting that paxillin alone has a limited clinical prognostic value in tumors. Compared with paxillin alone, the combination of paxillin and other tumor markers can be a better choice for tumor prognosis.Cell adhesion and migration are the cellular processes commonly used by tumor cells to invade surrounding tissues and metastasize. Tumor metastasis is one of the leading causes of human cancer death since epithelial tumors form in the normal tissue stroma and migrate outward in the tissue stroma in two modes of single-cell migration and collective migration . HoweverThe cyclic regulation of FA is a key step in the control of cell adhesion and motility. Paxillin and FAK are key components of focal adhesions and changes in their expression or localization and their phosphorylation status are often associated with cancer cell metastasis . StudiesIt is currently believed that the Rho family of GTPases is involved in the migration and invasion of cancer cells, and the expression and activation of RhoA and ROCK affect the formation of actin stress fibers . PaxilliIn addition, paxillin can also promote cancer cell migration by regulating the EMT process. Since EMT is involved in the process of the lysis of cell–cell adhesion, the loss of apical–basolateral polarity, and the reorganization of the cytoskeleton, it is believed that EMT plays a key role in cancer cell metastasis ,66. E-caTumor cells can also utilize adherent structures called invadopodia, which contributes to the invasive metastasis of tumor cells by crossing the basement membrane. The dynamics of invadopodia are regulated by the phosphorylation of paxillin, which accumulates in the center of the invadopodia ring and may lead to the disassembly of the invadopodia core at the inner edge of the ring, resulting in the complete disassembly of the invadopodia. Since paxillin is also a major component of invadopodia/podosomes, paxillin is involved in invadopodia ring expansion to trigger the invasive migration of cells . The dowSome kinases and regulatory proteins can promote the phosphorylation of paxillin to elevate cancer cell invasion. The phosphorylation of paxillin by kinases such as the Src family enables breast tumor cells and metastatic breast tumor cells with a basal-like phenotype to exhibit enhanced invasiveness in confined spaces . SphingoIn addition, actin is an important part of the cytoskeleton, and the filaments (F-actin) formed by actin are one of the basic elements of the eukaryotic cytoskeleton, and F-actin is involved in maintaining cell shape characteristics, aspects of cell motility, and other processes. The actin network, made up of actin filaments, can provide mechanical support for cells and help cells perform signal transduction and material transportation. At the same time, the assembly and disassembly of the actin network is the source of power for cell movement . Cancer Many studies have shown that adhesion during tumor cell invasion depends mainly on the cell adhesion molecules of the integrin family ,88. The Due to the strong adaptability of cancer cells to various environmental changes, compared with normal tissue cells, cancer cells are more able to survive and proliferate in different tissue microenvironments. This also facilitates the distant metastasis of cancer cells, and this metastatic potential exhibited by malignancies correlates with their ability to grow independently of anchorage . PaxilliMoreover, to some important extent, the abnormal expression of paxillin has an effect on the survival of cancer cells. The overexpression of paxillin promotes the proliferation of glioma cells , gastricIn the process of tumor-induced angiogenesis, tumor cells secrete diffusible angiogenic factors to induce vascular endothelial cells to proliferate and migrate to form new tumor blood vessels, and the development of new blood vessels also contributes to tumor growth . Tumor-sIt has long been believed that neovascularization derived from vascular endothelium is the only way for tumors to obtain blood supply. In 1999, Maniotis et al. first proposed a new tumor microcirculation model that is different from the classic tumor angiogenesis pathway and does not depend on the body’s endothelial cells. This is angiogenesis mimicry (VM) . VM is aIn the development of tumors, genetic changes will occur in signaling pathways such as cell growth, apoptosis, and cycle progression, and the degree and mechanism of these changes vary with different tumors . Many paThere are three Wnt signaling pathways, namely the Wnt/β-catenin signaling pathway, Wnt/Ca2+ pathway, and Wnt/PCP pathway. The Wnt/β-catenin pathway is a classic pathway, and the main ligands include Wnt1, Wnt3, and Wnt8b. After the ligands bind to the receptor Frizzled, they can lead to the accumulation of β-catenin in the cytoplasm. Unphosphorylated β-catenin, which accumulates to a certain extent, is transported to the nucleus, where it regulates the expression of target genes. The main ligands in other Wnt signaling pathways include Wnt5a, Wnt7a, and Wnt11. When the ligand binds to its receptor Frizzled, the Wnt/Ca2+ pathway activates phospholipase C to increase the amount of intracellular Ca2+, which activates Ca2+/calmodulin-dependent kinase II and calcineurin to regulate gene expression. The Wnt/PCP pathway activates the small GTPase Rho/Rac and JNK through the disheveled protein to regulate the expression of downstream target genes to affect cell movement ,118. AltWhen cells come into contact with the ECM, FAK, as one of the important signaling molecules of integrins, is recruited into focal adhesions and activated via phosphorylation during integrin-mediated adhesion. Activated FAK regulates the physiological or pathological process of cells by recruiting different signaling protein molecules to activate different downstream signaling pathways, such as proliferation, motility, and differentiation ,121. As The abnormal TGF-β signaling pathway can lead to the occurrence of various diseases such as tumors, cardiovascular diseases, and immune diseases. In addition, the TGF-β signaling pathway has two sides in the process of tumor development. It can not only play an inhibitory role in the early stage of the tumor but also play a promoting role in the late stage of the tumor ,131. TheThe MAPK signaling pathway consists of three different levels of signaling molecules, namely mitogen-activated protein kinase kinase kinase (MAPKKK), mitogen-activated protein kinase kinase (MAPKK), and mitogen-activated protein kinase (MAPK). The process is that after the ligand binds to the receptor, MAPKKK, MAPKK, and MAPK are sequentially activated to regulate gene expression . MAPK isThe PI3K/AKT pathway is activated in a variety of cancers and is involved in the process of cancer cell proliferation, survival, invasion, and metastasis and is considered a potential therapeutic target. Phosphatidylinositol kinase 3 (PIK3) is a dimer composed of regulatory subunit p85 and catalytic subunit p110, which catalyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3, 4, 5-triphosphate (PIP3). PIP3 can activate the downstream signaling molecules by activating the proto-oncogene Akt protein to regulate various physiological and pathological processes ,147,148.Current research shows that non-coding RNA plays an increasingly important role in the occurrence and development of various human diseases, and its dysfunction is closely related to cancer . As one In summary, paxillin can directly or indirectly regulate Wnt, integrin-FAK, TGF-B, PIK3/AKT, and MAPK signaling pathways and participate in tumor invasion, metastasis, proliferation, apoptosis, and other processes. It can also be directly or indirectly regulated by some miRNAs, lncRNAs, and transcription factors to promote or inhibit tumor progression, which suggests that paxillin can be used as a target for antitumor drug development in the future.Aberrant paxillin expression is associated with the malignant progression of cancer, so the modulation of paxillin expression may serve as a potential therapeutic target. Currently, certain drugs to treat cancer work by targeting paxillin or signaling pathways involving paxillin. Therefore, a further understanding of paxillin’s function may lead to the development of new cancer therapies developed against paxillin. Here, we will briefly discuss cancer therapeutics and potential drugs targeting paxillin as well as its signaling pathways .From the above, it can be seen that the FAK/paxillin signaling pathway is involved in several tumor-promoting pathways, so reducing FAK signaling by inhibiting FAK-paxillin interaction is considered a potential tumor therapy strategy. For example, a synthetic antibody-selective inhibitor designed against the paxillin LD2 and LD4 motifs can alter FA kinetics by inhibiting FAK-paxillin interaction by competing with FAK for the binding site of paxillin . FurtherSome other potential tumor therapeutic compounds can play a certain role in tumor therapy by targeting paxillin and its signaling pathway. For example, magnolol can inhibit the expression of lysyl oxidase from disrupting FAK/Src/paxillin signaling to inhibit the migration and invasion of breast cancer cells, which is considered to be an ideal strategy for breast cancer treatment . A newlyIn addition, some natural compounds are also involved in targeting paxillin and its signaling pathway in the process of assessing their antitumor abilities as they are expected to become potential anticancer drugs. For example, docetaxel inhibits the growth of prostate cancer cells and promotes apoptosis by inhibiting the phosphorylation level of paxillin . The natHowever, tumor heterogeneity and resistance to chemotherapeutic drugs are the main reasons for tumor recurrence and poor patient survival. Tumor drug resistance is a limitation of many of the existing anticancer drugs, many of which are associated with paxillin. Cisplatin, as a commonly used anticancer drug, can effectively fight against a variety of tumors, but the chemoresistance generated in the process of medication limits the clinical application of cisplatin. It has been reported that phosphorylated paxillin increases Bcl-2 expression through the ERK signaling pathway as the cause of cisplatin resistance in non-small cell lung cancer, and Src or ERK inhibitors help restore the sensitivity of lung cancer patients to cisplatin chemotherapy . On the Therefore, gene therapy is now considered to be one of the best options to address the limitations of current treatments for the characteristics of chemotherapy drugs that have serious side effects and easily lead to drug resistance in cancer cells. To overcome the barriers of cell permeability and nuclease-mediated degradation, the use of pH-sensitive carbonate apatite nanocarriers as delivery vehicles for the targeted delivery of paxillin RNAi has become an effective potential therapy for breast cancer . To explAll in all, further exploration of the paxillin pathway will help towards finding a solution to cancer metastasis and chemoresistance in the future.A growing body of research is supplementing our understanding of the potential role of aberrant paxillin expression in tumor cells and its impact on tumor malignant progression. According to the above summary, aberrant paxillin expression can regulate different biological functions such as tumor migration, heterotypic adhesion, invasion, survival, and angiogenesis in tumor malignant development by participating in different molecular mechanisms. In addition, the abnormal expression of paxillin in cancer patients is also closely related to the poor clinical prognosis of the patients. At the same time, there are more and more studies involving antitumor compounds and gene drugs targeting paxillin, some of which have achieved initial success in clinical trials. Consequently, paxillin may be a promising target for cancer therapy and prognosis in the future.Though the detection of paxillin expression and the development of new oncology drugs targeting the paxillin gene are promising prospects for cancer clinical prognosis and treatment, many unanswered questions arise. For example, given the viability of paxillin as a single prognostic factor, many of the oncology therapeutics developed for paxillin are in the early stages of development, and there are still many uncertainties. Therefore, future research needs to fully combine paxillin with other prognostic factors to explore the relationship with poor clinical prognosis and to improve the sensitivity and specificity of paxillin in cancer prognosis. Therefore, a lot of basic research and clinical research is still needed to understand the function and therapeutic significance of paxillin fully. Furthermore, research on the drug treatment of paxillin and its molecular mechanism of drug sensitivity also needs to be conducted in the future. This will fully unleash the potential role of paxillin as a tumor therapy target in the future. A better understanding of the functional mechanism of paxillin will help us to understand tumor survival and metastasis processes and provide valuable opportunities for tumor therapeutic intervention in the future. Overall, this review highlights the role of the abnormal expression of paxillin in tumor progression and related molecular mechanisms, as well as the potential for paxillin to be used in tumor therapy.


Fagopyrum tataricum Gaertn.) originates in mountain regions of Western China, and is cultivated in China, Bhutan, Northern India, Nepal, and Central Europe. The content of flavonoids in Tartary buckwheat grain and groats is much higher than in common buckwheat (Fagopyrum esculentum Moench), and depends on ecological conditions, such as UV-B radiation. Buckwheat intake has preventative effects in chronic diseases, such as cardiovascular diseases, diabetes, and obesity, due to its content of bioactive substances. The main bioactive compounds in Tartary buckwheat groats are flavonoids (rutin and quercetin). There are differences in the bioactivities of buckwheat groats obtained using different husking technologies, based on husking raw or pretreated grain. Husking hydrothermally pretreated grain is among the traditional ways of consuming buckwheat in Europe and some parts of China and Japan. During hydrothermal and other processing of Tartary buckwheat grain, a part of rutin is transformed to quercetin, the degradation product of rutin. By adjusting the humidity of materials and the processing temperature, it is possible to regulate the degree of conversion of rutin to quercetin. Rutin is degraded to quercetin in Tartary buckwheat grain due to the enzyme rutinosidase. The high-temperature treatment of wet Tartary buckwheat grain is able to prevent the transformation of rutin to quercetin.Tartary buckwheat ( Fagopyrum tataricum (L.) Gaertn.) originates in regions of South-western China, and is cultivated in China, Korea, northern parts of India, Bhutan, and Nepal .,41.40,41During husking and the hydrothermal pretreatment of buckwheat grain, phenolic substances have an impact on protein digestibility . SubstanThe treatment of Tartary buckwheat grain with water impacts the transformation of rutin to quercetin by the rutin-degrading enzyme  49,50,5,52. The Ingested quercetin can cross the blood–brain barrier and accumulate in the brain tissue . Indeed,Phenolic compounds are often transformed in the gut before their absorption. The gut microbiota are essential in this process . Large-sThe complexation of quercetin in Tartary buckwheat materials with molecules of starch has an influence on the in vitro digestibility and physicochemical properties of starch . The effRat experiments with common buckwheat have further suggested the complexity of the impact of the gut microbiota. Indeed, Peng et al.  suggesteIn Japan, buckwheat groats are less well known than in Europe . HoweverMany dishes can be made with common or Tartary buckwheat kasha ,62. SomeDuring the treatment of Tartary buckwheat groat, the concentrations of bioactive substances with strong impacts on human health are altered. This includes the concentration of rutin and quercetin in buckwheat groats .The supplementation of rutin-rich diets with vitamin C is able to reduce oxidative stress, have an impact on glycemic stress, and reduce fasting blood glucose in patients with type 2 diabetes . A rutinPhenolic substances in buckwheat have significant bioactivities in addition to their antioxidative and anti-inflammatory effects . PhenoliIngested quercetin and its glycosides are metabolized during human digestion, and are absorbed and transported as conjugates with the blood. A major metabolite of quercetin is quercetin-glucuronide, which is transported to the target tissues. Following the separation of the sugar part of hydrophilic quercetin-glucuronide, the hydrophobic aglycone remains at injured sites to perform the improvement of pathological conditions .High levels of rutin and quercetin in Tartary buckwheat, and high levels of antioxidative impacts, have further effects on the cytotoxic and antigenotoxic impacts ,67. A stThe grain and groat of common buckwheat contain a low concentration of rutin, while its concentration in the grain of Tartary buckwheat could be up to 1%. The solar UV irradiation of plants may increase the amount of rutin and other UV-absorbing secondary metabolites in buckwheat grain. During the processing of buckwheat grain using hydrothermal treatment to obtain husked product (groats or kasha), there are various possible transformations and interactions among the constituents, including the formation of quercetin, as a degradation product of rutin by rutin-degrading enzyme. The activity of rutin-degrading enzyme is prevented by hydrothermal treatment of buckwheat grain products at about 80 °C or more. In Tartary buckwheat groats, quercetin complexation with starch molecules has an impact on the in vitro digestibility of the starch and the appearance of resistant starch, thus altering the physicochemical properties of Tartary buckwheat products. The effects of such flavonoid–starch or flavonoid–protein complexation indicate that food products based on Tartary buckwheat will show lower starch or protein digestibility. Quercetin in Tartary buckwheat can reduce body weight, serum triacylglycerols, and low-density lipoprotein. During digestion in the large intestine, due to protein–phenol interactions of the buckwheat grain, protein digestion is slowed down. However, again, the microbial processes in the colon partly enhance the digestibility of the proteins. Slowly digestible buckwheat groat protein can reduce cholesterol levels in serum by increasing the fecal excretion of steroids. Tartary buckwheat has also been shown to prevent increases in body weight and fat deposition during high fat intake in rats. A buckwheat diet can also reduce insulin and ameliorate glucose intolerance in humans. Important bioactivities have been established for ingested quercetin and its derivatives, not just in blood vessels, muscle, and the gastrointestinal system, but also in the brain. Further understanding of the metabolism of rutin and quercetin in buckwheat plants and food products, and how different forms of flavonoids impact the health of consumers, should prove useful in achieving better human health. Hopefully, continuous progress on the wider use of Tartary buckwheat and its products, including groats, over time can fulfill the yield gap needed to feed our global community with a health-preserving diet.


Venous thromboembolic complications (VTCs), which include deep vein thrombosis (DVT) and pulmonary embolism (PE), have remained a pressing problem in modern clinical medicine for a long time. Despite the already wide arsenal of modern methods for diagnosing and treating this disease, VTCs rank third in the structure of causes of death among all cardiovascular diseases, behind myocardial infarction (MI) and ischemic stroke (IS). Numerous studies have confirmed the importance of understanding the molecular processes of VTCs for effective therapy and diagnosis. Significant progress has been made in VTC research in recent years, where the relative contribution of microRNAs (miRNAs) in the mechanism of thrombus formation and their consideration as therapeutic targets have been well studied. In this case, accurate, timely, and as early as possible diagnosis of VTCs is of particular importance, which will help improve both short-term and long-term prognoses of patients. This case accounts for the already well-studied circulating miRNAs as non-invasive biomarkers. This study presents currently available literature data on the role of miRNAs in VTCs, revealing their potential as therapeutic targets and diagnostic and prognostic tools for this terrible disease. Venous thromboembolic complications (VTCs), which include deep vein thrombosis (DVT) and pulmonary embolism (PE), remain the most important problem in clinical medicine and affect the professional sphere of doctors of all specialties without exception. The importance of VTCs is due to their extremely high potential risk to the health and life of the patient. Improving the quality of prevention, diagnosis, prognosis, and treatment of VTCs can save the lives of thousands of people and ensure a noticeable reduction in financial pressure on the healthcare budget, thanks to the prevention of severe disabling diseases ,2,3.Currently, there are effective surgical and drug treatments for VTCs that can reduce disability in the population. However, the early diagnosis and prognosis of the disease is a key factor in the success of the treatment and is directly related to understanding the pathogenesis of VTCs, which leads to the possibility for forming risk groups for PE among patients with DVT . CurrentThe relevance of the problem of PE is due to the difficulties of timely diagnosis due to the polymorphism of clinical syndromes. To detect PE, various research methods are used—both laboratory and instrumental. The degree of their information content varies . Among tAccording to the literature, miRNAs control the expression of several key factors of hemostasis , indicating that the dysregulation of these miRNAs can lead to hemostatic imbalance and, accordingly, increased thrombosis or bleeding  21,22,2,24,25,26Tissue factor (TF) is a critical factor in the initiation of coagulation, and its overexpression has been extensively studied in patients with cancer complicated by coagulopathy . While tTeruel et al. demonstrated significantly lower expression levels of miR-19b and miR-20a in monocytes from patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) compared with controls, and miR-19b and miR-20a expressions were inversely correlated with TF expression in the corresponding monocytes . Thus, tCurrently, the molecular mechanisms of DVT pathogenesis are not fully understood, which significantly limits the creation of new therapeutic, diagnostic, and prognostic tools. It is known that the processes of thrombus lysis and the restoration of the venous wall are associated with proinflammatory cytokines, chemokines, and leukocytes. Additionally, the definition of Virchow’s triad considers three major factors that contribute to the formation of blood clots, including changes in blood flow, endothelial damage, and a hypercoagulable state. However, the molecular mechanism of DVT is not fully understood. Recent studies have suggested that miRNAs are involved in the formation and development of DVT. In their study, Zhang et al. observed increased interleukin 6 (IL-6) expression in the peripheral blood mononuclear cells (PBMCs) of patients with DVT and investigated the expression profile of miR-338-5p in patients with DVT, in the HUVEC cell line, and in DVT animal models, using microarrays . The autKnowledge accumulated in recent years suggests that DVT is closely associated with the fibrotic remodeling of vein walls, which consists of a switch in the vascular smooth muscle cell (VSMC) phenotype from contractile to synthetic, with VSMC proliferation, collagen deposition, and damage to the extracellular matrix (ECM) by matrix metalloproteinases (MMPs). More recently, the involvement of MMPs together with the tissue inhibitors of metalloproteinases (TIMPs) in the mechanism of DVT has been recognized as significant and is actively being discussed ,38. FranEndothelial nitric oxide (NO) regulates several physiological processes, such as platelet adhesion and aggregation, which may influence susceptibility or resistance to thrombosis . There iPE is a critical and potentially life-threatening medical condition characterized by the formation of blood clots, typically in the deep veins of the legs, which can dislodge and travel to the pulmonary arteries, causing obstruction and compromising cardiopulmonary function. Pulmonary hypertension, often resulting from recurrent PE, can lead to progressive respiratory dysfunction and long-term disability. Considering these serious consequences, there is a pressing need for improved innovative therapeutic strategies for PE . Recent Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pathology that develops because of the chronic obstruction of large/medium branches of the pulmonary arteries and secondary changes in the microvasculature of the lungs. CTEPH is a late complication of acute PE, with an incidence of 0.1–9.1% during the first two years after the episode . The comAlthough our comprehension of the role of miRNAs in PE is still in its nascent stages, these findings underscore the potential of miRNAs to be instrumental in unraveling the intricate mechanisms of PE and potentially devising novel treatment strategies. However, it is crucial to emphasize that further research, particularly in larger cohorts and comprehensive confirmatory experiments, is imperative before clinical applications can be fully realized. Numerous studies have attempted to find accurate and early diagnostic laboratory biomarkers for PE and DVT. However, to date, plasma D-dimer is the only well-established and clinically applicable biomarker for the identification of PE and DVT. The D-dimer test reflects the level of fibrin degradation. A negative D-dimer result is relative evidence to exclude PE and DVT, but a positive result has low specificity and low diagnostic and prognostic value for VTCs . D-dimerCirculating miRNAs, as biomarkers of PE and DVT, have been less studied, although circulating miRNAs may be more sensitive and accurate in the diagnosis and prognosis of VTCs. Recently, several studies have been carried out showing that circulating microRNAs are preferable as biomarkers because they are highly stable in human biological fluids, such as blood, and can be detected in the early stages of disease development, while protein structures, such as D-dimer, are found in blood only when damage has already occurred ,79. In aWang et al. found that among the 13 plasma miRNAs studied, the expression of circulating miR-424-5p was significantly higher, while the expression levels of circulating miR-136-5p were significantly lower in patients with DVT compared with patients without DVT . The autQin et al. systematically measured serum concentrations of three circulating miRNAs  in patients following orthopedic surgery complicated by lower extremity DVT . The expIn a study by Jiang et al., high expression levels of plasma miR-320b were found in DVT patients compared with control groups . The ROCPreviously, it has been proven that the miR-320 family is overexpressed in human platelets, while circulating miR-320b could possibly be transferred through extracellular vesicles (EVs) to ECs with the control of the intercellular adhesion molecule type 1 (ICAM-1) expression, which indicates the potential role of existing extracellular communications in the vascular bed .The identification of circulating miRNAs associated with DVT is of great interest and has the potential to significantly impact the diagnosis and monitoring of therapies for this disease. The use of circulating miRNAs in clinical medicine as diagnostic and prognostic biomarkers is the subject of extensive study but is very far from practical implementation. Another critical dimension of PE research revolves around enhancing its diagnostic accuracy. Diagnosing pulmonary embolism remains a formidable challenge due to its nonspecific clinical symptoms and the absence of highly reliable biomarkers. Nevertheless, recent studies have explored the potential utility of circulating miRNAs as diagnostic tools. In one such study, researchers scrutinized the expression levels of circulating miR-190 and miR-197 in patients with PE . These iXiao et al. showed the involvement and possibility of using circulating miR-134 in the diagnosis and prognosis of PE . The expWang et al. examined the levels of circulating miR-27a and miR-27b as diagnostic biomarkers in patients with PE . The resLastly, the diagnosis of the acute exacerbation of chronic obstructive pulmonary disease (COPD) complicated by PE presents unique diagnostic challenges due to the variability in clinical presentations and the absence of reliable screening biomarkers or instruments . To addrOne intriguing area of exploration lies in the intersection between PE and CTEPH. It is known that CTEPH is the most severe complication of PE, making it a focal point for research. The tasks of early diagnosis for patients with CTEPH are aimed at the timely establishment of the operability of patients because a successful pulmonary thromboendarterectomy leads to the regression of pulmonary hypertension in most patients .p < 0.05). The let-7b-3p expression showed a trend toward a positive correlation with the mean pulmonary arterial pressure (mPAP).Guo et al. analyzed plasma samples from patients with CTEPH and healthy donors and found that circulating let-7b expression was positively correlated with the PAI-1 levels, D-dimer, and cardiac index . In addiIn summary, these studies collectively highlight the burgeoning significance of circulating miRNAs in the realm of VTC research. From miRNAs’ pivotal roles in comprehending the pathophysiology of this condition to their potential as predictive, diagnostic, and prognostic non-invasive biomarkers, circulating miRNAs represent a beacon of hope for the enhanced identification of patients with problems and more effective management of patients with DVT and PE and their related conditions. As we continue to unravel the complexities of VTC processes, miRNAs offer the potential for transformative breakthroughs in this critical area of medicine. ClinicalTrials.gov, more than 30 miRNA-based drugs are in Phase 3–4 clinical trials. Despite the great potential for using miRNA for therapeutic purposes, only a few drugs have had satisfactory results. Under physiological conditions, miRNA is unstable. The effective action of miRNAs involves their delivery to target cells through the bloodstream; however, when administered intravenously, the molecules are degraded under the action of serum nucleases, excreted by the kidneys, absorbed by phagocytes, and aggregated with whey proteins. Nuclease activity in blood serum and tissues is, in fact, the first barrier to miRNA delivery. The half-life of siRNA in the bloodstream ranges from several minutes to 1 h. The delivery vehicles that are used today, including nanoparticles and liposomes described in many studies, are characterized by high toxicity, poor selectivity, and low efficiency in penetrating cells. It is because of this that miRNA preparations for external use are being actively developed, mainly for the treatment of eye diseases and skin diseases, in which the issues of specific delivery are partially removed. Regarding the treatment of DVT and PE, there are currently no active clinical trials. Despite the specificity of action of miRNAs and their ability to selectively block the activity of individual protein genes, such drugs cannot be expected to be effective in the treatment of cancer, even if they successfully block the expression of key proteins. One of the reasons for this may be that thrombosis is a complication of the underlying disease, such as cancer. Therefore, therapies may be complicated by the choice of tactics. One approach to increasing the effectiveness of targeted compounds is the use of a combination of drugs with multidirectional effects that simultaneously block several signaling pathways in the cell/cells.Close attention to miRNA-based therapy for various human diseases, as a promising tool for targeting gene expression, is explained by the following factors: (1) specificity of action, (2) minor side effects, and (3) ease of synthesis of miRNA-based drugs. Correctly selected RNA sequences can selectively inhibit the expression of genes associated with certain disorders, such as the overexpression of genes responsible for blood clots. Currently, according to information from Although circulating-miRNA expression analysis has been studied worldwide, this research has mainly focused on applications in the fields of biomedicine and oncology. To truly unlock the full potential of circulating miRNAs in DVT and PE, it is critical to understand the molecular complexity of the available samples and the hemostatic system itself. There are not very many published studies in this area, but their number is growing. The success of their implementation in clinical practice will largely depend on the availability of a method that allows for the effective verification and validation of promising biomarkers based on circulating miRNAs. Frequent inconsistencies, and sometimes contradictions, in research results are associated with the difficulty in determining the functional involvement of a specific miRNA in the development of a particular process owing to the simultaneous effects of the miRNA on several target genes. As mentioned above, thrombosis is often a complication of the underlying disease. In other words, the use of circulating miRNAs for diagnostic purposes will be limited until their precise relationships with genes are established.Research over the past few years has shown that miRNAs serve as modulators of hemostasis. Understanding the mechanism by which microRNAs are involved in the development of thrombosis is especially important because it can be applied in clinical practice. Circulating miRNAs have enormous potential as non-invasive biomarkers for use in the diagnosis and prognosis of VTCs. However, there are several limitations, such as the lack of studies examining both endogenous and circulating miRNAs in DVT and PE. Another limitation stems from the fact that thrombosis is a dynamic process that is influenced by multiple factors, such as primary diseases, the timing of sampling, and prophylactic anticoagulation. Consequently, there is clinically significant heterogeneity among the study population. Inevitably, problems will arise because one miRNA can have hundreds of target genes, and one gene can be the target of many miRNAs. The formation of a blood clot in the venous system is a rather complex process controlled by many miRNAs. It is very important, but extremely difficult, to determine the exact mechanisms that are regulated by specific miRNAs, so further research is needed to solve this problem.


Recent studies have indicated that cinnamon is a safe and cost-effective treatment for improving body weight, lipid profiles, insulin resistance, and blood pressure. This systematic review aimed to summarize the effect of cinnamon supplementation on adipokines and appetite-regulating hormones.This comprehensive literature search was conducted using databases such as PubMed, Scopus, ISI Web of Science, and Google Scholar up to March 2022 without any limitation. The quality of eligible studies was evaluated through the Cochrane Collaboration’s tool for assessing the risk of biasThis systematic review included six clinical trial studies (363 participants), among which, only one study was performed on children, and two investigations were conducted on obese participants. A decreasing effect was found in the level of leptin and visfatin after cinnamon supplementation. Two out of three studies examined adiponectin levels and revealed non-significant effects of cinnamon consumption on this parameter. Two studies evaluated ghrelin levels and found an increase after cinnamon supplementation. The result of cinnamon supplementation on other biomarkers such as glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and resistin was inconsistent.The result of this systematic review indicated the increasing effect of cinnamon supplementation on ghrelin levels and decreasing effect on leptin and visfatin levels. However, more clinical data are required to clarify the beneficial effects of cinnamon on adipokines levels due to the controversial findings of the studies. Cinnamon is extracted from the inner bark of Cinnamomum trees, which belongs to the Lauraceae family and are widely distributed in South America, Australia, and Asia  guidelines  AND  NOT (mouse OR mice OR rats OR in-vitro OR in vitro)This study was not restricted by language, publication time, or other filters. Two reviewers (A GH and M GH) independently screened the title and abstract to exclude irrelevant studies, and another investigator resolved the disagreements. Moreover, reference lists of original articles were searched manually to find relevant studies. Furthermore, the related published articles were found after the initial search using the search alert service.Eligibility criteria The inclusion criteria for papers were those that evaluated the effect of cinnamon supplementation on humans, the impact of cinnamon consumption and its products on adipokines, and appetite-regulating hormones conducted in a clinical trial with the publication type of original article. The exclusion criteria were trials assessing irrelevant markers (lack of favorite results), reporting the results of the same studies, and observational, review, letter to editor, and animal studies. Data extractionThe data were extracted by two researchers (Z N and E N-E) and checked by the third reviewer. The extracted data included the first author's name, study design, age and gender of subjects, publication date, intervention duration, study location, sample size, intervention and placebo type, and cinnamon supplementation daily dose. Any discrepancies between the two researchers were concluded by group consultation.Risk of bias and quality assessmentA tool developed by the Cochrane Collaboration was used to assess the risk of bias in five eligible studies  Helbowicz et al. (2009)Risk of bias and quality assessmentThe quality assessment details of studies selected in this systematic review are presented in As shown in this Table, four out of six studies defined the random sequencing generation method  production and by increasing glucose transporter type 4 (GLUT-4) function, which enhances glucose absorption. Therefore, glucose can stimulate leptin secretion from adipocytes as an intracellular signal This systematic review analyzed clinical trial studies on cinnamon and any forms of cinnamon effects on adipokine levels and appetite-regulating hormones. Although some studies have shown the increasing effects of cinnamon supplementation on ghrelin levels and its decreasing effects on leptin and visfatin parameters, these findings do not seem to indicate a precise effect on increasing or decreasing appetite or related adipokines. Detailed studies with larger sample size and long-term duration are required to evaluate these effects.The authors have declared that there is no conflict of interest.