Workplace moral behavior  and immoral behavior  have received substantial attention over the past decades moral behavior, offering the diverse insights to the individual emotion-centric models and social cognitive process models, exploring the individual dynamic moral emotions and moral cognition before and after the conduct of workplace (im)moral behavior, and clarifying the respective boundary conditions. Totally, we have accepted 28 papers for publication in the Frontiers in Psychology, which deal with different aspects of workplace (im)moral behavior, exploring mechanisms of these behaviors from the perspectives of moral cognition and moral emotion, and investigating the relevant antecedents and outcome variables. Some studies examined positive leadership  and its impacts on subordinate performance and behavior . We also included articles that investigate immoral behaviors in the organizations such as abusive supervision and counterproductive behavior. These studies have systematically examined the role of immoral behavior in the organizations from both moral cognition and emotion perspectives, which provide a complete understanding of the mechanisms underlying the immoral behavior. Moreover, we included one systematic review of executives' unethical behavior. Here, we provide an overview of the articles that have been included in this Research Topic.Saeed et al., which examines the impact of ethical leadership on knowledge sharing through the social learning theory. In this study, psychological ownership serves as a mediating variable and professional commitment serves as a moderating variable. The data was collected from employees of 307 Pakistani listed companies. The findings reveal that ethical leadership had a positive effect on knowledge sharing via psychological ownership which was buffered by professional commitment, enhancing the understanding in the field of leadership and knowledge management by identifying the role of ethics.The study “Linking Ethical Leadership to Followers' Knowledge Sharing: Mediating Role of Psychological Ownership and Moderating Role of Professional Commitment” was conducted by Cheng, Guo, et al. employ social information processing theory and social learning theory to build a moderated mediation model. Based on the sample of 557 participants, the results suggest that responsible leadership could inhibit unethical pro-organizational behavior and customer-oriented perspective taking partially may mediate the negative link between responsible leadership and unethical pro-organizational behavior.What about the relationship between responsible leadership and unethical pro-organizational behavior? In their work “Standing in Customers' Shoes: How Responsible Leadership Inhibits Unethical Pro-Organizational Behavior,” Chen J. et al., have used the sample of 287 teachers to examine the relationship between moral leadership and innovation performance.In their work “The Impact of Moral Leadership on Physical Education Teachers' Innovation Behavior: The Role of Identification with Leader and Psychological Safety,” Zada S. et al. utilized social learning theory and data from 347 employees in 56 teams to investigate the relationship among servant leadership, psychological safety, and knowledge hoarding. The findings suggest that servant leadership negatively affects knowledge hoarding by positively influencing psychological safety, and mastery climate moderated the relationship.The article “Servant Leadership Behavior at Workplace and Knowledge Hoarding: A Moderation Mediation Examination,” written by Zada M. et al., examined the impact of servant leadership on the task performance of employees in virtual working environments during the COVID-19 crisis. Drawing on the conservation of resources theory, the findings revealed that servant leadership is positively related to task performance in a virtual environment during crises. The study also found that psychological empowerment partially mediates this relationship, and perceived supervisor support positively moderates the relationship between servant leadership and task performance.The study “How Classy Servant Leader at Workplace? Linking Servant Leadership and Task Performance During the COVID-19 Crisis: A Moderation and Mediation Approach” by Liu L. et al. have examined one type of destructive leadership, the self-serving leadership. Drawing from the social identity theory and 377 survey data via a three-wave time lagged design, the findings showed that self-serving leadership may induce employees' deviant behavior, organizational identification partially mediates self-serving leadership and employees' deviant behavior, and employees' moral identity negatively moderates the relationship between self-serving leadership and employees' organizational identification.In their work “The Influence of Self-Serving Leadership on Deviant Behaviors in the Workplace: A Moderated Mediation Model,” Zhu et al.. This bibliometric analysis has reviewed 428 articles published between the years 2000 and 2020 on executives' unethical behavior in the emerging markets.The study “Executives' unethical behavior with directions for future research,” is written by Xu et al. have used conservation of resources theory to build a moderated mediation model with emotional exhaustion as a mediating variable and supervisor-subordinate guanxi as a moderating variable. The data was collected from 440 tourism employees. The results show that leaders' knowledge hiding is positively linked to employees' withdrawal behavior and emotional exhaustion.In their work “The influence of leader–signaled knowledge hiding on tourism employees' work withdrawal behavior: A moderated mediating model,” Su et al., employed the social cognitive theory and social exchange theory to explain how, when and why self-sacrificial leaders may trigger knowledge sharing. Totally, 481 pair sample has been used to test the theoretical model. The results showed that good guanxi between employees and their leaders, could lead employees to better understand leaders' self-sacrificial behavior and engage in knowledge sharing.Regarding the relationship between self-sacrificial leadership and employees' knowledge sharing, they study “How Does Self-Sacrificial Leadership Foster Knowledge Sharing Behavior in Employees? Moral Ownership, Felt Obligation and Supervisor-Subordinate Guanxi,” conducted by Liu X. et al.. Drawing upon purposeful work behavior theory and using two-wave time lagged design, data was collected from 216 employee-supervisor dyads. The findings showed that duty orientation and achievement orientation have opposite relationship to pro-social rule breaking. Furthermore, job autonomy strengthens the positive effect of duty orientation and the negative effect of achievement orientation on pro-social rule breaking.The study entitled “Does Self-Sacrifice Make Me Great? Research on the Relationship Between Employee Conscientiousness and pro-Social Rule Breaking” is written by Wang and Ma used social comparison theory and a sample of 331 employees, to examine the interaction between perceptions of coworkers' receiving idiosyncratic deals and respective deprivation. The findings showed the moderating role of conscientiousness, which may weaken the relationship between deprivation and social undermining.We have included another contribution related to employee consciousness. In their work “When Do Coworkers' Idiosyncratic Deals Trigger Social Undermining? – The Moderating Roles of Cored Self-Evaluations and Conscientiousness,” Zhang H. et al., examined the impacts of three helping behaviors  on helpers themselves. Drawing from the resource conservation theory and using a three-wave time-lagged design, the findings suggested that caring and coaching were more negatively associated with emotional exhaustion and helpers of these two styles were less likely to adopt subsequent deviant behaviors. This study has also identified the role of extrinsic career goals in the direct relationship between the three helping behavior and emotional exhaustion.They study “When and How Workplace Helping Promotes Deviance? An Actor-Centric Perspective,” conducted by Cheng, Hu, et al., uses the data collected from 218 salespeople in the internet technology service company and develops a contingent model to show how moral identity and impression management motives could moderate the links between pro-organizational motives, unethical pro-organizational behavior, and organizational behavior.The contribution “A Contingency Perspective of Pro-Organizational Motives, Unethical Pro-Organizational Behavior, and Organizational Citizenship Behavior,” written by Xiao J. et al., has examined the implicit coordination from the perspective of team mentality, and discussed the incentive mechanism of status competition by using knowledge sharing as a mediating variable and psychological safety as a moderating variable. The empirical study has used a sample of 367 employees from 44 companies. The findings revealed that prestige-type status competition was positively related to implicit coordination, while dominant-type status competition was negatively related to implicit coordination. Furthermore, knowledge sharing mediated the relationship between both types of status and implicit coordination, and psychological safety enhanced both relationships.The article “Status Competition and Implicit Coordination: Based on the Role of Knowledge Sharing and Psychological Safety” written by Zhang M. et al. uncovered the situational factors that influence employees' unethical pro-organizational behavior to repay the organization. Based on the social exchange theory, the authors used multisource data from 139 human resource managers and 966 employees to examine why and how high-commitment work systems affect employees' unethical pro-organizational behavior. The findings revealed that high-commitment work systems promote employees' unethical pro-organizational behavior through relational psychological contract. Besides, the findings showed that balanced reciprocity beliefs strengthen the positive relationship between relational psychological contract and employees' unethical pro-organizational behavior.In the study “Research on the Relationship Between High-Commitment Work Systems and Employees' Unethical Pro-Organizational Behavior: The Moderating Role of Balanced Reciprocity Beliefs,” Zhang Z. et al. conducted the study “Does Technostress Increase R&D Employees' Knowledge Hiding in the Digital Era?” and introduced work exhaustion as a mediating variable for exploring how five sub-dimensions of technostress impact R&D employees' knowledge hiding. The authors have used job demand-resource theory to examine technostress—an antecedent of knowledge hiding. The sample of 254 participants was collected through a two-stage survey. The findings showed that techno-invasion, techno-insecurity, and techno-complexity were significantly and positively associated with work exhaustion. Furthermore, work exhaustion mediated the relationship between aforementioned three variables and knowledge hiding, while workplace friendship negatively moderated the association between techno-invasion, techno-insecurity and work exhaustion, reducing the emergence of knowledge hiding, while it also positively moderated the association between techno-complexity and work exhaustion.Wu et al. examined the relationship between workplace suspicion and employees' silence, as well as the mediating role of knowledge hiding from a colleague's perspective. Drawing from resource conservation theory and self-regulation theory, data of 303 pair sample from 23 companies in China was collected through three-waves questionnaire method. The results revealed that workplace suspicion positively influenced employees' silence via knowledge hiding, and knowledge-based psychological ownership strengthened the mediating effect. However, face consciousness weakened the positive impact of workplace suspicion on knowledge hiding.The study “Workplace Suspicion, Knowledge Hiding, and Silence Behavior: A Double-Moderated Mediation Model of Knowledge-Based Psychological Ownership and Face Consciousness” conducted by Zheng et al. uses 176 valid responses to examine whether employees' personal ethics and perceptions of corporate hypocrisy can be beneficial for reducing employees' mental fatigue. The theories used to develop the hypotheses are stakeholder theories and sociological theories. The findings showed that employees' mental fatigue reduces when internal or external corporate social responsibility (CSR) has a positive impact on employees' altruistic choice and employees' mental fatigue increases when CSR has a negative effect on ethical egoism.The study “Impacts of Corporate Social Responsibility on Employees' Mental Fatigue” written by Jiang et al. conducted the study of “Benefits of Non-Work Interactions with Your Supervisor: Exploring the Bottom-Up Effect of Employee Boundary Blurring Behavior on Abusive Supervision” and explored how employees' boundary blurring behavior can prevent themselves from being abused by supervisors. Drawing from the self-disclosure theory, authors have used a scenario-based experimental study and a multi-wave field study to find out that employees' boundary blurring behaviors inhibit the emergence of abusive supervision through the mediating effect of supervisor liking toward the employee.Existing research seldom employs a bottom-up perspective to examine how employees can reduce abusive supervision. In their work, Fousiani et al. explored the effect of morality and competence in recruiters' hiring decisions. The authors used the Big Two theoretical framework to examine how instrumental or relational goals of organizations might influence the importance of morality or competence of candidates during the hiring process. The authors conducted three studies  to test the proposed hypotheses. The findings showed that the primacy effect of morality might hold when organizational goals are relational but might get reversed when organizational goals are instrumental. They also found that perceived appropriateness of a candidate positively affects hiring recommendations.In the article “Appearing competent or moral? The role of organizational goals in the evaluation of candidates,” Carminati and Héliot, titled “Between Multiple Identities and Values: Professionals' Identity Conflicts in Ethically Charged Situations,” adopted a qualitative approach. Forty-seven semi-structured interviews had been conducted among doctors and nurses working for the English National Healthcare Service. The findings showed that micro processes such as cognitive and emotional perspective taking, plus identifying with the other may trigger identity conflict.The contribution of Khan et al. examined the relationship between perceived overqualification and counterproductive work behavior (CWB) among textile sector employees, considering job boredom as a mediator and job crafting as a moderator. The findings showed a positive relationship between perceived overqualification and CWB. Furthermore, the study found that job boredom mediated the relationship between perceived overqualification and CWB, and job crafting moderated the positive association between perceived overqualification and job boredom.The study “Person–Job Misfit: Perceived Overqualification and Counterproductive Work Behavior” by Shen et al. titled “How I Speak Defines What I Do: Effects of the Functional Language Proficiency of Host Country Employees on Their Unethical Pro-Organizational Behavior” investigates the relationship between functional language proficiency  and unethical pro-organizational behavior of host country employees in multinational corporations (MNCs). The authors used data from 309 full-time host country employees to test their predictions guided by social identity theory. The findings suggested that host country employees' functional language proficiency enhances their unethical pro-organizational behavior through their linguistic group identification and moral disengagement.The article by Liu J.-N. et al.. Drawing from planned behavior theory and 200 civil servants' data, the findings showed that public sector leaders' information-sharing behavior is positively related to their subordinates' taking charge behavior, and public service motivation mediates this relationship. The results also found emotional trust strongly moderates the effect of leaders' information-sharing behavior on subordinates' taking charge behavior.The article “How does leaders' information-sharing behavior affect subordinates' taking charge behavior in public sector? A moderated mediation effect,” is written by Dai et al. have examined the role of positive workplace gossip through a moderated mediation model. Data from 327 employees in the Pearl River and Yangtze River Delta regions of China was collected to test the theory model. The results showed that positive workplace gossip may promote employee innovation.In their work “Is not workplace gossip bad? The effect of positive workplace gossip on employee innovative behavior,” Wang and Tang aimed to investigate the impact of daily supervisor abuse and coworker support on daily work engagement. Drawing from the conservation of resources (COR) theory, the study utilized a daily diary approach and collected data from 73 employees during five consecutive days in China. The results showed that daily abusive supervision had a negative impact on daily work engagement and that daily negative emotions mediated this relationship. Coworker support had a cross-level moderating effect between daily abusive supervision and daily negative emotions.The article “How Daily Supervisor Abuse and Coworker Support Affect Daily Work Engagement” by Xiao W. et al. investigates the impact of crowdsourcing innovation community reference on creative territory behavior from the perspective of reference group theory. A two-stage survey has been used and 524 valid responses were collected. The results suggested that the crowdsourcing innovation community reference influences members' impression management behavior and then inhibits creative territory behavior. Interestingly, there are different community reference effects among members of different community age groups. These findings contribute to understanding the influence of the crowdsourcing innovation community on crowd participation decision-making and suggest implications for exploring the cooperation mechanism of crowdsourcing innovation.The study “Influence of Crowd-sourcing Innovation Community Reference on Creative Territory Behavior” by Chen H. et al. examined the relationship between leader's aggressive humor and bystander's workplace withdrawal behavior. The study used the Cognitive-Affective Personality System Theory and collected data from 443 employees and their direct supervisors in the Chinese enterprises. The results showed that leader-aggressive humor positively affected bystander affective rumination and bystander workplace anxiety, which in turn mediated the relationship between leader-aggressive humor and bystander workplace withdrawal behavior. Additionally, organization-based self-esteem moderated the indirect impact of leader-aggressive humor on bystander workplace withdrawal behavior through bystander affective rumination and bystander workplace anxiety.In another perspective, the article “Why Does Leader Aggressive Humor Lead to Bystander Workplace Withdrawal Behavior?—Based on the Dual Path Perspective of Cognition Affection,” Dai et al. have explored the effect of positive workplace gossip on employee's innovative behavior; Zhang H. et al. have studied when and how workplace helping promotes workplace deviance from an actor-centric perspective; Zhang M. et al. have explained the dark side of high-commitment work systems and linked it to employees' unethical pro-organizational behavior. These findings point out the importance to review and manage workplace (un)ethical/(im)moral behaviors with a balanced but critical perspective.This Research Topic has made the following contributions. First, in this Research Topic, scholars attempted to conduct research from different perspectives and methodologies on the “good” behaviors  and negative behaviors , which have enriched the research on the “dark sides” of workplace positive behavior and the “bright sides” of workplace negative behavior. For example, the study of Cheng, Guo, et al. have examined how positive leadership can prevent employees' workplace unethical/immoral behaviors. This contribution has greatly enriched the current understanding of how responsible leadership is related to employees' unethical pro-organizational behavior. Furthermore, this study has explicitly explained the impacts of positive leadership and the important role that positive leadership can play in inhibiting and governing the negative behaviors of employees.Second, prior research has explored the relationship between various types of destructive leaders' behavior  and workplace unethical/immoral behaviors such as counterproductive work behavior, and the relationship between positive leadership  and employees' positive workplace behaviors such as innovative behavior and prosocial behavior. However, how positive leadership can help prevent unethical organizational behaviors requires further development. In this Research Topic, Xu et al. have explored the influence of leader-signaled knowledge hiding on tourism employees' withdrawal behavior. Jiang et al. have advocated the benefits of employees' non-work interactions with their supervisors and verified the bottom-up effect of employee boundary blurring behavior on abusive supervision. Liu J.-N. et al. have investigated how leaders' information sharing behavior affect subordinates' taking charge behavior in public sector. Chen H. et al. have further studied the relationship between leader's aggressive humor and employee's withdrawal behavior from a bystander's perspective. Su et al. have demonstrated the impacts of leaders' self-sacrificial behaviors and supervisor-subordinate guanxi on employees' knowledge sharing. Wang and Tang have integrated daily supervisor abuse and coworker support in influencing employees' daily work engagement. These contributions point out that when managing leaders' or employees' workplace (un)ethical/(im)moral behaviors, one should not only look for the reasons and respective governance strategies from the actors' perspectives. In fact, the influence of others is an important source of the formation of individual behaviors in the workplace. Managers should improve the positive interpersonal interactions through building the healthy and meaningful relationship at the workplace, and reduce the contagion effects through lead by example, open communication, promotion of positive corporate culture, rewards on the ethical/moral behaviors, and so on.Third, this Research Topic focuses on the mechanisms by which relationships and interpersonal interactions between supervisors and subordinates and between coworkers influence each other's (un)ethical/(im)moral behaviors. We have included studies of top-down leadership behaviors and their impacts on employees' behaviors, and the studies of the bottom-up employees' behaviors and their impacts on leaders' behaviors. The (un)ethical/(im)moral behaviors in the workplace are examined through multiple directions. For example, Liu J.-N. et al.; Su et al.; Xiao J. et al.; Saeed et al.), knowledge hiding , and knowledge hoarding  have attracted increasing attention. The contributions have employed theoretical lens such as the conservation of resources theory, the self-regulation theory, the framework of “cognition-motivation-behavior,” and the psychological safety and psychological ownership perspectives, to examine the formation mechanism between knowledge sharing behavior and counterproductive knowledge behavior. In addition, these contributions have provided a systematic review related to the moral concern of knowledge hiding. Thanks to these studies, we are able to enrich the knowledge hiding research by diversifying the existing theoretical perspectives, realizing the interdisciplinary studies, introducing and integrating the moral ownership, moral self-regulation and other moral psychology, cognitive psychology and other disciplines in the theoretical perspectives, forming new insights to call for research on the novel knowledge hiding phenomenon . Furthermore, the contributions that have been included in this Research Topic have taken the lead in exploring how technostress increase R&D employee knowledge hiding in the digital era. These findings draw practitioners' attention to the ethical nature of knowledge hiding behaviors and the respective moral issues. This Research Topic offers practitioners with knowledge on how to better anticipate the harmfulness of immoral behavior and the dark sides of moral behavior, developing the knowledge governance practices from the perspectives of employees' moral emotion and moral cognition.Last, knowledge-related behaviors such as knowledge sharing (see for example All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Animal welfare and economic implications of infectious diseases in cattle demand an efficient surveillance as the foundation for control and eradication programmes. Bovine respiratory syncytial virus (BRSV), Parainfluenza virus type 3 (PI3V), Bovine herpes virus-1 (BoHV-1), Bovine viral diarrhoea virus (BVDV), and Enzootic bovine leukosis virus (EBLV) cause common and often underdiagnosed diseases in cattle that are endemic in most countries [ Th. Th31]. All assays were highly sensitive and able to discriminate the presence of antibodies from the 1 : 2 dilution. Nonetheless, the dilution that characterized the detection limit varied slightly for each antigen, with the 1 : 1024 dilution successfully discriminating positive samples from non-specific binding values for all five antigens tested. Albeit assays could discriminate positive samples in a wide range of dilutions, the MFI was diminished at low dilutions (1 : 8 or below). This counter-intuitive phenomenon (hook effect) occurs when an excess of antibodies impairs their effectiveness to form immune complexes . With hiet al. [et al. 2007 [et al. [Multiplexing in its various platforms will likely substitute monoplex assays for massive serological surveillance. As with ELISA, xMAP allows for the in-house development of assays, optimizing the antigens of interest and permitting the customization of antigen panels to suit specific needs. The development of an xMAP assay is no more complicated than that of an ELISA that uses the same antigens, in most cases yielding similar or even higher sensitivity. Several multiplex assays have been developed by other research groups to study bovine diseases. Fontana et al.  created al. 2007 ). Anders [et al.  devised  [et al. . NonetheThe viruses chosen for the development of the pentaplex assay in this study , have been targeted in eradication/control programmes in Europe and North America due to increasing disease prevalence  and the


With remarkable progress being witnessed in recent years in the development of sensors, these advances in sensor technology provide unprecedented opportunities for (1) the early diagnosis and prevention of human diseases by detecting critical biomarkers; (2) health assessments by monitoring and analyzing human physiological signals in healthcare and biomedical applications; and (3) the efficient evaluation of human-health-relevant environmental factors by monitoring and measuring environmental determinants.This Special Issue aims to provide an overview of recent advances being made in sensing technology, including sensors and smart devices, and their applications in healthcare, biomedical, and environmental research. The purpose of this Special Issue is to publish a collection of papers that highlight insightful and influential concepts, designs, algorithms, and techniques in this field. We expect these high-quality papers to be widely read and cited for improving the understanding of physiological mechanisms through accurate and sensitive detection, providing new perspectives and technology to solve health-related problems and state-of-the-art designs to integrate multifunctional sensors.Mingyu Sun et al.  proposedRamona B. Damalerio et al.  fabricatHamed Samimi and Hilmi R. Dajani  focused Haoran Liu et al.  proposedChuan Dai et al.  proposedAli Barzegar Khanghah et al.  presentePanayiotis Antoniou et al.  investigJie Huang and Daqing Huang  designedn = 19) were increased to either 25, 35 or 45 mmHg for 4 h before returning to normal pressure levels at 15 mmHg for the remaining 4 h. Changes in tissue hydration were assessed by differences in spectral slopes between 0.4 and 0.8 THz. They demonstrated that THz can noninvasively assess the corneal endothelium and provide valuable complimentary information for the study and diagnosis of corneal diseases that perturb the hydration of the tissue.Andrew Chen et al.  utilizedPengsu Mao  divided n = 8), fractal analysis (n = 3), recurrence quantification (n = 2), and the Lyapunov exponent (n = 2). This review demonstrated that, in adolescents assessed in a real context, entropy measures are preferred when studying the complexity of human movement, especially when examining multiscale entropy.Sandra Silva et al.  aimed toWe would like to express our profound appreciation for the authors and reviewers who made this Special Issue possible. Our reviewers and authors have dedicated tremendous effort into the preparation of this Special Issue, in order to allow it come to life and flourish.


Pain Medicine community regarding the recent Cochrane review entitled “Spinal cord stimulation for low back pain” by Traeger et al.,We write to the When making broad recommendations about the use of SCS in the real world, the full context and breadth of available literature must be taken into consideration. The authors designed search criteria that included clinical trials comparing SCS to placebo or “no treatment”  studies with parallel-group design).While high-quality placebo-controlled studies of SCS for CLBP are indeed needed, there is an abundance of Level 1 comparative effectiveness data that supports the effectiveness of SCS for CLBP. These studies have long-term follow-up and answer key clinical questions, such as defining the optimal SCS waveform for a specific patient phenotype, and whether SCS provides outcome and cost benefits over revision decompression and/or fusion surgery. The summation of these data demonstrates large magnitudes of effect, although with indirectness and potential for risk of bias. As such, GRADE assessment should reveal moderate-certainty evidence of medium to long-term effectiveness of SCS for CLBP.2 statistical analysisTraeger et al.,The authors’ conclusions about SCS’s probable lack of efficacy rested singularly on the Hara et al.Surgery, the ultimate placebo and 2) Hippocrasy: How doctors are betraying their oath. Furthermore, while a pain physician was acknowledged at the end of the publication,Generalizations about CLBP care interventions, drawn from data limited by narrow search criteria, are problematic and misleading. The reader is left questioning whether Traeger et al.We respectfully urge the Cochrane Library to retract and revise the Traeger et al.


Tan et al. and Zhu et al. A diversity of preclinical/translational research studies were also presented in the Research Topic. Lozon et al. presented a novel chemotherapy combination that was validated in vitro in colon cancer and lung cancer cell lines. Abdollah et al., Yang et al., and Lee et al. highlighted a promising anticancer activity for a variety of natural products against hepatocellular carcinoma. On the other hand, the work of Lee et al., Lin et al., Irshad et al., and Kuttikrishnan et al. presented mechanistic insights in pancreatic cancer, breast cancer, non-small-cell lung cancer, and leukemia. The Research Topic also encompasses two literature reviews by Bannoura et al. and Yuan et al.Continuous research efforts have significantly unraveled fundamental molecular pathways that have contributed to paving the way for the development of a multitude of therapeutic strategies, which have and expanded the arsenal of weapons against cancer. This has been tremendously reflected on the uplifting of the cancer survival curve and the improvement of the quality of life of cancer patients. The Research Topic herein was dedicated to highlighting the emerging talents of student researchers pursuing studies in the area of pharmacology of anticancer drugs. The articles in this Research Topic have shed light on the quality and diversity of student researchers across this field and focused on three main themes: 1) Remodeling Cancer Epigenome: Therapeutic Advances; 2) Cancer Immunosurveillance: From Mechanisms to Therapy; 3) Anticancer Drug Discovery and Translational Oncology. The studies herein include two reports of clinical trials by Zhu et al. employed a Markov decision-analytic model to compare the cost-effectiveness of T-DXd with chemotherapy in HER2-low ABC patients. While T-DXd showed improved quality-adjusted life years (QALYs), its incorporation led to increased costs and an unfavorable incremental cost-effectiveness ratio (ICER) compared to chemotherapy, making it devoid of cost-effectiveness in HER2-low ABC patients in the United States. The authors, however, believe that it may still provide health benefits to patients with HR+/HER2-low ABC.Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate, has shown antitumor activity in patients with HER2-low advanced breast cancer (ABC) in clinical trials. However, the cost-effectiveness of T-DXd was not clearly established. In order to determine whether the benefits of this treatment outweigh its costs, Tan et al. suggested that pembrolizumab plus nab-paclitaxel might be a potential treatment option for patients with cholangiocarcinoma (CCA), which is a highly aggressive malignancy with poor overall survival. In this report, a metastatic extrahepatic CCA patient achieved durable response and good tolerance to a combination treatment of pembrolizumab plus nab-paclitaxel following progression on a chemotherapy of gemcitabine and capecitabine.In their case report, Lozon et al. contributed an original article highlighting the importance of safranal (SAF) as a promising candidate-sensitizing agent of human colon cancer cells (HCT116) and lung cancer cells (A549) to the cytotoxic effect of the topoisomerase inhibitor topotecan (TPT). The combination augmented TPT-induced alterations in DNA repair and boosted the incidence of double-strand breaks with subsequent induction of apoptosis. The sensitization only occurred when the cells were pretreated with SAF 24 h before TPT treatment. However, simultaneous exposure or adding SAF 24 h after TPT did not recapitulate the same results. Hence, the effect was sequence dependent.Abdollah et al. aimed to determine whether fucoidan’s chemomodulatory benefits may be enhanced by using it in combination with the FDA-approved antiangiogenic drugs sorafenib and Avastin (bevacizumab) in order to augment their anticancer activity in hepatocellular carcinoma (HCC) cells. The authors reported that the combination treatment inhibited the PI3K/AKT/mTOR and KRAS/BRAF/MAPK pathways in addition to apoptosis induction in HCC both in vitro and in vivo.An article by Yang et al. identified a potential pharmacological mechanism by which Ganji Fang (GJF) can treat HCC at the systemic level. The underlying mechanisms were shown to involve immune control, cell migration, cell proliferation, apoptosis, and inflammation induction. Furthermore, it was demonstrated that the G0/G1 phase cycle arrest subsequent to the apoptosis after GJF treatment in liver cancer cells was triggered by blocking the PI3K/Akt signaling pathway. Pachymic acid has been shown to be the significant active component of GJF that exhibits anticancer action, and EPHA2 may be a potential key target for GJF in HCC.Lee et al. reported that WGM extracts induced cell death by targeting mTOR and MAPK signaling pathways in liver cancer cells, suggesting that they could be used as a pharmacologically safe natural dietary chemopreventive agent for HCC treatment.It was previously found that white genius mushroom (WGM), a popular edible mushroom in Taiwan, mediates strong antiproliferative activities against human Hep3B liver cancer cells. However, the underlying mechanisms have not been fully investigated. Lee et al. investigated the efficacy and molecular mechanisms of ivermectin/gemcitabine combination in pancreatic cancer. They observed that a combination treatment of ivermectin and gemcitabine suppressed pancreatic cancer both in vitro and in vivo more effectively than gemcitabine alone. Mechanistically, this combination was found to exert its effects by inhibiting cell proliferation via G1 cell cycle arrest and augmenting apoptosis by inducing mitochondrial dysfunction. Based on these findings, the study concluded that ivermectin, an antiparasitic drug, can exhibit synergistic effects with gemcitabine and may be repurposed to serve as a promising therapeutic agent for pancreatic cancer therapy.The article by Lin et al. demonstrated the anticancer effects of gallic acid, a phenolic acid known for its antioxidant properties, against triple-negative breast cancer cells in vitro. The study showed that gallic acid was able to inhibit the growth of HCC1806 cells and stimulate their apoptosis by triggering the production of reactive oxygen species, which modulate the PI3K/AKT/EGFR and MAPK signaling pathways.Irshad et al. employed integrative network pharmacology, molecular docking, and in vitro experiments to elucidate the mechanism of action of glycyrrhetinic acid (18α-GA), a triterpenoid found in licorice against non-small-cell lung cancer (NSCLC). Their network pharmacology study identified EGFR, AKT1, PI3KR1, MAPK1, IGF1, and SRC as crucial hub targets for 18α-GA against NSCLC. The authors further showed that 18α-GA augmented G1 cell cycle arrest, triggered apoptosis, reduced the migratory potential, and inhibited the EGFR-PI3K/AKT pathway in NSCLC cell lines.Kuttikrishnan et al. explored the role of neosetophomone-B (NSP-B), a meroterpenoid fungal secondary metabolite, on the FOXM1/BUB1B signaling pathway. The development and progression of various types of cancer, including chronic myelogenous leukemia, have been linked to the abnormal expression of FOXM1 and BUB1B genes. A TCGA data analysis elaborated that BUB1B is overexpressed in most cancers and linked with poor prognosis. Using gene expression profiling, the authors showed the significant downregulation of BUB1B in leukemia cells treated with NSP-B. In addition, they validated their in silico findings in vitro by showing that NSP-B suppresses the expression of FOXM1 and BUB1B in a dose-dependent manner, leading to compromised cell viability and apoptosis induction in leukemia cells.Bannoura et al. summarized the recent data on targeting KRAS G12D, which is among the most common mutations (45%) in pancreatic cancer that are associated with poor prognosis. The article discussed several modalities under development for targeting KRAS G12D, including small molecule inhibitors and immunotherapy.The minireview by Yuan et al. contributed a bibliometric article of the literature from the Web of Science Core Research Topic (2002–2021) on the emerging trends and research foci of the natural compound berberine in cancer. Berberine is a multitarget Chinese medicine monomer compound that is extensively studied for its antitumor/antiproliferative effects and its capacity to sensitize cancer cells to chemotherapy. The collected data showed that berberine exhibits anticancer capacity through a diversity of mechanisms, including halting the cell cycle, inhibition of tumor cell invasion and migration, and inducing autophagy and apoptotic cell death.


Natural products have played important roles in drug discovery and development as more than 60% drugs are associated with natural products . Yunnan Chen et al., Lei et al., Yan et al., and Clements-Decker et al.), new synthetic approaches towards the key units of natural products , total synthesis of natural products , and structure-activity-relationship (SAR) studies on bioactive natural-product-like molecules . Taken overall, 10 contributions including 2 reviews and 8 original research articles comprise this Research Topic.This Research Topic presents a Research Topic of reviews and original research articles on isolation and structural characterization of novel natural products . A study on antioxidant and anti-inflammatory activity of constituents isolated from Dendrobium nobile (Lindl.) by Lei et al. shows that nineteen compounds, including two new vitamin E homologues, one new sesquiterpene, and two new dendrobines were isolated. New compound aldehyde-α-tocopherol demonstrated significant antioxidant activity compared with ascorbic acid (VC), as well as equal cytotoxic effect against Hela cell lines to cisplatin, indicating its potential application in the pharmaceutical and food industries. Yan et al. found fourteen C19-lycaconitine-type diterpenoid alkaloids, including six new alkaloids, grandiflolines A–F, isolated from Delphinium grandiflorum L. New alkaloids grandiflolines A-C and E possess a characteristic Δ2,3 functional group in the A ring, while grandiflolines E and F feature a rare OH-16 substituent. New alkaloids exhibit potential inhibition activities of NO in LPS-activated RAW 264.7 macrophages. A review conducted by Clements-Decker et al. delved into the antimicrobial properties of lipopeptides derived from various bacteria strains. The study sheds light on the structures and recently discovered frameworks of lipopeptide families produced by these bacteria, which possess promising antimicrobial properties. Furthermore, utilizing the genome mining approach, underexplored sources of novel antimicrobial lipopeptides have been uncovered. A detailed understanding of the mode of action and biosynthesis included in the review provides a clear path for the development of potential antimicrobial therapeutics in the future.Rao et al. reported a new transitionmetal-free direct oxidative cyclocondensation reaction. The protocol highlighted the use of readily available o-aminobenzyl alcohols and N,N-dimethyl enaminones as starting materials, thus provided a flexible strategy for the preparation of 3-substituted or 3,4-disubstituted quinolones with broad substrate scope in moderate to excellent yields. The strategy enriched the quinoline synthesis method. Jiang et al. reported an effective palladium-catalyzed method for the synthesis of aryl acrylonitriles. This process uses simple and readily available arylacetonitriles and vinyl halides/triflates as raw materials, and the resultant aryl acrylonitriles can undergo a series of useful conversion reactions, such as reduction, hydrolysis and epoxidation.Wei et al. reported a general strategy for the total synthesis of arylnaphthalene lactone lignans (NALLs) including justicidins B and E and taiwanin C. Key features of this synthesis include an aryl–alkyl Suzuki cross-coupling, a novel intramolecular cation-induced cyclization, and a base-mediated oxidative aromatization. Wei et al. explored the uses of dioxinones in synthesizing macrocyclic natural products and terpenoids. The review highlights the versatility and efficiency of dioxinones as reactive intermediates, making them valuable tools for the synthesis of diverse and complex natural products.Zhou et al. designed and synthesized a series of anti-ZIKV active compounds, acetylarylamine-S-DACOs, and conducted in-depth research on the action mechanism of the representative compound through molecular docking analysis and a series of biological experiments. The results confirmed the anti-ZIKV activity at the molecular and protein levels, and discovered that this selected compound targeted ZIKV RNA-dependent RNA polymerase (RdRp). Yin et al. created a series of podophyllotoxin derivatives containing nitrogen-containing heterocycles, which may have potential as anticancer drugs. After synthesizing several derivatives, imidazolium salts and triazolium salts were found to be the most effective against different types of human tumor cells. Additionally, experiments on cell cycle and apoptosis revealed that these compounds could trigger G2/M cell cycle arrest and apoptosis in HCT-116 cells.We hope that this Research Topic could provide an opportunity to school fellows of YNU to introduce their recent research findings in natural product chemistry to the chemical community, which could also provide an incentive for further scientific collaborations between school fellows of YNU and other researchers in this field.


Mast cells have existed for almost 500 million years  in many The international Journal of Molecular Sciences recently published Special Issues dedicated to aspects of the pathophysiology of mast cells, such as “Mast cells in human health and diseases” edited by Giovanna Traina , and “MaThe emphasis of this Special Issue entitled “The Role of Mast Cells and Their Inflammatory Mediators in Immunity” was to address aspects of mast cell involvement in immune and inflammatory processes not covered by previous volumes.A major review communicated via Dr. Domenico Ribatti and authored by Solimando et al. described in detail the production of interleukins by mast cells, as well as their important role in immune processes . Given tFor the longest time, the notion persisted that all mast cells are the same. Then, they were separated into mucosal-type (MMC), containing only tryptase, and those of the connective-tissue-type (CTMC), containing both chymase and tryptase. However, increasing evidence indicates that there are unique subpopulations with distinct histological and secretory characteristics. The submission via Dr. Lars Hellman by Akula et al. using quantitative transcriptome analysis describes a particular subtype of mucosal mast cell in bronchoalveolar lavage fluid (BALF) that contributes to inflammation in the lungs of asthmatic horses  that mayThe paper submitted via Dr. Claudia González-Espinosa by Martínez-Aguilar et al. identifies the augmenting effect of lysophosphatidylinositol  on mast cell functions promoting inflammation through the differential participation of the GPR55 and cannabinoid 2 (CB2) receptors . PI servThe submission via Dr. Zenke by De Toledo et al. describes the important finding that human-induced pluripotent stem cell (hiPSC)-derived mast cells can mimic mastocytosis-like mast cells , suggestThe article by Drs. Tsilioni and Theoharides reports for the first time that nanomolar amounts of recombinant coronavirus spike protein stimulated human mast cells to secrete proteases via the activation of the angiotensin-converting enzyme 2 (ACE2) receptor, but stimulates the release of the proinflammatory cytokine IL-1b via the activation of TLR4; these processes are augmented by alarmin IL-33 . This noThe contribution communicated via Dr. Tsilioni by Jingshu et al. reported the development of a 3-D hydrogel formed by collagen I and culture human mast cells and showed that different Aβ peptides could stimulate mast cells to secrete inflammatory mediators. This model could incorporate microglia and neurons that could better reflect the mechanisms involved in the pathogenesis of neuroinflammation and Alzheimer’s disease .The submission submitted via Dr. Marcus Maurer by Dr. Buttgereit et al. describes that the mitochondrial Complex I can act as a critical innate inhibitory component of the mast cell secretion of pro-inflammatory mediators . ComplexFinally, the review by Theoharides and Kempuraj discusses the potential role of the ezrin, radixin, moesin (ERMS) family of proteins, especially moesin, in regulating the exocytotic mechanism of mast cell secretion of granule-stored mediators .These papers highlight key aspects of the potential role of mast cells in immunity and inflammation by presenting novel findings on the subtypes, regulatory mechanisms, and unique associations with innate and external triggers. However, there are still gaps in our knowledge, such as the effect of the microenvironment on the tissue mast cell phenotype and ways to regulate mast cell activation. An improved understanding may be obtained through the use of in vitro disease surrogate models using organoids  with hiP


Leishmania parasites and cancer cells. The information regarding common expressed proteins, as possible therapeutic targets, in Leishmania parasites and cancer cells is scarce. Therefore, the current study reviews proteins, and investigates the regulation and functions of several key proteins in Leishmania parasites and cancer cells. The up- and down-regulations of such proteins were mostly related to survival, development, pathogenicity, metabolic pathways and vital signalling in Leishmania parasites and cancer cells. The presence of common expressed proteins in Leishmania parasites and cancer cells reveals valuable information regarding the possible shared mechanisms of pathogenicity and opportunities for therapeutic targeting in leishmaniasis and cancers in the future.The association of leishmaniasis and malignancies in human and animal models has been highlighted in recent years. The misdiagnosis of coexistence of leishmaniasis and cancer and the use of common drugs in the treatment of such diseases prompt us to further survey the molecular biology of  Leishmania. Annually, approximately 1.5–2 million new cases are reported worldwide being 310 million people at risk. The mortality rate of the disease varies from 40 000 to 70 000 cases per year  are mostly restricted to the skin lesions with diverse appearances, from localized to body extended wounds or mucosal affectations. However, visceral leishmaniasis (VL) is characterized by severe organic symptoms and might lead to death    can also raise the risk of developing some types of cancers and may contribute to the appearance of malignancies which makes them possible models to study host–parasite interactions and mechanisms of cancer  Liao, . Howeveret al., et al., et al., et al., et al., et al., et al., Leishmania parasites also modulate and destabilize the host chromatin structure leading to potential changes in relevant immune-related genes and responses  pathway  and PKC. The metabolic action of miltefosine affects the biosynthesis of glycolipids and membrane glycoproteins of the Leishmania parasite, leading to apoptosis  signalling , interleukin-12 (IL-12), IFN-γ, inducible nitric oxide synthase and IL-2, and finally, inducing tumour cell death. Cancer therapy is an essential research area and protein kinases are major targets for drugs. The mTOR is a highly conserved serine/threonine protein kinase that is central regulating essential cellular processes and mTOR inhibitors are used in cancer therapy  and parasite survival inside macrophages through down-regulation of the nuclear factor-κB and signal transducer and activator of transcription 3 oncogene factors  levels  led to the reduction of lesions size and decreased the load of parasites in skin in the L. amazonensis-infected BALB/c mice. However, the use of such an inhibitor also induced hepatotoxicity in BALB/c mice   were correlated with the development of oral cancer  selectively targeted proliferation and survival of tumour initiating cells in SCC and ovarian cancer cells. This compound prevented cancer cells from entering the S-phase under growth-factor stimulation without cell death induction  is an inhibitor of HSP90, which has been investigated in the treatment of cancer such as solid tumours and leukaemia. Alternatively, geldanamycin, and its analogues, 17-dimethylamino ethylamino-17-demethoxygeldanamycin (17-DMAG) and 17-AAG, may show a promising therapeutic activities against leishmaniasis . However, the delivery of 17-AAG is difficult because of its poor aqueous solubility  and is overexpressed in the promastigote forms compared to the amastigotes  and a combination of gossypol (a pan-ALDH inhibitor) and phenformin leads to cancer cell death  and beta (TOP 2B) which exhibit differences in their molecular weight, genetic regulation and the location of the active site. TOP II expression in cancer lines has been largely studied Doyle, . Althougδ) and epsilon (Pol ɛ). It also interacts with other proteins involved in cell-cycle progression which are not parts of the DNA polymerase complex. PCNA has demonstrated its role in the replication and repair of DNA, chromatin assembly and RNA transcription. Its importance in Leishmania pathology is related to its significant role in drug response in clinical isolates  dimers polymerize to form microtubules, which serve as a skeletal system for living cells and participate in several essential functions, such as mitosis or intracellular transport among others  has been suggested as potential drug target in leishmaniasis treatment    structure. Data produced by genome sequencing in protozoa has indicated the presence of TOM-40 homologues in in vitro’. It seems that TOM-40 increases the replication of cancer cells through regulating the mitochondrial activity and improving cellular energy and redox status , the expression of OAT is up-regulated and the mechanism of this gene up-regulation is related to the activation of β-catenin signalling (Cadoret et al., et al., β-catenin signalling and the metabolism of glutamine are important factors in carcinogenesis especially in HCC (Cadoret et al., Leishmania parasites (Zigmond et al., OAT as a Leishmania parasites (Iribar et al., et al., et al., Selenoproteins are a group of enzymes bearing selenocysteine in their catalytic domain. Many of the Se-bearing proteins participate in oxidative stress protection as observed in et al., et al., Leishmania, with promising results. However, this compound seems not to target selenoproteins in these parasites, but rather interact with trypanothione reductase, a key enzyme of Leishmania polyamine-dependent redox metabolism (Ilari et al., et al., et al., et al., The role of selenoproteins and their metabolites including methylselenol, selenodiglutathione, Se-methylselenocysteine and selenomethionine has been underlined in the metabolism of lung cancer cells (Seng and Tiekink, Leishmania parasites has been previously reported (Hart and Opperdoes, et al., et al., Leishmania. Therefore, they might be related to the pathogenicity of these parasites (Blattner et al., et al., Leishmania isolates suggesting resistant strains require higher energy to protect against antimony-induced oxidative stress. Alternatively, the overexpression of such enzyme might lead to enhancing in pyruvate which can remove peroxides and participate to reduce oxidative stress (Biyani et al., Leishmania and mammalian cells, PGKs are encoded by two genes: gene B and gene C, and PGK-1 and PGK-2, respectively (Watson and Littlechild, et al., T. brucei PGK. Of these, 2-amino-N6-substituted analogues represented appropriate activity against the parasite kinase compared with the N6 compounds that lacked the C2 amino group, although activity was still weak (Merritt et al., PGKs are transferases involved in ATP production from ADP and 1,3-diphosphoglycerate. Their involvement in the glycolytic pathway and survival of et al., et al., et al., et al., et al., et al., et al., The importance of PGK-1 in cancer development resides on its involvement in drug-resistance and its dual action depending on the cellular environment. Under intracellular hypoxia conditions, it plays an oncogenic role. However, it decreases tumour growth when it is secreted extracellularly through angiogenesis inhibition (Daly Leishmania parasites and cancer cells. As an interesting issue, the regulation of these markers can be investigated in interactions that can be occurred between Leishmania parasites and cancer cells under ‘in vivo’ and ‘in vitro’ conditions. The reliable validation of the expression of such proteins in Leishmania parasites and cancer cells using further experiments is warranted to subsequently confirm their possible functions. Further investigation of the differentially regulation of common expressed proteins between cancer cells, normal human cells, low-pathogenic and high-pathogenic forms of Leishmania parasites might elucidate novel and attractive information concerning such proteins. The existence of common triggering factors reflects mutual features in the etiopathogenetic mechanisms underlying leishmaniasis and cancer. Given these similarities, lessons learned from strategies against cancer may be relevant to design adequate approaches to reduce and eliminate leishmaniasis. Herein, we focused specifically on the shared mechanisms at protein scale. Taken together, the introduction of common expressed proteins in Leishmania parasites and cancer cells might reveal valuable information regarding the possible common mechanisms of pathogenicity and therapeutic targets in leishmaniasis and cancers. Taking into account that current therapies for neglected diseases are based in drugs lacking effectiveness, the lack of new specific anti-Leishmania compounds and of research focused on this group of diseases, drug repurposing constitutes a useful tool to find effective candidates in leishmaniasis control and elimination. This review reinforces the likely functional similarities between many proteins in cancer and parasites, some of them being recognized therapeutic targets and thus the potential use of drugs with proven efficacy in the treatment of cancer for treating parasitic diseases and vice versa, opening new avenues to the one health approach.The up- and down-regulation of the aforementioned proteins were mostly related to the survival, development, pathogenicity, metabolic pathways and vital signalling in


Iron is essential for life, and the dysregulation of iron homeostasis can lead to severe pathological changes in the neurological system. Iron deficiency slows the development of the neural system and causes mental and emotional disorders ,2,3, whiIn this Special Issue, “Iron Metabolism, Redox Balance and Neurological Diseases”, five original research articles and five scientific review papers are published. These papers highlight the most recent advances in different aspects of iron regulation and redox imbalance in various diseases, including the molecular mechanisms of iron-induced oxidative damage in disease pathogenesis, potential therapeutic targets and approaches for the regulation of iron metabolism and related damages, and challenges to current studies attempting to understand an aberrant iron metabolism in the pathology of different diseases and its potential clinical applications.In the original research articles, Han et al. revealed a novel role of iron in the maintenance of cell stemness via the Wnt/GSK-3β/β-catenin signaling pathway . The intBao et al. designed and characterized a mitochondrial-targeted pseudo-mitochondrial membrane potential (PMMP) constructed by antioxidant MitoQ , which sLiu et al. demonstrated that IRP2 not only regulated cellular iron homeostasis, but also medicated tissue iron distribution by managing the involvement of hypoxia-inducible factor 2 (HIF2) and nuclear receptor coactivator 4 (Ncoa4) . This stHan et al. investigated the underlying mechanisms of CY-09, a specific inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome, on ameliorating AD classical pathology and cognitive impairment in AD mice . Their fChen et al. revealed that the dopaminergic neuronal death and Parkinsonian symptoms in OTU domain-containing protein 3 (OTUD3) knockout mice might be caused by activating inositol-requiring enzyme 1α (IRE1α) signaling, which mediated endoplasmic reticulum (ER) stress . The OTUIn the review articles, Luo et al. summarized the molecular mechanisms of ferroptosis in glioma cell growth, invasion, migration, and resistance, and introduced potential applications and challenges of manipulating ferroptosis in the development and treatment of gliomas . They alJiménez-Jiménez et al. systematically reviewed the role of antioxidant coenzyme Q10 (CoQ10) in AD and other dementias . CombineHolbein et al. described biological iron requirements, iron regulation, and the nature of iron dysregulation in detail in various disease conditions , includiLee et al. reviewed the interplay between intracellular iron homeostasis and neuroinflammation in neurodegenerative diseases . They inGao et al. summarized and elucidated the interplay between the dysregulation of iron metabolism, redox imbalance, and different neurological diseases  such as In conclusion, the original research and review articles in this Special Issue provide an updated overview of the advances on the mechanisms or treatments of neurological diseases related to iron dysregulation and redox imbalance. These papers offer fresh perspectives on the expanding knowledge and research possibilities in the field of iron metabolism, redox balance, and neurological diseases, and may stimulate future studies to better target the regulation of brain iron metabolism for the prevention and treatment of neurological diseases.


Advanced Parkinson’s disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally. Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of nigrostriatal dopamine neurons and its incidence is increasing fast globally  is defined as a condition where periods of poor mobility with or without dyskinesia are present and have an impact on functional independence of the affected person  in a water solution of carboxymethyl cellulose into the patient’s proximal small intestine through a portable pump and a tube placed via percutaneous endoscopic gastro-jejunostomy (PEG-J)  of withdrawal  of 1.72 h in “Good ON” time. The trial also demonstrated positive and clinically meaningful results for the key secondary endpoint of “OFF” time (p < 0.0001) and other secondary endpoints including the MDS-Unified Parkinson's Disease Rating Scale Part II score (MDS-UPDRS motor experiences of daily living sub-score) (p < 0.0001); the Patient Global Impression of Change (PGIC) (p < 0.0001); and the Clinical Global Impression of Improvement (CGI-I) (p < 0.0001).ND0612 is a drug-device combination consisting of a sterile solution of levodopa/carbidopa continuously delivered via a dedicated subcutaneous pump (Olanow et al. ABBV-951 is a new soluble formulation of foslevodopa/foscarbidopa, both levodopa and carbidopa prodrugs, which can be delivered subcutaneously for up to 24 h/day. After administration, foslevodopa/foscarbidopa is quickly converted to levodopa/carbidopa by alkaline phosphatases, reaching and maintaining therapeutic steady-state plasma levels in a very short time (Rosebraugh et al. Research in PD has increasingly focused on the development of new and effective biological therapies for disease modification (Antonini et al. Limitations will still be related to the lack of direct comparative efficacy and safety studies among advanced treatments and the difficulty of identifying specific patients’ profiles.Infusion therapies might also become more integrated with remote monitoring technologies and telemedicine, allowing healthcare providers to track patient responses, adjust treatments and offer support from a distance (Guerra et al. Along with the progressive increase in the number of options, the selection of more appropriate device-aided therapy for APD will be more complex, it will involve multiple specialties as well as the carers and affected ones. A shared decision approach is, therefore, essential. While treatment decisions need to be individualized, the choice of device-aided therapies can be guided by some general principles based on the patient’s age, cognitive and behavioral status, dyskinesia and frailty.Understanding the comparative benefits of each treatment provides additional information that can help patients, caregivers and providers in the selection of the most appropriate therapy to ensure optimal symptom control and improved QoL (Martinez-Martin et al.


Flow cytometry is a single-cell based technology aimed to quantify the scattering of light and the emission of multiple fluorescence signals by individual cells, biological vesicles, or synthetic microscopical particles when examined one by one at high speed using lasers or other suitable illumination sources ,2. In coThis new Special Issue entitled “Flow Cytometry and Its Applications to Molecular Biology and Diagnosis 2.0” of the International Journal of Molecular Sciences includes a total of five contributions: three original articles and two reviews, providing new information about advanced applications of flow cytometry in the fields of molecular and cell biology for basic and translational research.Rossi et al.  extensivDrug development has evolved rapidly, and in the last years, cell and gene therapies are becoming efficient alternatives to small chemical and biomolecule pharmacology. Several cell and gene therapies have reached regulatory approval, specially in the field of tumor immunotherapy, and such a breakthrough demands suitable bioanalytical techniques for fully characterizing the pharmacokinetics of these therapies. However, these different techniques may not always lead to concordant results, and this fact requires a deep understanding of the technical grounds of each technique, which data are generated, and how these data can be compared and interpreted. In their review, Hays et al.  critical+ extracellular vesicles (EVs). These results support that the conjugation of antitumor drugs to SiNPs is an efficient way for drug delivery that potentiates drug cytotoxicity, while reducing side effects.Among the new directions for cancer therapy, nanomaterials appear as a promising tool for drug delivery into specific cells or subcellular compartments. In this regard, fluorescent silica nanoparticles (SiNPs) appear to be a promising imaging platform, as they show intramitochondrial colocalization in biological cell models and can be used as efficient drug delivery systems when conjugated to a therapeutic molecule. Sola et al.  performeCampylobacter jejuni and other Gram-negative bacteria. In the first part of their in vitro experimental design, Montanari et al. showed that CDT-containing bacterial lysates induce lethal and sublethal alterations in intestinal (CaCo-2) and myeloid (U937) cell lines, including cell cycle arrest, mitochondrial dysfunction, and oxidative stress. These intracellular changes were accompanied by relevant changes in lysosomal exocytosis, secretory autophagy, and EV release. Based on these effect on the secretion processes, Montanari et al. investigated the presence of active CDT in EVs secreted by CDT-treated CaCo-2 cells and found that CDT-like effects were transferred from infected CaCo-2 cells to uninfected heterologous (U937) and homologous (CaCo-2) cells. Their results suggest that EVs from CDT-treated CaCo-2 cells are reliable CDT carriers and could potentially be used in the treatment of colorectal cancer.The paper by Montanari et al.  exploredEscherichia coli B strains deficient in key genes of the antioxidant defense, namely oxyR, sodA, and sod B. Jávega et al. applied this model for systematically assessing issues of ROS specificity of several relevant fluorescent probes and the involvement of different ROS in the oxidative stress induced on these strains by exogenous prooxidants. Their results suggest that the antioxidant-deficient Escherichia coli B strains can be used as ROS biosensors in flow cytometric studies of oxidative stress and confirm the specificity issues of ROS-sensitive fluorescence that have already been detected in eukaryotic models. In addition, Jávega et al. provided recommendations for the proper design of flow cytometric studies involving ROS detection.Analysis of reactive oxygen species (ROS) and oxidative stress is a very relevant application of flow cytometry. However, to ascertain the specific role of ROS in oxidative stress studies via cytomic methodologies, it is essential to detect and characterize these species accurately. While there is a large availability of fluorescent probes for ROS analysis via flow cytometry, these reagents exhibit important limitations in their specificity and sensitivity that may affect the accuracy of the analysis. Jávega et al.  presente


Real-world data from wearable devices has the potential to understand mental health status in everyday life. We aimed to investigate the feasibility of estimating mental health status using a wrist-worn wearable device (Fitbit Sense) that measures movement using a 3D accelerometer and optical pulse photoplethysmography (PPG).Participants were 110 patients with mental illnesses from different diagnostic groups. The study was undertaken between 1 October 2020 and 31 March 2021. Participants wore a Fitbit Sense on their wrist and also completed the State–Trait Anxiety Inventory (STAI), Positive and Negative Affect Schedule (PANAS), and EuroQol 5 dimensions 5-level (EQ-5D-5L) during the study period. To determine heart rate (HR) variability (HRV), we calculated the sdnn , coefficient of variation of R-R intervals, and mean HR separately for each sleep stage and the daytime. The association between mental health status and HR and HRV was analyzed.The following significant correlations were found in the wake after sleep onset stage within 3 days of mental health status assessment: sdnn, HR and STAI scores, HR and PANAS scores, HR and EQ-5D-5L scores. The association between mental health status and HR and HRV was stronger the closer the temporal distance between mental health status assessment and HR measurement.A wrist-worn wearable device that measures PPG signals was feasible for use with patients with mental illness. Resting state HR and HRV could be used as an objective assessment of mental health status within a few days of measurement. BecauseHowever, because of concerns about the time and effort involved in self-administered questionnaires, an objective and less burdensome method of monitoring mental health status using wearable devices has attracted attention. One way of estimating mental health status is to use heart rate (HR) variability (HRV), as HR is controlled by the autonomic nervous system (ANS) . The parThere is growing interest in the use of wrist-worn wearable devices that can measure movement using a 3D accelerometer and optical pulse photoplethysmography (PPG) to obtain biometric information in the real world, rather than in a special environment such as a laboratory. However, the validity of such data for the assessment of patients with mental illness has not been adequately demonstrated. HRV measures the variation in time between heartbeats and is usually calculated from electrocardiogram (ECG) R-R intervals; however, wearable devices record an optical PPG signal and therefore the peak of the R waves cannot be detected accurately. The accuracy of PPG-based HR data has been previously reviewed and validated in comparison with ECG data; PPG-based HR data is typically accurate within a 10% error range . As reseIn this study, we examined the feasibility and validity of using wearable devices to estimate mental health status in patients enrolled in the Mental Illness Registry, using standardized tests for anxiety, affect, and QOL as a reference. As a wearable device, Fitbit Sense was chosen because Fitbit device is the most researched , widely 2.2.1.A total of 110 patients who were enrolled in the Mental Illness Registry during the study period between 1 October 2020 and 31 March 2021 and provided their informed consent, participated in the study. Participants were either inpatients or outpatients at six sites: the National Center of Neurology and Psychiatry Hospital, Nara Medical University Hospital, Kansai Medical University Hospital, Nagoya University Hospital, Hokkaido University Hospital, and Akita University Hospital. The sample included patients with a wide range of clinical presentations from different diagnostic groups . Most paThe Ethics Committee of the National Center of Neurology and Psychiatry approved the study protocol and experimental procedures (B2021-086).2.2.This was a multisite observational study. Participants were either inpatients or outpatients at six sites: the National Center of Neurology and Psychiatry Hospital, Nara Medical University Hospital, Kansai Medical University Hospital, Nagoya University Hospital, Hokkaido University Hospital, and Akita University Hospital. The software setup for data acquisition was conducted in advance by the researchers. Participants had only to wear a Fitbit Sense on their left or right wrist for as long as they could tolerate it between the day of consent and their next visit to the hospital (for outpatients), or until their first visit to the hospital after discharge (for inpatients). While wearing the Fitbit Sense, participants were contacted via their smartphones to inquire about their current socioenvironmental situation and to ask them to complete the following self-administered questionnaires: the STAI FORM X-I, II  to meas  and cvrr , which are modulated by the ANS. We also assessed HR. The sdnn, cvrr, and HR were calculated using a sampling time of 5 s with 30 min as one epoch; if there were multiple epochs appropriately recorded, the average value was used as the representative value. Assuming that during the daytime HR is sensitive to activity, we excluded data in which the HR was greater than 90/min or fell below 50/min, and in which the difference between the maximum and minimum within one epoch was greater than 40/min or less than 5/min. During sleep, only the latter condition was used; data in which the difference between the maximum and minimum HRs within one epoch was greater than 40/min or less than 5/min were excluded because of the suspected possibility of measurement noise. The Fitbit device used in the present study records an optical PPG signal and thus the peak of the R waves cannot be detected accurately. Therefore, the interval between the pulse wave (estimated by 60/mean HR) was used as a surrogate for the R-R intervals obtained from an ECG.Sleep stage information in this study was provided by the Fitbit Research Library, which analyzed the 3D accelerometer and optical PPG data collected in this study. Unfortunately, the algorithm for determining sleep stage from 3D accelerometer and PPG data obtained from Fitbit is not publicly available. However, Beattie et al. provides an overview of the analysis using the generated features on a 30 s time scale based on motion, HRV, and breathing rate parameters were used to develop an automated sleep staging algorithm . Specifi2.4.As reference, we used electronic self-reported assessments of anxiety, affect, and QOL. Patients reported their data using a smartphone. The following self-administered questionnaires were used: the STAI Form X-I and Form X-II to measure state and trait anxiety, the PANAS to measure positive and negative affect, and the EQ-5D-5L visual analog scale (VAS) and utility score to measure QOL.The STAI Form X-I and Form X-II were developed by Spielberger et al. ; they haThe PANAS consists of 20 items that comprise adjectives representing positive and negative affect . The rel5) possible health states, and utility scores are derived from a preference-based algorithm used to calculate quality-adjusted life years . In this study, an algorithm developed using survey results based on the composite time trade-off in Japan was used  were performed to examine associations between HR and HRV indices  and mental health status variables  for each sleep stage and the daytime to estimate which time period HR and HRV indices best reflected mental health status. Then, to explore the effect of focusing on the period showing the strongest association, the effect of temporal distance between the time of HR measurement and mental health status assessment on the association between them was examined using univariate correlation analyses (Pearson’s product moment correlation) between HR and HRV indices and mental health status variables when HR and HRV data were restricted to within 7 days and within 3 days of the mental health status assessment. For the data set that was ultimately estimated to have the strongest association, multivariable regression analysis was performed with each HRV index, age, sex, chlorpromazine-equivalent of antipsychotics, imipramine-equivalent dose of antidepressants, and diazepam-equivalent dose of anxiolytics and hypnotics as independent variables, and each mental health status variable as a dependent variable, to adjust for possible confounding factors , 21.P-value of <0.05 was considered statistically significant for all tests.The statistical analysis was performed using JMP version 13.0.0 ; a 3.Of the 110 patients who consented to participate in the study, available data on HRV indices were obtained from 92 patients . For theThe exploratory analyses of correlations between HR and HRV indices and mental health status variables for each sleep stage and the daytime showed a significant correlation between sdnn and STAI Form X-II scores, between HR and STAI Form X-I and Form-II scores, between HR and EQ-5D-5L VAS and utility scores in the WASO stage; between HR and STAI Form X-I scores and EQ-5D-5L VAS scores in the light stage; between HR and STAI Form X-I scores, PANAS positive affect scores, and EQ-5D-5L VAS scores in the deep stage; and between HR and STAI Form X-I scores in the REM stage . As can Focusing on data obtained in the WASO stage, the correlations between HR and HRV indices and mental health status variables within 14 days, 7 days, and 3 days of the time of mental health status assessment are shown in P = 0.035); HR and STAI Form X-I scores ; HR and PANAS positive affect scores ; HR and EQ-5D-5L VAS scores ; and HR and EQ-5D-5L utility scores .Multivariable regression analyses were conducted on the variables that showed significant intercorrelations for data obtained within 3 days of mental health status assessment . After a4.In this study, we explored the feasibility of using PPG obtained by a wrist-worn wearable device to assess mental health status in patients with mental illness. Of 110 patients, 92 (83.6%) returned usable HR data. HR and HRV measured within 14 days of the mental health status assessment were significantly associated with anxiety and QOL in different sleep stages, and the association was strongest in the WASO stage. Although exploratory, the results also suggest that HR and HRV in the WASO stage may reflect anxiety, positive affect, and QOL within 3 days.ECG data on HR and HRV are one of the most important biomarkers of emotion . When anOur findings suggest that HR and HRV in the WASO stage better reflect current mental health status than data in other sleep stages and in the daytime. This may be because the resting state is maintained during the WASO stage, as it is less affected by daytime activities or ANS activity during REM sleep. In addition, the accuracy of wearable devices in estimating sleep stages in healthy individuals has been reported as reasonable , 14. OneA recent review  found thThe present study had several limitations. Although a common technique is to develop a peak detector algorithm to detect the peaks in the PPG signal, and the time between PPG peaks is used as a surrogate for the R-R intervals  in the pThis study examined the feasibility and potential of a wrist-worn wearable device to assess the mental health status of mentally ill patients. Although the results were exploratory and cross-sectional, they suggest the potential utility of this method. Additional validation studies, including longitudinal studies, are warranted. If it is possible to objectively monitor mental health status in the home by the wearing of a wrist-worn device for a relatively short period, this could reduce the burden on patients in cohort studies and improve their well-being.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of the National Center of Neurology and Psychiatry. The patients/participants provided their written informed consent to participate in this study.KN contributed toward conceptualization, methodology, investigation, project administration, and writing of the original draft. KMin and TF contributed toward data curation, provision of resources, and formal analysis. MM, MU, MK, NO, SM, KI, NH, AT, MO, MT, and KMis contributed toward conceptualization, methodology, and investigation. MOb, KT, and HO contributed toward conceptualization, data curation, and supervising the statistical analysis. All authors contributed toward acquisition of data, critical revision of the manuscript for important intellectual content, approval of the final version of the manuscript, and agree to be accountable for all aspects of the work and ensure that any questions related to the accuracy or integrity of any part of the work will be appropriately investigated and resolved.This research was supported by AMED under Grant number JP21dk0307103 and an Intramural Research Grant (3-1) for Neurological and Psychiatric Disorders of NCNP. KN confirms that he had full access to all the data in the study and takes final responsibility for the decision to submit for publication.KN reports grants from AMED during the conduct of this study and from Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd. and Janssen Pharmaceutical K.K., and personal fees from Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Meiji-Seika Pharma Co., Ltd., Janssen Pharmaceutical K.K., MOCHIDA PHARMACEUTICAL CO., LTD., Mitsubishi Tanabe Pharma Corp., Viatris Inc., and Eisai Co., Ltd. He has received payment for advisory work from Takeda Pharmaceutical Co., Ltd., Lundbeck Japan, and Nippon Boehringer Ingelheim Co., Ltd., outside the submitted work. MM has received research grants from Sumitomo Pharma Co., Ltd. and Kyowa Kirin Co., Ltd. MK has received grant funding from the Japanese Ministry of Health, Labour and Welfare, the Japan Society for the Promotion of Science, SENSHIN Medical Research Foundation, the Japan Research Foundation for Clinical Pharmacology, and the Japanese Society of Clinical Neuropsychopharmacology, and speaker honoraria from Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Meiji-Seika Pharma Co., Ltd., Eli Lilly Japan K.K., Merck & Co., Inc., Pfizer Inc., Janssen Pharmaceutical K.K., Shionogi & Co., Ltd., Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd., Lundbeck Japan, Viatris Inc., Eisai Co., Ltd., and ONO PHARMACEUTICAL CO., LTD., and has participated in advisory/review boards for Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Shionogi & Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. NO has received research support or speaker honoraria from, or has served as a joint researcher with, or a consultant to, Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., KAITEKI, Mitsubishi Tanabe Pharma Corp., Eli Lilly Japan K.K., MOCHIDA PHARMACEUTICAL CO., LTD., DAIICHI SANKYO CO., LTD., TSUMURA & CO., Takeda Pharmaceutical Co., Ltd., Meiji-Seika Pharma Co., Ltd., EA Pharma Co., Ltd., Viatris Inc., Ricoh Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Lundbeck Japan, Nihon Medi-Physics Co., Ltd., and Nippon Chemiphar Co., Ltd., outside the submitted work. KI has received speaker honoraria from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Meiji-Seika Pharma Co., Ltd., Merck & Co., Inc., Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., TOWA PHARMACEUTICAL CO., LTD., and Viatris Inc., outside the submitted work. NH has received personal fees from Janssen Pharmaceutical K.K., Yoshitomiyakuhin Corporation, Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Novartis Pharma K.K., Meiji-Seika Pharma Co., Ltd., Lundbeck Japan, and Takeda Pharmaceutical Co., Ltd. AT received a research grant from Nippon Boehringer Ingelheim Co., Ltd. and personal fees from MOCHIDA PHARMACEUTICAL CO., LTD., Sumitomo Pharma Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. KMis has received research grants from Eisai Co., Ltd., Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Sony Corporation and has also received speaker honoraria from Eisai Co., Ltd., Nobelpharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck & Co., Inc., Otsuka Pharmaceutical Co., Ltd., and Viatris Inc. MT has received speaker honoraria from Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., DAIICHI SANKYO CO., LTD., Sumitomo Pharma Co., Ltd., Meiji-Seika Pharma Co., Ltd., Viatris Inc., Merck & Co., Inc., Eisai Co., Ltd., and Yoshitomiyakuhin Corporation outside the submitted work. KMin and TF were employed by TechDoctor Inc.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


International Journal of Molecular Sciences includes original research and reviews on the molecular mechanisms of active, natural products  and phytochemicals in vitro and in vivo.The Special Issue “Molecular Mechanisms of Natural Products and Phytochemicals in Immune Cells and Asthma” in the Allergic asthma, an increasingly common immunologic disease in industrialized countries, is a chronic inflammatory condition of the airways that causes airway hyperresponsiveness (AHR). A Th1-Th2 cytokine imbalance has been hypothesized to underlie allergic asthma through a change in immune responses from a Th1 profile to a Th2  profile. Additionally, the recruitment of inflammatory cells such as T cells, mast cells, eosinophils, epithelial cells, macrophages and neutrophils is mediated via a number of chemokines and their receptors. Chemokines and their receptors are important therapeutic targets in asthma and allergic diseases because of their key role in immune cell recruitment and activation during inflammation [Two highly relevant papers have recently been published in the Special Issue of Bioactives and Nutraceuticals entitled “Molecular Mechanisms of Natural Products and Phytochemicals in Immune Cells and Asthma”. These two papers exhibit antiallergic and antiasthmatic effects of the active components in natural products.Lithospermum erythrorhizon on Mast Cells and Ovalbumin-Induced Allergic Rhinitis” by Le et al. [Lithospermum erythrorhizon, N,N’-dicoumaroylspermidine, inhibited the release of β-hexosaminidase, as well as the production of Th2 cytokines  by IgE-sensitized and BSA-stimulated RBL-2H3 cells. Using the allergic rhinitis mouse model, they showed that N,N’-dicoumaroylspermidine reduced the number of inflammatory cells in nasal lavage fluid and the production of serum OVA-specific IgE. N,N’-dicoumaroylspermidine isolated from Lithospermum erythrorhizon exhibits antiallergic properties, and it can be potentially effective for allergic rhinitis.The first article, “Antiallergic Effects of N,N’-dicoumaroylspermidine Isolated from e et al.  revealedGynostemma pentaphyllum Attenuates Airway Inflammation and Th2 Cell Activities in a Murine Asthma Model” by Huang et al. [G. pentaphyllum. The study revealed that gypenoside A significantly reduced the expression of inflammatory genes and proteins in the lungs and bronchoalveolar lavage fluid and Th2 cytokine expression. Moreover, gypenoside A significantly inhibited the secretion of chemokines and inflammatory cytokines in tracheal epithelial cells. Gypenoside A is a natural phytochemical that can effectively attenuate airway hyperresponsiveness (AHR) and inflammation in asthma, mainly by blocking Th2 cytokines production. In summary, the two papers successfully demonstrate the antiallergic effects of phytochemicals from Lithospermum erythrorhizon roots and Gynostemma pentaphyllum.The second article, “Gypenoside A from g et al.  investigRecently, natural products and their phytochemicals play increasingly critical roles, especially multi-ingredient synergistic effects . The theWe hope that this Special Issue can provide a comprehensive overview of the current state of research on molecular mechanisms of natural products and phytochemicals in immune cells and asthma.In conclusion, the Guest Editor would like to thank all authors for their remarkable contributions and the Editorial Board for their support.


The ripening process of fruits is complicated and coordinated and is characterized by obvious changes in pericarp color (green color loss and non-photosynthetic pigment increases), flesh texture , taste (variation of sugars and organic acids), and aroma flavour (volatile productions) of fleshy fruits . SpecifiTeixeira et al. showed that the exocarp of green and mature grape berries is rich in chloroplasts, and they applied proteomic analysis of chloroplasts from the two phases. The authors observed that proteins associated with the Calvin cycle were stimulated in green berries, while those related to energy-generating metabolism were enriched in mature berries. Wang et al. systematically identified a batch of lignin biosynthesis-related genes and constructed a co-expression network of these genes via weighted gene co-expression network analysis. Specifically, they found the major lignin biosynthesis genes involved in ripening process and stress resistance in banana. Liu et al. reviewed NAC transcription factors, which show extensive participation in fruit yield and quality and regulate fruit ripening by directly acting on critical genes related to the biosynthesis and signal transduction of the plant hormones abscisic acid (ABA) and ethylene (ET). These articles provide the basis for the improvement of fruit development and ripening.The material basis and regulator underlying fruit development and ripening still remain challenges. Huang et al. and Jiang et al. reported that salicylic acid (SA) treatment could maintain the organoleptic quality and postharvest storability of pummelo and blueberry. Li et al. recorded that pear had a greasy coating and yellowing process during postharvest storage, while 1-methylcyclopropene (1-MCP) could decrease the wax content of postharvest pear and delay the development of peel greasiness and yellowing by suppressing the transcription of a series of cluster genes associated with ethylene synthesis, ethylene signal transduction, wax accumulation, and chlorophyll degradation. Choi et al. investigated the molecular details of kiwifruit ripening using ethylene and its action inhibitor 1-MCP. Through a time-course transcriptomic analysis, they found that the genes related to ET synthesis and signalling suffered from opposite influence from postharvest application of 1-MCP and ET, conversely, in the process of kiwifruit ripening. They identified that the ET transcription factor AcEIL might exhibit an essential function in ET-induced kiwifruit ripening. These articles suggest a practical foundation for improving the protective mechanisms in relation to fruit ripening and senescence.Postharvest ripening and senescence restrict the shelf life of horticultural crops. Both Lin et al. compared two cultivars of hardy kiwifruit that have high frost hardiness and show similar trends in antioxidant capacities and nutritional compounds. The authors noted that the antioxidant capacity of the two hardy kiwifruit cultivars decreased but glucose increased progressively during maturation, in which the conversion from starch to total sugar was dominantly due to the expression of sucrose phosphate synthase (SPS) and fructokinase (FK). The predominant acids in the two hardy kiwifruit cultivars were quinic acid and citric acid from the early developmental to late maturity stages, respectively. These findings are conducive to a wider understanding of the physiological and biochemical basis of hardy kiwifruit for the cultivation of chilling-tolerant cultivars.Sensitivity to chilling can influence plant growth in the field and storability and quality during the postharvest storage period . AccordiLin et al. assessed the effect of fucoidan application on cold storage quality, reactive oxygen species (ROS) homeostasis, and energy metabolism in cucumber fruit. The authors determined that the optimum concentration of coated fucoidan was 15 g/L, which could increase DPPH and -OH scavenging rates and reduce H2O2 accumulation. The authors suggested that the improved chilling tolerance in cucumbers with fucoidan treatment may be related to the increased antioxidant enzyme activities and ROS scavenging rates, as well as high levels of ATP, ADP, and energy charge. In accordance with the effects of fucoidan in cucumbers, Zhou et al. confirmed that γ-aminobutyric acid (GABA) could lighten CI symptoms in peach fruit and that the reduction efficiency of GABA on chilling injury was associated with the accumulation of ascorbic acid (AsA) and glutathione (GSH) contents and the amplified expression profiles of AsA-GSH recycling-related genes. Moreover, the authors indicated that several ERF transcription factors, which are potentiated by GABA treatment in peach fruit, regulate AsA and GSH contents to reduce chilling injury. Overall, the authors proposed potential strategies of fucoidan coating and GABA immersion in alleviating CI symptoms in postharvest horticultural crops.Xing et al. investigated the mechanism of action of Sly-miR171d on chilling injury in tomato fruit. They found that down-regulated Sly-miR171d promotes GRAS24 expression, which obviously increased gibberellin production and C-repeat binding factor (CBF) expression and maintained cell membrane stability, therefore enhancing the chilling tolerance of tomato fruit. This study sheds light on the genetic improvement of postharvest tomato to chilling injury.In general, microRNAs (miRNAs) are a class of small, non-protein coding RNA molecules that function as negative regulators of target gene messages , and theIn summary, the articles in this Research Topic provide advanced information on ripening and chilling injury alleviation in horticultural crops. New insights into phytohormones, transcription factors and epigenetic modifications will impel our future applied research in the alleviation of crop ripening and chilling injury.CL: Conceptualization, Writing – original draft. ZY: Supervision, Validation, Writing – review & editing. SC: Writing – review & editing. CW: Supervision, Writing – review & editing. KW: Conceptualization, Writing – review & editing.