Modulating root system architecture: cross-talk between auxin and phytohormones.

Root architecture is an important agronomic trait that plays an essential role in water uptake, soil compactions, nutrient recycling, plant-microbe interactions, and hormone-mediated signaling pathways. Recently, significant advancements have been made in understanding how the complex interactions of phytohormones regulate the dynamic organization of root architecture in crops. Moreover, phytohormones, particularly auxin, act as internal regulators of root development in soil, starting from the early organogenesis to the formation of root hair (RH) through diverse signaling mechanisms. However, a considerable gap remains in understanding the hormonal cross-talk during various developmental stages of roots. This review examines the dynamic aspects of phytohormone signaling, cross-talk mechanisms, and the activation of transcription factors (TFs) throughout various developmental stages of the root life cycle. Understanding these developmental processes, together with hormonal signaling and molecular engineering in crops, can improve our knowledge of root development under various environmental conditions.

A second-generation M1-polarized CAR macrophage with antitumor efficacy.

Chimeric antigen receptor (CAR) T cell therapies have successfully treated hematological malignancies. Macrophages have also gained attention as an immunotherapy owing to their immunomodulatory capacity and ability to infiltrate solid tumors and phagocytize tumor cells. The first-generation CD3ζ-based CAR-macrophages could phagocytose tumor cells in an antigen-dependent manner. Here we engineered induced pluripotent stem cell-derived macrophages (iMACs) with toll-like receptor 4 intracellular toll/IL-1R (TIR) domain-containing CARs resulting in a markedly enhanced antitumor effect over first-generation CAR-macrophages. Moreover, the design of a tandem CD3ζ-TIR dual signaling CAR endows iMACs with both target engulfment capacity and antigen-dependent M1 polarization and M2 resistance in a nuclear factor kappa B (NF-κB)-dependent manner, as well as the capacity to modulate the tumor microenvironment. We also outline a mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we provide a second-generation CAR-iMAC with an ability for orthogonal phagocytosis and polarization and superior antitumor functions in treating solid tumors relative to first-generation CAR-macrophages.

Insights into the selectivity of a brain-penetrant CDK4/6 vs CDK1/2 inhibitor for glioblastoma used in multiple replica molecular dynamics simulations.

Cyclin dependent kinases (CDKs) play an important role in cell cycle regulation and their dysfunction is associated with many cancers. That is why CDKs have been attractive targets for the treatment of cancer. Glioblastoma is a cancer caused by the aberrant expression of CDK4/6, so exploring the mechanism of the selection of CDK4/6 toward inhibitors relative to the other family members CDK1/2 is essential. In this work, multiple replica molecular dynamics (MRMD) simulations, principal component analysis (PCA), free energy landscapes (FELs), molecular mechanics Poisson-Boltzmann/Generalized Born surface area (MM-PB/GBSA) and other methods were integrated to decipher the selectively binding mechanism of the inhibitor N1J to CDK4/6 and CDK1/2. Molecular electrostatic potential (MESP) analysis provides an explanation for the N1J selectivity. Residue-based free energy decomposition reveals that most of the hot residues are located at the same location of CDKs proteins, but the different types of residues in different proteins cause changes in binding energy, which is considered as a potential developmental direction to improve the selectivity of inhibitors to CDK4/6. These results provide insights into the source of inhibitor and CDK4/6 selectivity for the future development of more selective inhibitors.Communicated by Ramaswamy H. Sarma.

Advanced Glycation End Products-Induced Activation of Keratinocytes: A Mechanism Underlying Cutaneous Immune Response in Psoriasis.

Psoriasis is a common inflammatory skin disease, in which epidermal keratinocytes play a vital role in its pathogenesis by acting both as the responder and as the accelerator to the cutaneous psoriatic immune response. Advanced glycation end products (AGEs) are a class of proinflammatory metabolites that are commonly accumulating in cardiometabolic disorders. Recent studies have also observed the increased level of AGEs in the serum and skin of psoriasis patients, but the role of AGEs in psoriatic inflammation has not been well investigated. In the present study, we initially detected abnormal accumulation of AGEs in epidermal keratinocytes of psoriatic lesions collected from psoriasis patients. Furthermore, AGEs promoted the proliferation of keratinocytes via upregulated Keratin 17 (K17)-mediated p27KIP1 inhibition followed by accelerated cell cycle progression. More importantly, AGEs facilitated the production of interleukin-36 alpha (IL-36α) in keratinocytes, which could enhance T helper 17 (Th17) immune response. In addition, the induction of both K17 and IL-36α by AGEs in keratinocytes was dependent on the activation of signal transducer and activator of transcription 1/3 (STAT1/3) signaling pathways. At last, the effects of AGEs on keratinocytes were mediated by the receptor for AGEs (RAGE). Taken together, these findings support that AGEs potentiate the innate immune function of keratinocytes, which contributes to the formation of psoriatic inflammation. Our study implicates AGEs as a potential pathogenic link between psoriasis and cardiometabolic comorbidities.

Molecular insights and optimization strategies for the competitive binding of engineered ACE2 proteins: a multiple replica molecular dynamics study.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally, and rapid viral evolution and the emergence of new variants pose challenges to pandemic control. During infection, the spike protein of SARS-CoV-2 interacts with the human ACE2 protein via its receptor binding domain (RBD), and it is known that engineered forms of ACE2 can compete with wild-type (WT) ACE2 for binding to inhibit infection. Here, we conducted multiple replica molecular dynamics (MRMD) simulations to study the mechanisms of the engineered ACE2 variants 3N39 and 3N94 and provide directions for optimization. Our findings reveal that engineered ACE2 is notably more efficacious in systems that show weaker binding to WT ACE2 (i.e., WT and BA.1 RBD), but also faces immune escape as the virus evolves. Moreover, by modifying residue types near the binding interface, engineered ACE2 alters the electrostatic potential distribution and reconfigures the hydrogen bonding network, which results in modified binding to the RBD. However, this structural rearrangement does not occur in all RBD variants. In addition, we identified potentially engineerable beneficial residues and potentially engineerable detrimental residues in both ACE2 and RBD. Functional conservation can thus enable the optimization of these residues and improve the binding competitiveness of engineered ACE2, which therefore provides additional immune escape prevention. Finally, we conclude that these findings have implications for understanding the mechanisms responsible for engineered ACE2 and can help us to develop engineered ACE2 proteins that show superior performance.

Dual-Active-Sites Single-Atom Catalysts for Advanced Applications.

Dual-Active-Sites Single-Atom catalysts (DASs SACs) are not only the improvement of SACs but also the expansion of dual-atom catalysts. The DASs SACs contains dual active sites, one of which is a single atomic active site, and the other active site can be a single atom or other type of active site, endowing DASs SACs with excellent catalytic performance and a wide range of applications. The DASs SACs are categorized into seven types, including the neighboring mono metallic DASs SACs, bonded DASs SACs, non-bonded DASs SACs, bridged DASs SACs, asymmetric DASs SACs, metal and nonmetal combined DASs SACs and space separated DASs SACs. Based on the above classification, the general methods for the preparation of DASs SACs are comprehensively described, especially their structural characteristics are discussed in detail. Meanwhile, the in-depth assessments of DASs SACs for variety applications including electrocatalysis, thermocatalysis and photocatalysis are provided, as well as their unique catalytic mechanism are addressed. Moreover, the prospects and challenges for DASs SACs and related applications are highlighted. The authors believe the great expectations for DASs SACs, and this review will provide novel conceptual and methodological perspectives and exciting opportunities for further development and application of DASs SACs.

Ultrasensitive and on-site eDNA detection for the monitoring of crown-of-thorns starfish densities at the pre-outbreak stage using an electrochemical biosensor.

The coral reef crisis has significantly intensified over the last decades, mainly due to severe outbreaks of crown-of-thorns starfish (COTS). Current ecological monitoring has failed to detect COTS densities at the pre-outbreak stage, thus preventing early intervention. In this work, we developed an effective electrochemical biosensor modified by a MoO2/C nanomaterial, as well as a specific DNA probe that could detect trace COTS environmental DNA (eDNA) at a lower detection limit (LOD = 0.147 ng/µL) with excellent specificity. The reliability and accuracy of the biosensor were validated against the standard methods by an ultramicro spectrophotometer and droplet digital PCR (p > 0.05). The biosensor was then utilized for the on-site analysis of seawater samples from SYM-LD and SY sites in the South China Sea. For the SYM-LD site suffering an outbreak, the COTS eDNA concentrations were 0.33 ng/µL (1 m, depth) and 0.26 ng/µL (10 m, depth), respectively. According to the ecological survey, the COTS density was 500 ind/hm2 at the SYM-LD site, verifying the accuracy of our measurements. At the SY site, COTS eDNA was also detected at 0.19 ng/µL, but COTS was not found by the traditional survey. Hence, larvae were possibly present in this region. Therefore, this electrochemical biosensor could be used to monitor COTS populations at the pre-outbreak stages, and potentially serve as a revolutionary early warning method. We will continue to improve this method for picomolar or even femtomolar detection of COTS eDNA.

SET/PP2A signaling regulates macrophage positioning in hypoxic tumor regions by amplifying chemotactic responses.

Tumor-associated macrophages (TAMs) are one of the main cellular components in the tumor microenvironment (TME). In many types of solid tumors, TAMs tend to accumulate in hypoxic areas and are intimately related to poor patient prognosis. However, the underlying mechanisms by which TAMs infiltrate hypoxic tumor regions remain unclear. In this study, we report that genetic deletion of SE translocation (SET) in myeloid cells inhibited the entry of TAMs into the hypoxic tumor region and abated their proangiogenic and immunosuppressive functions, ultimately inhibiting tumor growth. Mechanistically, in response to hypoxic tumor supernatant stimulation, SET in macrophages shuttled between the nucleus and cytoplasm via the PKC-CK2α signaling axis. Cytoplasmic retention of SET increased ERK and P38 signaling by inhibiting PP2A, which promoted TAM migration into the hypoxic area and polarization toward the M2 phenotype. Therefore, we conclude that SET modulates tumor immunity by acting as a key regulator of macrophage positioning and function in the tumor.

Deciphering the binding mechanism of inhibitors of the SARS-CoV-2 main protease through multiple replica accelerated molecular dynamics simulations and free energy landscapes.

The pneumonia outbreak caused by the SARS-CoV-2 virus poses a serious threat to human health and the world economy. The development of safe and highly effective antiviral drugs is of great significance for the treatment of COVID-19. The main protease (Mpro) of SARS-CoV-2 is a key enzyme for viral replication and transcription and has no homolog in humans. Therefore, the Mpro is an ideal target for the design of drugs against COVID-19. Insights into the inhibitor-Mpro binding mechanism and conformational changes of the Mpro are essential for the design of potent drugs that target the Mpro. In this study, we analyzed the conformational changes of the Mpro that are induced by the binding of three inhibitors, YTV, YSP and YU4, using multiple replica accelerated molecular dynamics (MR-aMD) simulations, dynamic cross-correlation map (DCCM) calculations, principal component analysis (PCA), and free energy landscape (FEL) analysis. The results from DCCM calculations and PCA show that the binding of inhibitors significantly affects the kinetic behavior of the Mpro and induces a conformational rearrangement of the Mpro. The binding ability and binding mechanism of YTV, YSP and YU4 to the Mpro were investigated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The results indicate that substitution of the tert-butanol group by methylbenzene and trifluoromethyl groups enhances the binding ability of YSP and YU4 to the Mpro compared with YTV; moreover, massive hydrophobic interactions are detected between the inhibitors and the Mpro. Meanwhile, T25, L27, H41, M49, N142, G143, C145, M165, E166 and Q189 are identified as the key residues for inhibitor-Mpro interactions using residue-based free energy decomposition calculations, which can be employed as efficient targets in the design of drugs that inhibit the activity of the Mpro.

The Efficacy and Psychoneuroimmunology Mechanism of Camouflage Combined With Psychotherapy in Vitiligo Treatment.

Background and Objectives: The efficacy of camouflage combined with psychotherapy and the underlying mechanisms are poorly understood in vitiligo management. This study aimed to investigate the joint efficacy and further explore psycho-neuro-endocrine-immune-skin interactions. Patients and Methods: In a prospective, non-randomized and concurrent controlled trial, patients were divided into two groups. Quality of life (QOL) was evaluated using the Chinese version of the Vitiligo Life Quality Index (VLQI-C). Serum levels of neuropeptides and cytokines were detected by enzyme-linked immunosorbent assay. Results: A total of 149 patients were included for final evaluation. After treatment for 4 weeks, total and subcategory quality of life scores in the intervention group were much lower than in the control group. Serum levels of neuropeptide-Y (NPY) and melanin-concentrating hormone (MCH) significantly decreased, and serum level of adrenocorticotropic hormone (ACTH) increased in both active and stable patients of the intervention group, but not in the control group. In addition, the serum levels of interferon-γ (IFN-γ), CXC chemokine ligand 10 (CXCL10), and interleukin-1ß (IL-1ß) decreased in both the active and stable patients of the intervention group and only in the active patients of the control group. Conclusions: The combination of camouflage and psychotherapy provided a clinically meaningful improvement in quality of life and ameliorated the outcome by likely modulating the psycho-neuro-endocrine-immuno-skin system during vitiligo management. Clinical Trial Registration: www.clinicaltrials.gov/ct2/show/NCT03540966, identifier: NCT03540966.

Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS.

Mutations of G12 in KRAS have been involved in different cancers. Multiple replica-Gaussian accelerated molecular dynamics (MR-GaMD) simulations are applied to investigate conformational changes of the switch domains caused by G12C, G12D and G12R. Free energy landscapes suggest that G12C, G12D and G12R induce more energetic states compared to the GTP-bound WT KRAS and make the conformations of the switch domains more disordered, which disturbs bindings of KRAS to effectors. Dynamics analyses based on MR-GaMD trajectory show that G12C, G12D and G12R not only change structural flexibility of the switch domains but also affect their motion behavior, indicating that these three mutations can be used to tune the activity of KRAS. The analyses of interaction networks verify that the instability in interactions of the GTP with the switch SⅠ plays an important role in the high disorder states of the switch domain. This work is expected to provide useful information for deeply understanding the function of KRAS.

Atomically Dispersed NiN3 Sites on Highly Defective Micro-Mesoporous Carbon for Superior CO2 Electroreduction.

Direct electrochemical conversion of CO2 to CO product powered by renewable electricity is widely advocated as an emerging strategy for alleviating CO2 emissions while addressing global energy issues. However, the development of low-cost and efficient electrocatalysts with high Faradaic efficiency for CO production (FECO ) and high current density remains a grand challenge. Herein, a robust single nickel atomic site electrocatalyst, which features isolated and dense single atomic NiN3 sites anchored on highly defective hierarchically micro-mesoporous carbon (Ni-SAs/HMMNC-800), to enable enhanced charge transport and more exposed active sites for catalyzing electrochemical CO2 -to-CO conversion, is reported. The Ni-SAs/HMMNC-800 catalyst achieves excellent activity and selectivity with high FECO values of >90% throughout a wide potential range (the FECO reaches 99.5% at -0.7 V vs reversible hydrogen electrode) and a CO partial current density as high as 13.0 mA cm-2 at -0.7 V versus reversible hydrogen electrode, as well as a far outstanding durability during long-term continuous operation, indicating a superior CO2 electroreduction performance than that of other reference samples and most of previously reported carbon-based single atom electrocatalysts. Experimental and density functional theory calculations reveal that atomic NiN3 coordination sites coupled adjacent defects are favorable to significantly enhancing the formation of COOH* reaction intermediates while suppressing the competing hydrogen evolution reaction, thereby enhancing the electrocatalytic activity for CO2 -to-CO reduction. Notably, this work provides a valuable new prospect for designing and synthesizing efficient and cost-effective single atom CO2 electroreduction catalysts for practical applications.

Vaspin promotes chondrogenic differentiation of BMSCs via Akt activation in osteoarthritis.

BACKGROUND: The aim of this study was to investigate the role of Vaspin on the chondrogenic differentiation of bone mesenchymal stem cells (BMSCs), and its effect on chondrocyte survival and ECM secretion. We also assessed whether the Akt activation participates in these processes. METHODS: In vivo, immunohistochemistry was used to examine the positive rate of the protein expressions of Akt in Wistar rat articular cartilage and subchondral bone after Vaspin intraperitoneal injection for 14 days. In vitro, we isolated and expanded BMSCs from Wistar rats, and further cultured BMSCs as pellets in a chondrogenic-differentiation medium supplemented with different concentrations of Vaspin. After 21 days, the pellets were processed for cell counting kit assay. The mRNA level of Akt, SOX9 and COL2A1 in the pellets were investigated using quantitative Real-Time polymerase chain reaction, and the protein level of COMP was detected using western blot. RESULTS: During the chondrogenic differentiation of BMSCs, Vaspin promoted the chondrogenic differentiation of BMSCs and chondrocyte survival by activating the Akt pathway. These effects were significantly reduced by treatment with an Akt inhibitor. Moreover, Vaspin promoted chondrogenic differentiation of BMSCs by increasing the expression of markers in cartilage formation and extracellular matrix secretion. Furthermore, our study also found that Vaspin could increase Akt expression in cartilage cavities and subchondral bone in vivo. CONCLUSION: These findings demonstrate that Vaspin can promote the chondrogenic differentiation of BMSCs and chondrocyte survival via Akt activation. Our study provides new insights into the potential ability of Vaspin to ameliorate the chondrogenic differentiation of BMSCs and chondrocyte survival in OA.

Dynamics of estrogen-induced ROS and DNA strand break generation in estrogen receptor α-positive breast cancer.

DNA repair machinery is involved in estrogen-dependent transactivation. Mounting evidence suggests that mechanisms underlying estrogen-induced DNA damage are complicated. To date estrogen-induced DNA oxidation and its impact on ERα-mediated transaction remains ambiguous. Herein, we found that the process of 17ß-estradiol (E2)-induced ROS production can be approximately divided into two phases according to responding time and generation mechanisms. The intracellular Ca2+ fluctuation and ERα-dependent transcription lead to temporospatially different oxidative DNA damage. Further, we demonstrate that DNA oxidation is dispensable for estrogen-responsive gene expression. Dynamics of estrogen-induced DNA strand break generation also show two-phase pattern and topoisomerase-mediated DNA stand breaks are essential in estrogen signaling. Collectively, our findings have provided new insights into oxidative DNA damage in estrogen signaling.

Cloning, expression, and characterization of a novel endo-type alginate lyase from Microbulbifer sp. BY17.

BACKGROUND: Alginate oligosaccharides (AOS), with various physiological effects, have been widely used in the food, agricultural, and pharmaceutical industries. The biological enzymatic method of preparing AOS, using alginate lyase, has more advantages compared with physical and chemical methods. Cloning and heterologously expressing alginate lyase are therefore very important. RESULTS: A novel alginate lyase, BY17PV7, from Microbulbifer sp. BY17, isolated from Gracilaria, was cloned and expressed in Escherichia coli BL21(DE3). BY17PV7 was about 27 KDa. BY17PV7 showed the greatest activity (150.42 ± 3.32 U/mg) at 43 °C and pH 8.9. It could be activated by Ca2+ , Mn2+ , Co2+ , Fe3+ , Na+ , and inhibited by Mg2+ , Zn2+ , Ba2+ , Cu2+ , sodium dodecyl sulfate (SDS), ethylene diamine tetraacetic acid (EDTA). BY17PV7 had a wide range of substrate specificity and good degradation effects for poly ß-D-mannuronate (polyM) and poly α-L-guluronate (polyG), demonstrating that it is a bifunctional alginate lyase. The kinetic parameters showed that BY17PV7 had a greater affinity for polyG. BY17PV7 released AOS with a degree of polymerization (DP) of 3-4 in an endolytic manner from sodium alginate. Alginate oligosaccharides showed strong antioxidant ability of reducing Fe3+ and scavenging radicals such as hydroxyl, 2,2-azion-bia (3-ethylbenzo-thiazoline-6-sulfonic acid diammonium salt) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH). CONCLUSION: A novel bifunctional alginate lyase, BY17PV7, was expressed and characterized in Escherichia coli BL21(DE3). The results were helpful for the analysis of the molecular mechanisms of degrading patterns in the polysaccharide lyase (PL) family. © 2022 Society of Chemical Industry.

Corresponding Changes of Autophagy-Related Genes and Proteins in Different Stages of Knee Osteoarthritis: An Animal Model Study.

OBJECTIVE: To investigate the effect of autophagy expression levels of different weight-bearing states and different stages of osteoarthritis in animal models, as well as the corresponding mechanisms. METHODS: We used the male Sprague-Dawley (SD) rats (12-week-old, SPF) to establish the OA animal models by modified Hulth method, and grouped animal models according to the length of time after surgery and different weight-bearing areas. RT-qPCR was carried out for detection of autophagy-related genes such as Atg7, Atg12, P62, etc. Western blot analysis was used to detect the expression levels of corresponding autophagy-related proteins such as LC3B, P62, etc. T test was performed for statistical analysis to compare different groups, while the differences were deemed statistically significant with P < 0.05. Transmission electron microscopy was used to observe the autophagosome to demonstrate the level of autophagy expression and the status of the chondrocytes. RESULTS: The results of the RT-qPCR testing showed that when the weight-bearing cartilage of the 4-week group (relatively mild) was compared with that of the 10-week group (relatively severe), there were statistically significant differences in all the genes tested, in detail: Atg3 (P < 0.01), Atg7 (P < 0.01), Atg12 (P < 0.01), P62 (P < 0.0001). The expression of autophagy-related mRNA in the 4-week group is increased compared with that of the 10-week group. As for the expression of proteins, Western blotting showed that in the comparison between the 4- and the 10-week groups, statistically significant results include Atg12 (P < 0.01) in the non-weight-bearing area, with decreased autophagy in the 10-week group compared with that of the 4-week group, while expression of LC3B (P < 0.05) protein was significantly higher in the 4-week group than in the control in the non-weight-bearing area. The expression of LC3B (P < 0.0001) and P62 (P < 0.05) in the 10-week group were higher than that of the control. Transmission electron microscope showed that autophagy in the weight-bearing area is stronger than that in the non-weight-bearing area, and autophagy in the 4-week group is stronger than in the 10-week group for the weight-bearing area. CONCLUSIONS: The expression of autophagy varies during different stages of osteoarthritis, in which the autophagy is stronger in the early stage of osteoarthritis, and gradually decreases with the progression of the disease. Autophagy in different weight-bearing areas may also be different.

Binding mechanism of inhibitors to SARS-CoV-2 main protease deciphered by multiple replica molecular dynamics simulations.

The outbreak caused by SARS-CoV-2 has received extensive worldwide attention. As the main protease (Mpro) in SARS-CoV-2 has no human homologues, it is feasible to reduce the possibility of targeting the host protein by accidental drugs. Thus, Mpro has been an attractive target of efficient drug design for anti-SARS-CoV-2 treatment. In this work, multiple replica molecular dynamics (MRMD) simulations, principal component analysis (PCA), free energy landscapes (FELs), and the molecular mechanics-generalized Born surface area (MM-GBSA) method were integrated together to decipher the binding mechanism of four inhibitors masitinib, O6K, FJC and GQU to Mpro. The results indicate that the binding of four inhibitors clearly affects the structural flexibility and internal dynamics of Mpro along with dihedral angle changes of key residues. The analysis of FELs unveils that the stability in the relative orientation and geometric position of inhibitors to Mpro is favorable for inhibitor binding. Residue-based free energy decomposition reveals that the inhibitor-Mpro interaction networks involving hydrogen bonding interactions and hydrophobic interactions provide significant information for the design of potent inhibitors against Mpro. The hot spot residues including H41, M49, F140, N142, G143, C145, H163, H164, M165, E166 and Q189 identified by computational alanine scanning are considered as reliable targets of clinically available inhibitors inhibiting the activities of Mpro.

Folic Acid Protects Melanocytes from Oxidative Stress via Activation of Nrf2 and Inhibition of HMGB1.

Vitiligo is a cutaneous depigmentation disease due to loss of epidermal melanocytes. Accumulating evidence has indicated that oxidative stress plays a vital role in vitiligo via directly destructing melanocytes and triggering inflammatory response that ultimately undermines melanocytes. Folic acid (FA), an oxidized form of folate with high bioavailability, exhibits potent antioxidant properties and shows therapeutic potential in multiple oxidative stress-related diseases. However, whether FA safeguards melanocytes from oxidative damages remains unknown. In this study, we first found that FA relieved melanocytes from H2O2-induced abnormal growth and apoptosis. Furthermore, FA enhanced the activity of antioxidative enzymes and remarkably reduced intracellular ROS levels in melanocytes. Subsequently, FA effectively activated nuclear factor E2-related factor 2 (Nrf2) pathway, and Nrf2 knockdown blocked the protective effects of FA on H2O2-treated melanocytes. Additionally, FA inhibited the production of proinflammatory HMGB1 in melanocytes under oxidative stress. Taken together, our findings support the protective effects of FA on human melanocytes against oxidative injury via the activation of Nrf2 and the inhibition of HMGB1, thus indicating FA as a potential therapeutic agent for the treatment of vitiligo.

Crosstalk between macrophages and natural killer cells in the tumor microenvironment.

The tumor microenvironment (TME) is jointly constructed by a variety of cell types, including tumor cells, immune cells, fibroblasts, and epithelial cells, among others. The cells within the TME interact with each other and with tumor cells to influence tumor development and progression. As the most abundant immune cells in the TME, macrophages regulate the immune network by not only secreting a large amount of versatile cytokines but also expressing a series of ligands or receptors on the surface to interact with other cells directly. Due to their strong plasticity, they exert both immunostimulatory and immunosuppressive effects in the complex TME. The major effector cells of the immune system that directly target cancer cells include but are not limited to natural killer cells (NKs), dendritic cells (DCs), macrophages, polymorphonuclear leukocytes, mast cells, and cytotoxic T lymphocytes (CTLs). Among them, NK cells are the predominant innate lymphocyte subsets that mediate antitumor and antiviral responses. The activation and inhibition of NK cells are regulated by cytokines and the balance between activating and inhibitory receptors. There is an inextricable regulatory relationship between macrophages and NK cells. Herein, we systematically elaborate on the regulatory network between macrophages and NK cells through soluble mediator crosstalk and cell-to-cell interactions. We believe that a better understanding of the crosstalk between macrophages and NKs in the TME will benefit the development of novel macrophage- or NK cell-focused therapeutic strategies with superior efficacies in cancer therapy.