Applications of Boron Cluster Supramolecular Frameworks as Metal-Free Chemodynamic Therapy Agents for Melanoma.

Chemodynamic therapy (CDT) is a highly targeted approach to treat cancer since it converts hydrogen peroxide into harmful hydroxyl radicals (OH·) through Fenton or Fenton-like reactions. However, the systemic toxicity of metal-based CDT agents has limited their clinical applications. Herein, a metal-free CDT agent: 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT)/ [closo-B12 H12 ]2- (TPT@ B12 H12 ) is reported. Compared to the traditional metal-based CDT agents, TPT@B12 H12 is free of metal avoiding cumulative toxicity during long-term therapy. Density functional theory (DFT) calculation revealed that TPT@B12 H12 decreased the activation barrier more than 3.5 times being a more effective catalyst than the Fe2+ ion (the Fenton reaction), which decreases the barrier about twice. Mechanismly, the theory calculation indicated that both [B12 H12 ]-· and [TPT-H]2+ have the capacity to decompose hydrogen into 1 O2 , OH·, and O2 -· . With electron paramagnetic resonance and fluorescent probes, it is confirmed that TPT@B12 H12 increases the levels of 1 O2 , OH·, and O2 -· . More importantly, TPT@B12 H12 effectively suppress the melanoma growth both in vitro and in vivo through 1 O2 , OH·, and O2 -· generation. This study specifically highlights the great clinical translational potential of TPT@B12 H12 as a CDT reagent.

Synthesis of iron-boride/carbon-nitride composites and their applications in chemodynamic therapy.

Chemodynamic therapy (CDT) is an emerging treatment strategy that inhibits tumor growth by catalyzing the generation of reactive oxygen species (ROS), such as hydroxyl radicals (•OH), using specific nanomaterials. Herein, we have developed a new class of iron-based nanomaterials, i.e., iron-based borides (FeB), using the superchaotropic effect of a boron cluster (closo-[B12H12]2-) and organic ligands, followed by high-temperature calcination. Experimental data and theoretical calculations revealed that FeB nanoparticles exhibit a Fenton-like effect, efficiently decomposing hydrogen peroxide into •OH and thus increasing the concentration of ROS. FeB nanomaterials demonstrate excellent catalytic performance, efficiently generate ROS, and exert significant antitumor effects in cell experiments and animal models. Therefore, FeB nanomaterials have considerable potential for application in tumor treatment and offer new insights for the development of novel and efficient cancer therapy strategies.

AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer. / AAZ2可通过靶向PDK1介导线粒体依赖的凋亡.

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-|(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.

Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer.

The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.

Autophagy and its role in osteosarcoma.

Osteosarcoma (OS) is the most common bone malignancy and preferably occurs in children and adolescents. Despite significant advances in surgery and chemotherapy for OS over the past few years, overall survival rates of OS have reached a bottleneck. Thus, extensive researches aimed at developing new therapeutic targets for OS are urgently needed. Autophagy, a conserved process which allows cells to recycle altered or unused organelles and cellular components, has been proven to play a critical role in multiple biological processes in OS. In this article, we summarized the association between autophagy and proliferation, metastasis, chemotherapy, radiotherapy, and immunotherapy of OS, revealing that autophagy-related genes and pathways could serve as potential targets for OS therapy.

Aa-Z2 triggers ROS-induced apoptosis of osteosarcoma by targeting PDK-1.

BACKGROUND: Osteosarcoma (OS) is the most frequent cancer derived from bone, and the prognosis of OS is poor. Metabolic alterations have been previously reported to contribute to the development of OS, and arsenic compounds have been suggested to exhibit strong anti-OS effects. However, few studies have described the therapeutic efficiency of arsenic compounds by targeting metabolism in OS. METHODS: Here, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo. RESULTS: Aa-Z2 induced OS cell apoptosis, G2/M phase arrest, and autophagy through the accumulation of reactive oxygen species (ROS). Elevated ROS functioned by promoting the mitochondrial-dependent caspase cascade and attenuating the PI3K/Akt/mTOR signalling pathway. N-acetylcysteine (NAC), a kind of ROS scavenger, could reverse the effects of Aa-Z2 treatment on 143B and HOS cells. Specifically, by targeting pyruvate dehydrogenase kinase 1 (PDK-1), Aa-Z2 induced changes in mitochondrial membrane potential and alterations in glucose metabolism to accumulate ROS. Overexpression of PDK-1 could partially desensitize OS cells to Aa-Z2 treatment. Importantly, Aa-Z2 suppressed tumour growth in our xenograft osteosarcoma model. CONCLUSION: The study provides new insights into the mechanism of Aa-Z2-related metabolic alterations in OS inhibition, as well as pharmacologic evidence supporting the development of metabolism-targeting therapeutics.

The organic arsenical-derived thioredoxin and glutathione system inhibitor ACZ2 induces apoptosis and autophagy in gastric cancer via ROS-dependent ER stress.

Developing novel drugs for gastric cancer (GC) is greatly needed, and a reactive oxygen species (ROS)-modulating strategy has been demonstrated to be useful for cancer treatment. However, no organic arsenical-derived ROS-modulating drug has been developed in GC. Here, we constructed ACZ2 and investigated its efficacy and potential mechanism for GC in vitro and in vivo. Our data showed that ACZ2 could inhibit GC proliferation and cause G2/M phase arrest. Moreover, ACZ2 induced ROS accumulation by depleting glutathione (GSH) and TrxR1, triggering a subsequent ER stress response by activating the PERK/EIF2/ATF4/CHOP signalling pathways, which is a crucial step for ACZ2-mediated apoptosis and autophagy. Vitally, ROS scavenger (NAC) and ER stress inhibitor (4PBA) reversed ACZ2/ROS/ER stress-mediated apoptosis and autophagy. Our in vivo results clearly demonstrated that ACZ2 suppressed tumour growth in a GC xenograft model. Collectively, our data indicated that ACZ2 is a potential agent against GC.

Construction and validation of a prognostic model for osteosarcoma patients based on autophagy-related genes.

BACKGROUND: Osteosarcoma is the most frequent primary bone malignancy with a poor prognosis because of pulmonary metastasis. Autophagy is strongly associated with tumor metastasis, and it is valuable to construct an autophagy-related gene risk model for predicting the prognosis of osteosarcoma. METHODS: We obtained ARGs from the Human Autophagy Database and RNA-sequencing data of osteosarcoma patients from the Gene Expression Omnibus (GEO) database. Subsequently, univariate and multivariate cox regression analyses were performed to construct a three-gene prognostic model and its accuracy was further confirmed in the Therapeutic Applications Research to Generate Effective Treatments (TARGET) database. Afterward, we detected the expression levels and effects on osteosarcoma cells metastasis of MYC and MBTPS2, which were involved in the model. RESULTS: In both training and verification cohorts, patients with lower risk scores had longer OS, and the model was identified as an independent prognostic factor in osteosarcoma. Besides, the ROC curve demonstrated the reliability of the model. Furthermore, RT-qPCR, Western Blotting and IHC results indicated that MYC and MBTPS2 were differently expressed in osteosarcoma tissues and cell lines. MYC knockdown or MBTPS2 overexpression prevented the capacity of migration and invasion in osteosarcoma cell lines through inhibiting cellular autophagy. CONCLUSION: The risk model based on three ARGs had a strong ability to predict the prognosis of osteosarcoma patients. Our findings also suggested that MYC and MBTPS2 were two major factors regulating autophagy in osteosarcoma, and could serve as potential therapeutic targets for osteosarcoma.

Stress and cancer: The mechanisms of immune dysregulation and management.

Advances in the understanding of psychoneuroimmunology in the past decade have emphasized the notion that stress and cancer are interlinked closely. Durable chronic stress accelerated tumorigenesis and progression, which is unfavorable for clinical outcomes of cancer patients. Available evidence has provided unprecedented knowledge about the role and mechanisms of chronic stress in carcinogenesis, the most well-known one is dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). With abnormal activation of neuroendocrine system, stress-related hormones contribute to increased oncogenes expression, exacerbated chronic inflammation and impaired immunologic function. In addition, accumulating studies have demonstrated that diverse stress interventions including pharmacological approaches, physical exercises and psychological relaxation have been administered to assist in mental disorders reduction and life quality improvement in cancer patients. In this review, we systematically summarize the connection and mechanisms in the stress-immune-cancer axis identified by animal and clinical studies, as well as conclude the effectiveness and deficiencies of existing stress management strategies.

Surface Adsorption-Mediated Ultrahigh Efficient Peptide Encapsulation with a Precise Ratiometric Control for Type 1 and 2 Diabetic Therapy.

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.

UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells.

Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is the hinge protein for the multi-subunit complex III of the mitochondrial electron transport chain and is involved in the electron transfer reaction between cytochrome c1 and c. Recent genome-wide transcriptomic and epigenomic profiling of clear cell renal cell carcinoma (ccRCC) by The Cancer Genome Atlas (TCGA) identified UQCRH as the top-ranked gene showing inverse correlation between DNA hypermethylation and mRNA downregulation. The function and underlying mechanism of UQCRH in the Warburg effect metabolism of ccRCC have not been characterized. Here, we verified the clinical association of low UQCRH expression and shorter survival of ccRCC patients through in silico analysis and identified KMRC2 as a highly relevant ccRCC cell line that displays hypermethylation-induced UQCRH extinction. Ectopic overexpression of UQCRH in KMRC2 restored mitochondrial membrane potential, increased oxygen consumption, and attenuated the Warburg effect at the cellular level. UQCRH overexpression in KMRC2 induced higher apoptosis and slowed down in vitro and in vivo tumor growth. UQCRH knockout by CRISPR/Cas9 had little impact on the metabolism and proliferation of 786O ccRCC cell line, suggesting the dispensable role of UQCRH in cells that have entered a Warburg-like state through other mechanisms. Together, our study suggests that loss of UQCRH expression by hypermethylation may promote kidney carcinogenesis through exacerbating the functional decline of mitochondria thus reinforcing the Warburg effect.

Effective combinatorial immunotherapy for penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.

TGF-ß receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-ß/SMAD4 signaling pathway.

Radiotherapy is used to treat gastric cancer (GC); however, radioresistance challenges the clinical outcomes of GC, and the mechanisms of radioresistance in GC remain poorly understood. Here, we report that the TGF-ß receptor inhibitor, LY2109761 (LY), is a potential radiosensitizer both in vitro and in vivo. As per the Cancer Genome Atlas database, TGF-ß overexpression is significantly related to poor overall survival in GC patients. We demonstrated that the TGF-ß/SMAD4 signaling pathway was activated in both radioresistant GC cells and radioresistant GC patients. As a TGF-ß receptor inhibitor, LY can enhance the activities of irradiation by inhibiting cell proliferation, decreasing clonogenicity and increasing apoptosis. Moreover, LY attenuated the radiation-induced migration and invasion, epithelial-mesenchymal transition (EMT), inflammatory factor activation, immunosuppression, and cancer stem cell characteristics of GC cells, thus leading to radiosensitization of the GC cells. We confirmed that LY reduced tumor growth, inhibited TGF-ß/SMAD4 pathway activation and reversed irradiation-induced EMT in a tumor xenograft model. Our findings indicate that the novel TGF-ß receptor inhibitor, LY, increases GC radiosensitivity by directly regulating the TGF-ß/SMAD4 signaling pathway. These findings provide new insight for radiotherapy in GC patients.

Predicting physical stability of solid dispersions by machine learning techniques.

Amorphous solid dispersion (SD) is an effective solubilization technique for water-insoluble drugs. However, physical stability issue of solid dispersions still heavily hindered the development of this technique. Traditional stability experiments need to be tested at least three to six months, which is time-consuming and unpredictable. In this research, a novel prediction model for physical stability of solid dispersion formulations was developed by machine learning techniques. 646 stability data points were collected and described by over 20 molecular descriptors. All data was classified into the training set (60%), validation set (20%), and testing set (20%) by the improved maximum dissimilarity algorithm (MD-FIS). Eight machine learning approaches were compared and random forest (RF) model achieved the best prediction accuracy (82.5%). Moreover, the RF models revealed the contribution of each input parameter, which provided us the theoretical guidance for solid dispersion formulations. Furthermore, the prediction model was confirmed by physical stability experiments of 17ß-estradiol (ED)-PVP solid dispersions and the molecular mechanism was investigated by molecular modeling technique. In conclusion, an intelligent model was developed for the prediction of physical stability of solid dispersions, which benefit the rational formulation design of this technique. The integrated experimental, theoretical, modeling and data-driven AI methodology is also able to be used for future formulation development of other dosage forms.

Reactive Oxygen Species Are Involved in the Development of Gastric Cancer and Gastric Cancer-Related Depression through ABL1-Mediated Inflammation Signaling Pathway.

BACKGROUND: The mechanisms of crosstalk between depression and gastric cancer (GC) remain ill defined. Given that reactive oxygen species (ROS) is involved in the pathophysiology of both GC and depression, we try to explore the activities of ROS in the development of GC and GC-related depression. METHODS: 110 patients with newly diagnosed GC were recruited in our study. The clinical characteristics of these patients were recorded. Inflammation and oxidative stress markers were detected by ELISA. The depression status of patients with GC was assessed during follow-up. The association between ROS, ABL1, and inflammation factors was evaluated in H2O2-treated GC cell lines and The Cancer Genome Atlas (TCGA) database. The effect of ABL1 on inflammation was detected with Imatinib/Nilotinib-treated GC cell lines. A chronic mild stress- (CMS-) induced patient-derived xenograft (PDX) mice model was established to assess the crosstalk between depression and GC. RESULTS: Depression was correlated with poor prognosis of patients with GC. GC patients with depression were under a high level of oxidative status as well as dysregulated inflammation. In the CMS-induced GC PDX mice model, CMS could facilitate the development of GC. Additionally, tumor bearing could induce depressive-like behaviors of mice. With the treatment of ROS, the activities of ABL1 and inflammatory signaling were enhanced both in vitro and in vivo, and blocking the activities of ABL1 inhibited inflammatory signaling. CONCLUSIONS: ROS-activated ABL1 mediates inflammation through regulating NF-κB1 and STAT3, which subsequently leads to the development of GC and GC-related depression.

Reactive Oxygen Species-Mediated Tumor Microenvironment Transformation: The Mechanism of Radioresistant Gastric Cancer.

Radioresistance is one of the primary causes responsible for therapeutic failure and recurrence of cancer. It is well documented that reactive oxygen species (ROS) contribute to the initiation and development of gastric cancer (GC), and the levels of ROS are significantly increased in patients with GC accompanied with abnormal expressions of multiple inflammatory factors. It is also well documented that ROS can activate cancer cells and inflammatory cells, stimulating the release of a variety of inflammatory cytokines, which subsequently mediates the tumor microenvironment (TME) and promotes cancer stem cell (CSC) maintenance as well as renewal and epithelial-mesenchymal transition (EMT), ultimately resulting in radioresistance and recurrence of GC.

Predictive value of 18 F-FDG PET/CT scanning in combination with clinical parameters in patients with newly diagnosed multiple myeloma.

OBJECTIVE: To evaluate the association of 18 F-2'-deoxy 2'-fluorodeoxyglucose (18 F-FDG) PET/CT with clinical parameters in predicting patients with newly diagnosed multiple myeloma (MM). METHODS: A total of 120 MM patients undergoing 18 F-FDG PET/CT scanning were analyzed in a retrospective cohort study. RESULTS: Based on multivariate analysis, ß2M, LDH, number of focal lesions (FLs), and SUVmax were significantly correlated with OS. These 4 variables were used to construct a new staging system (NSS) based on the number of risk factors. NSS provided a better discrimination of risk between stages III and II than International staging system (ISS) (P < .001 vs P = .086). For OS, there was no significant difference among risk groups in Durie-Salmon (DS) stage (P > .05). Based on Spearman correlation analysis, the presence of lesions in appendicular skeleton, number of FLs, and SUVmax appeared to indicate advanced stage of MM. ROC curves which showed the combination of ß2M with calcium got a specificity of 96.3% for lesions in appendicular skeleton, and LDH alone had 100% specificity in predicting the number of FLs, although the sensitivity was only 50%. CONCLUSIONS: 18 F-FDG PET/CT in combination with clinical parameters provided an accurate and simple method for risk stratification of patients with newly diagnosed MM.

Potential prognostic value of clinical characteristics, hormone status and major depressive disorder in breast cancer.

AIM: To identify independent factors predicting overall survival (OS) of breast cancer (BC) patients. PATIENTS & METHODS: Two hundred and eighty one women with BC were recruited and clinical characteristics including lymphovascular invasion, clinical stage of Tumor Node Metastasis and positive axillary lymph nodes were documented; immunohistochemistry/fluorescence in situ hybridization was used to examine the expression of estrogen receptor, progesterone receptor, HER2 and Ki-67; major depressive disorder was assessed with Diagnostic and Statistical Manual of Mental Disorders V. RESULTS: Multivariable analyses indicated that in BC patients, lymphovascular invasion, Tumor Node Metastasis, pN, Ki-67 and major depressive disorder were significantly negatively correlated with OS; estrogen receptor was significantly positively associated with OS. CONCLUSION: Early diagnostic approaches and effective psychologic intervention are indispensable for BC patients.

Nrf2 promotes progression of non-small cell lung cancer through activating autophagy.

The transcription factor, NFE2-related factor 2 (Nrf2) and autophagy have been implicated in the oxidative-stress response during tumor evolution. However, few studies focus on crosstalk between Nrf2 and autophagy in cancer progression of non-small cell lung cancer (NSCLC). Herein, we evaluated the effect of Nrf2 on autophagy in NSCLC and their role in development of NSCLC. Effect of Nrf2 on overal survival (OS) of NSCLC patients were evaluated. Cell biological behaviors in response to Nrf2 were evaluated by MTT, colony formation assay and flow cytometry. Effect of 3-MA (a classical inhibitor of autophagy) on 95D-Nrf2 cells was also analyzed using flow cytometry. After up/down-regulating Nrf2 in NSCLC cell lines, expression of autophagy-related proteins were evaluated with western blot analysis. The results revealed that Nrf2 was an independent prognositc factor negtively associated with OS of NSCLC patients. Elevated Nrf2 expression promotes NSCLC progression, enhancing the escape of tumor cells from apoptosis in vivo and in vitro. Double staining with Annexin V-APC and 7-AAD showed that the proportions of apoptotic cells in 95D-Nrf2 cells were gradually increased after the addition of 3-MA. Importently, Nrf2 induced autophagosome formation and enhanced autophagic activity, which subsequently inhibits NSCLC cell apoptosis. In conclusion, our present study demonstrates that Nrf2 promotes progression of non-small cell lung cancer through activating autophagy. It provides novel insights into Nrf2-mediated of cell proliferation in NSCLC and may facilitate therapeutic development against NSCLC.

Leptin-LepRb Expressed in Gastric Cancer Patients and Related to Cancer-Related Depression.

Depression is the most common psychiatric disorder among cancer patients. Studies have not only highlighted that leptin and its receptor (LepRb) are independent poor prognostic factors in gastric cancer (GC) patients but also shown that the leptin-LepRb is necessary for antidepressant-like behaviors. In this study, we examined the serum and tissue leptin-LepRb expression in GC patients. Enzyme-linked immunosorbent assay showed that depressive GC patients had significantly higher serum leptin-LepRb than healthy donors. Leptin-LepRb levels in GC tissues were also significantly higher than in matched paracarcinoma tissues using real-time RT-PCR. Moreover, we observed that both serum and tissue leptin-LepRb were significantly higher in depressive GC patients than those in nondepressive GC patients. Further, the patients with high tumor stage tend to have higher leptin-LepRb mRNA levels than that with low tumor stage. Together, our findings suggest that leptin-LepRb plays an important role in the pathogenesis and depression in GC. Leptin-LepRb therefore could be a potential diagnostic marker and therapeutic target in GC patients with depression.