CsPbBrxCl3-x Solid Solutions: Understanding the Relationship between Lattice Expansion and Optical Properties.

All-inorganic halide perovskite semiconductors have received extensive attention due to their excellent photoelectronic conversion efficiency. Prior studies have reported on compounds CsPbBr3 and CsPbCl3. However, the transition phases between them have not been systematically studied. Here, a series of large-size single crystals of CsPbBrxCl3-x (x = 0-3) were successfully grown by the Bridgman method, which proves that the Br and Cl atoms can be miscible in any proportion in the solid solution system, and the change of lattice parameters conforms to Vegard's law. Also, the bandgap and light emission were studied. It is found that the band gap (2.90-2.29 eV) and photoluminescence characteristics (from blue light to green light) can be effectively tuned by adjusting the content of the Br atom. These results provide valuable guidance for the development and optimization of photoelectronic semiconductors that can meet different practical demands.

Targeting E2 ubiquitin-conjugating enzyme UbcH5c by small molecule inhibitor suppresses pancreatic cancer growth and metastasis.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet. METHODS: Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR. RESULTS: UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models. CONCLUSIONS: These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.

The ubiquitin E3 ligase Nedd4-2 relieves mechanical allodynia through the ubiquitination of TRPA1 channel in db/db mice.

Neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2) is a member of the E3 ubiquitin ligase family that is highly expressed in sensory neurons and involved in pain modulation via downregulation of ion channels in excitable membranes. Ubiquitination involving Nedd4-2 is regulated by adenosine monophosphate-activated protein kinase (AMPK), which is impaired in the dorsal root ganglion (DRG) neurons of db/db mice. AMPK negatively regulates the expression of transient receptor potential ankyrin 1 (TRPA1), a recognised pain sensor expressed on the membrane of DRG neurons, consequently relieving mechanical allodynia in db/db mice. Herein, we studied the involvement of Nedd4-2 in painful diabetic neuropathy and observed that Nedd4-2 negatively regulated diabetic mechanical allodynia. Nedd4-2 was co-expressed with TRPA1 in mouse DRG neurons. Nedd4-2 was involved in TRPA1 ubiquitination, this ubiquitination, as well as Nedd4-2-TRPA1 interaction, was decreased in db/db mice. Moreover, Nedd4-2 levels were decreased in db/db mice, while an abnormal intracellular distribution was observed in short-term high glucose-cultured DRG neurons. AMPK activators not only restored Nedd4-2 distribution but also increased Nedd4-2 expression. These findings demonstrate that Nedd4-2 is a potent regulator of TRPA1 and that the abnormal expression of Nedd4-2 in DRG neurons contributes to diabetic neuropathic pain.

Strategies, techniques and applications for food authentication based on carbohydrates: A review.

The increasing complexity and ubiquity of food processing and the emergence of fraudulent practices have made effective and reliable methods to authenticate food products of utmost importance. Carbohydrates, with various nutritional functions, are abundant in foods and can serve as potential markers for food authentication. However, the complex and diverse structures and properties of carbohydrates, especially polysaccharides, pose challenges. Nonetheless, significant progress has been made in this area. This paper provides an overview of the utilization of carbohydrates in food authentication since 2000, focusing on strategies involving carbohydrate-based markers, carbohydrate profiles, and carbohydrate-protein interaction-based assays. The analytical techniques, applications, challenges and limitations of these strategies are reviewed and discussed. The findings demonstrate that these strategies offer origin verification, quality assessment, adulteration detection, process control, and food species identification. Notably, oligosaccharide analysis has proven effective in food authentication and remains a promising marker, especially for analyzing intricate matrices. The advances in chromatography separation and mass spectrometry identification of isomers and trace amounts of these compounds have facilitated the discovery of such markers. In conclusion, carbohydrate analysis can play a crucial role in food authentication. Future research and development will make the authentication of carbohydrate-rich foods ever more accurate and efficient.

Review on potential effects of traditional Chinese medicine on glaucoma.

ETHNIC PHARMACOLOGICAL RELEVANCE: Glaucoma is the second most common blindness in the world, which seriously affects the life quality of patients. Traditional Chinese Medicines (TCM), are important plant materials, widely used for ocular disease all over the world. With the help of modern ophthalmic detection technology, TCM has gradually become an important content in the field of ophthalmology, characterized by more targets and lower toxicity. AIM OF THIS REVIEW: This review presents an overview of the pathogenesis of glaucoma in both modern and traditional medicines, and summarizes the therapeutic effect of TCM on glaucoma including their formula, crude drugs and active components, and also the application of acupuncture. METHODS: A collection and collation of relevant scientific articles from different scientific databases was performed regarding TCM and its application on glaucoma. The therapeutic effects of TCM were summarized and analyzed according to the existing experimental and clinical researches, while the GSE26299 database were employed to screen bioinformatics analysis of glaucoma based on the GEO database chip. RESULTS: There were many positive signs showing that TCM could increase the survival rate of retinal ganglion cells, which may be related to its regulation of microcirculation, oxidative stress, and the immune system. Hence, TCM plays an active role in treating glaucoma. In addition, the bioinformatics analysis predicted that the pathogenesis of glaucoma might be related to p53, MAPK, NF-κB signal, as well as other pathways by KEGG analysis, and the results from bioinformatics analysis predicted that PIK3R6, FGF1, and TYRP1 etc. CONCLUSION: TCM exerts definite effects on preventing and treating ocular disease. It could alleviate and treat glaucoma in various ways. The differentiation syndrome should thus be taken as the basis to propose appropriate treatment options of TCM making their application on glaucoma more popular.

Platycodin D inhibits HFD/STZ-induced diabetic nephropathy via inflammatory and apoptotic signaling pathways in C57BL/6 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The dried root of Platycodon grandiflorum (Jacq.) A.DC. (PG) is a traditional herb used in Asian countries and is widely used in formulas for the treatment of diabetes. Platycodin D (PD) is one of the most important components of PG. AIM OF THE STUDY: This study aimed to investigate the improvement effects and regulatory mechanisms of PD on kidney injury in a high-fat diet (HFD) combined with streptozotocin (STZ)-induced diabetic nephropathy (DN). MATERIALS AND METHODS: Model mice were treated with oral gavage of the PD (2.5, 5 mg/kg) for 8 weeks. Determination of serum lipid and renal function-related indexes creatinine (CRE), and blood urea nitrogen (BUN) levels in mice, and histopathological section analysis of kidney. Molecular docking and molecular dynamics were utilized to study the binding ability of PD to target NF-κB and apoptosis signaling pathway-related proteins. Moreover, Western blot was used to test the expressions of NF-κB and apoptosis-related proteins. Vitro experiments were performed to validate the related mechanisms using RAW264.7 cells and HK2 cells cultured by high glucose. RESULTS: In vivo experiments, the administration of PD (2.5 and 5.0 mg/kg) reduced fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR) levels in DN mice, while lipid levels and renal function were significantly improved. Furthermore, PD significantly inhibited the development of DN in the model mice by regulating NF-κB and apoptotic signaling pathways, reduced the abnormal elevation of serum inflammatory factors TNF-α and IL-1ß, and repaired renal cell apoptosis. In vitro experiments, NF-κB inhibitor ammonium pyrrolidine dithiocarbamate (PDTC) was used to confirm that PD can alleviate high glucose-induced inflammation in RAW264.7 cells and inhibit the release of inflammatory factors. And in HK2 cell experiments, it was verified that PD can inhibit ROS generation, reduce the loss of JC-1 and suppress HK2 cell injury by regulating NF-κB and apoptotic pathways. CONCLUSIONS: These data suggested that PD has the potential to prevent and treat DN and is a promising natural nephroprotective agent.

Lobetyolin, a Q-marker isolated from Radix Platycodi, exerts protective effects on cisplatin-induced cytotoxicity in HEK293 cells.

This study investigated the protective effect of lobetyolin (LBT), a Q-marker isolated from the roots of Platycodon grandiflorum (Radix Platycodi), against cisplatin-induced cytotoxicity in human embryonic kidney (HEK293) cells. Results showed that LBT at 20 µM significantly prevented cisplatin-induced cytotoxicity by improving the viability of HEK293 cells, decreasing levels of MDA, and decreasing GSH content triggered by cisplatin. It also suppressed reactive oxygen species (ROS) levels. Molecular docking analysis revealed a strong binding affinity between LBT and the NF-κB protein, with a docking fraction of - 6.5 kcal/mol. These results provide compelling evidence suggesting a potential link between the visualization analysis of LBT and its protective mechanism, specifically implicating the NF-κB signaling pathway. LBT also reduced the expression level of tumor necrosis factor-alpha (TNF-α), phosphorylation NF-κB and IκBα in HEK293 cells which were increased by cisplatin exposure, leading to inhibition of inflammation. Furthermore, western blotting showed that LBT antagonized the up-regulation of Bax, cleaved caspase 3, 8, and 9 expression and inhibited the MAPK signaling pathway by down-regulating phosphorylation JNK, ERK, and p38, partially ameliorating cisplatin-induced cytotoxicity in HEK293 cells. Therefore, these results indicate that LBT has potentially protected renal function by inhibiting inflammation and apoptosis.

Platycodin D ameliorates hyperglycaemia and liver metabolic disturbance in HFD/STZ-induced type 2 diabetic mice.

In this work, we investigated the ameliorative effects of platycodin D (PD), a major active chemical ingredient isolated from the roots of Platycodon grandiflorum (PG), on high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes (T2D) mice. PD treatment (2.5 and 5.0 mg kg-1) improved HFD-induced body weight gain. PD administration also decreased the fasting blood glucose (FBG) level and improved glucose and insulin tolerance levels. These data collectively showed that PD could maintain glucose homeostasis. In addition, the diabetic mice with PD treatment also showed fewer pathological changes in liver tissues and improved hepatic functional indexes with respect to the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and recovery of abnormal liver function caused by T2D. Except for these, PD decreased the decomposition of hepatic glycogen. The results from western blot analysis showed that PD treatment might regulate the hepatic gluconeogenesis pathway with the increased phosphorylation/expression of AMPK and decreased expressions of PCK1 and G6Pase. In the aspect of lipid metabolism, PD decreased the whole-body lipid levels, including total cholesterol (TC), triglycerides (TG), and high-density lipoprotein (HDL), and reduced the hepatic fat accumulation induced by T2D through the AMPK/ACC/CPT-1 fatty acid anabolism pathway. In addition, the results of molecular docking showed that PD may have a potential direct effect on AMPK and other key glycolipid metabolism proteins. To summarize, PD modulation of hepatic glycolipid metabolism abnormalities is promising for T2D therapy in the future.

Inhibition of STAT3 Signaling Pathway by Terphenyllin Suppresses Growth and Metastasis of Gastric Cancer.

Gastric cancer is a common type of malignant tumor with a relatively poor prognosis and presents a serious threat to global health. Signal Transducer and Activator of Transcription-3 (STAT3) has been strongly implicated in many cancers, and its constitutive activation promotes growth, angiogenesis, inflammation, and immune evasion. Therefore, considerable efforts have been put into developing effective and safe STAT3 inhibitors. In this study, we performed a virtual screening by molecular docking and found that terphenyllin, a marine-derived natural product, directly interacted with STAT3. We further found that terphenyllin inhibited the phosphorylation and activation of STAT3 and decreased the protein levels of STAT3-dependent target genes, including c-Myc and Cyclin D1. Subsequently, we demonstrated that terphenyllin exerted its potent anticancer efficacy against gastric cancer in vitro and in vivo. Terphenyllin concentration-dependently inhibited growth, proliferation, and colony formation and induced cell cycle arrest and apoptosis of gastric cancer cells in vitro. Moreover, terphenyllin treatment suppressed the tumor growth and metastasis in a gastric cancer orthotopic mouse model without notable toxicity in vivo. Taken together, our results indicated that terphenyllin exerts its anticancer activity by inhibiting the STAT3 signaling pathway and may serve as a potent STAT3 inhibitor for gastric cancer treatment.

Acupuncture Ameliorates Depressive Behaviors by Modulating the Expression of Hippocampal Iba-1 and HMGB1 in Rats Exposed to Chronic Restraint Stress.

The antidepressant mechanism of acupuncture has not been fully elucidated recently. Thus, the objective of the present study is to investigate the antidepressant mechanism of acupuncture of modulating the neuroinflammation induced by high mobility group box-1 (HMGB1) in rats subjected to chronic restraint stress (CRS). Forty-four male Sprague Dawley rats were randomly divided into control, model, escitalopram, and acupuncture group. Except for rats in the control group, all rats were exposed to CRS for 21 days continuously. Rats in the escitalopram group were subjected to a suspension of escitalopram and saline. One hour before CRS procedures, acupuncture was performed at Baihui (GV20) and Yintang (GV29) for rats in the acupuncture group, 20 min per day for 21 days. All rats in each group were conducted to detect the body weight, sucrose preference test at 0, 7, 14, 21 days to evaluate the depression-like behaviors. The expression of microglial activation and HMGB1 in the hippocampus was detected by immunofluorescence. The expression of hippocampal interleukin-10 (IL-10) was detected by western blot. And the content of serum tumor necrosis factor-α (TNF-α) was detected by the enzyme-linked immunosorbent assay method. CRS-exposed rats showed obviously decreased body weight and sucrose preference when compared with the control group, which was reversed by acupuncture. The results have also shown that acupuncture ameliorated the CRS-induced activation of microglia and HMGB1 in the hippocampus CA1 region. Furthermore, acupuncture reduced the stress-induced upregulation of TNF-α in serum. Collectively, the current study highlights the role of acupuncture in alleviating depressive behavior associated with stress-induced neuroinflammation mediated by HMGB1 in the CRS model of depression.

Improved effect of fresh ginseng paste (radix ginseng-ziziphus jujube) on hyperuricemia based on network pharmacology and molecular docking.

Background: Hyperuricemia (HUA) is a metabolic disease caused by reduced excretion or increased production of uric acid. This research aims to study the practical components, active targets, and potential mechanism of the "Radix ginseng (RG)-Ziziphus jujube (ZJ)" herb pair through molecular docking, network pharmacology, and animal experiments. Methods: The potential targets of "Radix ginseng (RG)-Ziziphus jujube (ZJ)" herb pair were obtained from the TCMSP database. The therapeutic targets of HUA were acquired from the GendCards, OMIM, PharmGkb, and TTD databases. Protein-protein interaction network (PPI) was constructed in the STRING 11.0 database. The David database was used for enrichment analysis. Molecular Docking was finished by the AutoDock Vina. And we employed Radix ginseng and Ziziphus jujube as raw materials, which would develop a new functional food fresh ginseng paste (FGP) after boiling. In addition, benzbromarone (Ben) (7.8 mg/kg) and allopurinol (All) (5 mg/kg) were used as positive drugs to evaluate the hyperuricemia induced by FGP (400 and 800 mg/kg) potassium oxazine (PO) (100 mg/kg) and hypoxanthine (HX) (500 mg/kg) on mice. Results: The results showed that 25 targets in the "RG-ZJ" herb pair interacted with hyperuricemia. Then protein-protein interaction (PPI) analysis showed that TNF, IL-1ß, and VEGFA were core genes. KEGG enrichment analysis showed that the Toll-like receptor signaling pathway and IL-17 signaling pathway were mainly involved. Meantime, animal experiments showed that FGP could improve the HUA status of mice by reducing serum UA BUN, XO, and liver XO levels (p < 0.05, p < 0.01). Furthermore, we analyzed the main ingredients of FGP by HPLC. We found that the main ingredients of FGP had solid binding activity to the core target of HUA by molecular docking. Conclusion: This study explored the active ingredients and targets of the "RG-ZJ" herb pair on HUA through network pharmacology, molecular docking, and animal experiments. It revealed the improvement of FGP in mice with HUA.

Saponins From Platycodon grandiflorum Reduces Cisplatin-Induced Intestinal Toxicity in Mice through Endoplasmic Reticulum Stress-Activated Apoptosis.

Saponins from the roots of Platycodon grandiflorum, an edible medicinal plant, have shown a wide range of beneficial effects on various biological processes. In this study, an animal model was established by a single intraperitoneal injection of cisplatin (20[Formula: see text]mg/kg) for evaluating the protective effects of saponins from the roots of P. grandiflorum (PGS, 15[Formula: see text]mg/kg and 30[Formula: see text]mg/kg) in mice. The results indicated that PGS treatment for 10 days restored the destroyed intestinal mucosal oxidative system, and the loosened junctions of small intestinal villi was significantly improved. In addition, a significant mitigation of apoptotic effects deteriorated by cisplatin exposure in small intestinal villi was observed by immunohischemical staining. Also, western blot showed that PGS could effectively prevent endoplasmic reticulum (ER) stress-induced apoptosis caused by cisplatin in mice by restoring the activity of PERK (an ER kinase)-eIF2[Formula: see text]-ATF4 signal transduction pathway. Furthermore, molecular docking results of main saponins in PGS suggested a better binding ability with target proteins. In summary, the present work revealed the underlying protective mechanisms of PGS on intestinal injury induced by cisplatin in mice.

PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy.

Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.

Antidepressant effect of electroacupuncture on modulating the expression of c-Fos/AP-1 through the JNK signaling pathway.

The effectiveness and safety of electroacupuncture (EA) for depression have been identified by abundant clinical trials and experimental findings. The c-Jun-NH(2)-terminal kinase (JNK) signaling pathway is considered to be involved in the antidepressant mechanism of EA. However, the antidepressant effect of EA via modulating the expression of c-Fos/activator protein-1 (AP-1) under the condition of JNK inhibition remains unexplored. In this study, we investigated the antidepressant effect and possible mechanism of EA in regulating the expression of c-Fos/AP-1 under the condition of JNK inhibition by SP600125 in rats exposed to chronic unpredictable mild stress (CUMS). The depression-like behaviors were evaluated by the body weight, sucrose preference test (SPT), and open field test (OFT). The expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum of CUMS induced rat model of depression were detected by ELISA. The results indicated that treatment with EA and fluoxetine can reverse the CUMS-induced depression-like behaviors in rats and can up-regulate the expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum. Of note, the data demonstrated that SP600125, the inhibitor of JNK signaling pathway, can exert synergistic effect with EA in regulating CUMS-induced abnormal activation of the JNK signaling pathway. The antidepressant effect of EA might be mediated by modulating the expression of c-Fos/AP-1.

Integrative analysis reveals clinically relevant molecular fingerprints in pancreatic cancer.

Pancreatic cancer is a highly aggressive cancer with an exceedingly low rate of response to treatments, which calls for comprehensive molecular characterization of pancreatic cancer cell lines (PCCLs). We screened multi-layer molecular data of 36 PCCLs, including gene mutation, gene expression, microRNA (miRNA) expression, and protein profiles. Our comparative analysis of genomic mutations found that PCCLs recapitulated genomic alterations of the primary tumor and suggested potential therapeutic strategies for clinical interventions. The panel of 36 PCCLs was classified into 2 subgroups based on transcriptomic mRNA expression, wherein the C1 subgroup was characterized with differentiation, whereas C2 cell lines were featured with immunity, angiogenesis, epidermis, and proliferation. Transcriptomic classification was further recapitulated by miRNA and protein expression. Additionally, the differential proteins between C1 and C2 subgroups were prominently involved in epidermal growth factor receptor (EGFR) signaling, phosphatidylinositol 3-kinase (PI3K) signaling, and mitogen-activated protein kinase (MAPK) signaling pathways. Tumor samples from different subgroups exhibited distinct infiltration of CD4 naive cells and monocytes. Remarkably, patients in subgroups C1 showed longer survival, whereas those in C2 had worse clinical outcome. Further integrative analysis revealed that temozolomide and NVP-TAE684 showed higher sensitivity in the C1 subgroup, whereas the C2 cell lines were more sensitive to SR1001 and SRT-1720. Our results also showed that PCCLs with mutations in CDKN2A, TP53, and SMAD4 were more sensitive to certain anti-cancer drugs. Our integrative analysis identified molecular features of pancreatic cancer that were associated with clinical significance and drug sensitivity, providing potentially effective strategies for precision treatments of patients with pancreatic cancer.

Artemisinin attenuates early renal damage on diabetic nephropathy rats through suppressing TGF-ß1 regulator and activating the Nrf2 signaling pathway.

AIM: The present study aims to investigate the protective effects of artemisinin (ATZ) on early renal damage in experimental diabetic rats and its probable mechanism. METHODS: Models of diabetic nephropathy (DN) rats was established utilizing streptozotocin (STZ)-injection intraperitoneally (55 mg/kg) method. All rats were subsequently divided into normal control group, model group and ATZ (25, 50, 75 mg/kg) group randomly. Biochemical parameters including body weight, kidney index, blood glucose, 24 h UAER, Scr, BUN, T-SOD, GSH-Px and MDA were comprehensively determined after 8-week consecutive administrations. HE and PAS stainings were performed to observe the histopathological alterations of kidney. Western blot was conducted to detect the expressions of TGF-ß1, Nrf2, HQ-1 and NQO1. KEY FINDINGS: ATZ at three concentrations in ATZ group significantly increased the body weight. Biochemical parameters altered significantly between model group and ATZ group. Moreover, ATZ inhibited TGF-ß1 protein expression and activated the Nrf2 signaling pathway. Pathological histology results revealed the alterations including mesangial cells proliferation, thickness of glomerular capillary basement membrane, extracellular matrix (ECM) and the 24 h UAER. Western blot analysis demonstrated the increase of antioxidant proteins HO-1 and NQO1 and Nrf2-related proteins. SIGNIFICANCE: ATZ could reduce early renal oxidative stress damage in DN rats by inhibiting TGF-ß1 protein expression in kidney tissues as well as activating the Nrf2 signaling pathway and enhancing the expression of antioxidant proteins, thereby exerting the protective effects on DN kidney. The current study is the first report of ATZ on attenuating effects on kidney of DN rats, which could lay solid theoretical foundations on clinical application of ATZ to treat DN.

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitin-proteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.