Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it, while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing

Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

Discovery of 1,2,3triazolo4,5-pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors

Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound potently inhibited USP28 (IC = 1.10 ± 0.02 μmol/L,  = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC > 100 μmol/L). Compound was cellularly engaged to USP28 in gastric cancer cells. Compound reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound . Collectively, compound could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.

Effect of Chlorhexidine and/or Ethanol Pre-bonding Treatment on the Shear Bond Strength of Resin Composite to Dentin

Aim of the study: The aim of the study is to evaluate the effect of chlorhexidine and/or ethanol pre-bonding treatment on the shear bond strength of resin composite to dentin using etch and rinse adhesive system after 24 hours, 3 months and 6 months of aging. Materials and methods: Dentin surface of premolars were etched and randomly assigned into 4 groups (n=24). In Group A, dentin surfaces were bonded according to the manufacturer’s instruction. In Group B and C, dentin surfaces were treated with 2% CHX or 100% ethanol for 60 sec respectively. In Group D, dentin surfaces were treated with 2% CHX for 60 sec followed by 100% ethanol for another 60 sec. The adhesive resin was then applied and light cured according to the manufacturer’s instruction. Resin composite build ups were made above the dentin surface for shear bond strength test after 24 hours, 3 months and 6 months’ storage period in normal saline. Bond strength data were analyzed using one-way ANOVA and Tukey’s test. Mode of failure was also analyzed whether adhesive, cohesive or mixed between composite and dentin. Results: Significant differences were found for the 2 factors: ‘storage period’ (p<0.05) and ‘adhesive protocol’ (p<0.05) on bond strength. Numbers of mixed failure were higher when dentin surfaces were treated with 2% CHX and/or 100% ethanol. Conclusion: Dentin surface treatment with 2% CHX and/or 100% ethanol was effective in reducing the deterioration in shear bond strength of composite to dentin up to 6 months of storage.

Comparison of two commercial dentifrices in the reduction of gingivitis and plaque: a pilot study / Comparação de dois dentífricos comerciais na redução da gengivite e da placa bacteriana: um ensaio clínico randomizado controlado

Objectives: Chlorhexidine (CHX) and triclosan are the most used chemical agents in dentistry. However, the combination of these products has never been tested. We hypothesize that the addition of CHX to a triclosan dentifrice formulation may offer additional benefits in the reduction of plaque and gingivitis. Thus, the aim of this study was to compare a commercial dentifrice containing 0.05% chlorhexidine and 0.3% triclosan, with conventional toothpaste containing 0.3% triclosan, in the treatment of gingivitis and plaque reduction. Material and Methods: Thirty volunteers were randomly assigned to receive a dentifrice containing 0.05% CHX and 0.3% triclosan (CHX/ triclosan group) or a dentifrice containing basically 0.3% triclosan (Triclosan group). Subjects received clinical evaluation such as gingival index (GI) and plaque index (PI) at baseline, 30 and 60 days. Results: After 60 days, both treatments led to a significant improvement in GI and PI. There was no significant difference between groups as regards change in GI and PI (p>0.05). Conclusion: The combination of 0.05% CHX with 0.3% triclosan did not offer further benefits to gingival inflammation and plaque control when compared with a dentifrice containing 0.3% triclosan. (AU)

Objetivos: Clorexidina e triclosan são os agentes químicos mais utilizados em odontologia. No entanto, a combinação desses produtos nunca foi testada. Nós levantamos a hipótese de que a adição de clorexidina a um dentifrício contendo triclosan pode oferecer benefícios adicionais na redução de placa e gengivite. Assim, o objetivo deste estudo foi comparar um dentífrico comercial contendo 0,05% de clorhexidina e 0,3% de triclosan, com creme dental convencional contendo 0,3% de triclosan, no tratamento de gengivite e redução da placa. Material e Métodos: trinta voluntários foram distribuídos aleatoriamente para receber um dentifrício contendo 0,05% de clorexidina e 0,3% de triclosan ou um dentifrício contendo basicamente 0,3% de triclosan. Os indivíduos receberam avaliação clínica de índice gengival (IG) e índice de placa (IP) nos tempos 0, 30 e 60 dias. Resultados: após 60 dias, ambos os tratamentos levaram a uma melhora significativa no IG e IP. Não houve diferença significativa entre os grupos no que se refere à mudança no IG e IP (p> 0,05). Conclusão: A combinação de 0,05% de Clorexidina com 0,3% de triclosan não ofereceu benefícios adicionais para a redução de inflamação gengival e o controle da placa quando comparado com um dentifrício contendo 0,3% de triclosan (AU)

A study of injectable chlorhexidine thermosensitive hydrogel for periodontal application / 中国海洋药物

Objective To evaluate the potential of chlorhexidine(Chx)-thermosensitive hydrogel as a local drug delivery system for periodontal treatment.Methods The release profiles of Chx from CS-HTCC/GP thermosensitive hydrogel in vitro were investigated.Moreover,the antibacterial activity of S-HTCC/GP-0.1%Chx thermosensitive hydrogel to oral representative pathogens - Porphyromonas gingivalis(P.gingivalis),Prevotella intermedia(P.intermedia) and Actinobacillus actinorn ycetemcornitans(A.actinom ycetemcomitans) was determined by inhibitory zone measurement.Results Chlorhexidine(Chx) released in vitro over 18 hours from the CS-HTCC/GP thermosensitive hydrogel in artificial saliva pH 6.8 which more effectively retarded the release of Chx.Three periodontal pathogens were susceptible to Chx thermosensitive hydrogel with the inhibitory zone diameters over the range of 12～14mm.Conclusion All results indicated that Chx thermosensitive hydrogel can be used as a local drug delivery system for periodontal treatment.