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The functions of the bromodomain and extra terminal (BET) family of proteins have been proved to be involved in various diseases, particularly the acute myeloid leukemia (AML). In this work, guided by free energy perturbation (FEP) calculation, a methyl group was selected to be attached to the 1H-imidazo[4,5-c]quinoline skeleton, and a series of congeneric compounds were synthesized. Among them, compound 10 demonstrated outstanding activity against BRD4 BD1 with an IC 50 value of 1.9 nM and exhibited remarkable antiproliferative effects against MV4-11 cells. The X-ray cocrystal structure proved that 10 occupied the acetylated lysine (KAc) binding cavity and the WPF shelf of BRD4 BD1. Additionally, 10 displayed high selectivity towards BET family members, effectively inhibiting the growth of AML cells, promoting apoptosis, and arresting the cell cycle at the G 0 /G 1 phase. Further mechanistic studies demonstrated that compound 10 could suppress the expression of c-Myc and CDK6 while enhancing the expression of P21, PARP, and cleaved PARP. Moreover, 10 exhibited remarkable pharmacokinetic properties and significant antitumor efficacy in vivo. Therefore, compound 10 may represent a new, potent and selective BET bromodomain inhibitor for the development of therapeutics to treat AML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Despite the remarkable success of immune checkpoint inhibitors (ICIs), primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment (TME). Oncolytic viruses (OVs) can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts. Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy. According to the diverse immune cell landscapes among different types of tumors, we rationally and precisely generated three recombinant oncolytic adenoviruses (OAds): OAd-SIRPα-Fc, OAd-Siglec10-Fc and OAd-TIGIT-Fc. These viruses were designed to locally deliver SIRPα-Fc, Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47, CD24 or CD155, respectively, in the TME to achieve enhanced antitumor effects. Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors, while OAd-TIGIT-Fc showed the best antitumor immunity in CD8 + T-cell-dominated tumors. Importantly, the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory. In addition, the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME. In summary, rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer., (© 2023. The Author(s).)

Studies have shown that antidiabetic drugs can alter the gut microbiota. The hypoglycemic effects of the drugs can be attributed in part to certain species in the gut microbiome that help the drugs work more effectively. In addition, increasing energy expenditure via the induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Currently, glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment for metabolic disorders such as obesity and type 2 diabetes has been widely studied. To determine the mechanism of a long-acting GLP-1 RA affects adipose tissue browning and the gut microbiome, we treated high-fat diet mice with GLP-1 RA and demonstrated that the drug can regulate adipose tissue browning. 16S rRNA and untargeted metabolomics assays suggested that it increased the abundance of bacterium Lactobacillus reuteri and decreased serum ceramide levels in mice. L. reuteri was negatively correlated with ceramide. We found that the mechanism of ceramide decline was alkaline ceramidase 2 (Acer2) overexpression. Moreover, L. reuteri can play a therapeutic synergistic role with GLP-1 RA, suggesting that gut microbiota can be used as a part of the treatment of diabetes., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

In situ vaccination is a desirable strategy for cancer immunotherapy due to its convenience and capacity to target tumor antigens. Here, an in situ nanovaccine based on a cationic peptide with cholesterol-modified, DP7-C, for cancer immunotherapy is rationally designed, and developed a cancer nanovaccine that is easy to preparate. The nanovaccine includes cocktail small interfering RNAs (siRNAs) and immunologic adjuvant CpG ODNs, has synergistic effect in the cancer treatment. This nanovaccine can induce tumor cell death, promote antigen presentation and relieve immune suppression in the tumor microenvironment (TME). Moreover, this nanovaccine is administered to CT26 (hot) and B16F10 (cold) tumor model mice, in which it targeted the primary tumors and induced systemic antitumor immunity to inhibit metastasis. It is validated that the nanovaccine can convert cold tumors into hot tumors. Furthermore, the nanovaccine increased the immune response to anti-PD-1 therapy by modulating the TME in both CT26- and B16F10-tumor-bearing mice. The siRNA cocktail/CpG ODN/self-assembling peptide nanovaccine is a simple and universal tool that can effectively generate specific tumor cell antigens and can be combined with immuno-oncology agents to enhance antitumor immune activity. The versatile methodology provides an alternative approach for developing cancer nanovaccines., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The clinical efficacy of personalized cancer vaccines still needs to be improved due to their insufficient immune effect. The development of innovative adjuvants and lymph node-targeted delivery systems is the key to improving the clinical efficacy of personalized vaccines. However, there is still a lack of an adjuvant delivery system that is simple in preparation and capable of mass production and integrates adjuvant and lymph node targeted delivery functions. Here, this work reports that a simple dendrimer polypeptide (KK2DP7) nanoparticle enhances the immune efficacy of an OVA/neoantigen-based vaccine. Due to its multiple functions as a delivery vehicle, immune adjuvant, and facilitator of dendritic cell migration, KK2DP7 efficiently increases the efficiency of antigen uptake and cross-presentation by antigen-presenting cells (APCs) and delivers antigens to lymph nodes via APCs. Strikingly, the antitumor effect of KK2DP7/OVA is superior to that of commonly used adjuvants such as poly(I:C), CpG, and aluminum adjuvant combined with OVA. Furthermore, KK2DP7/OVA combined with anti-PD-1 antibody is able to prevent tumor recurrence in a postoperative recurrent tumor model. Thus, KK2DP7-based cancer vaccines alone or in combination with immune checkpoint blockade therapies to treat tumors or postoperative tumor recurrence are a powerful strategy to enhance antitumor immunity., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The blood-brain barrier (BBB) has a key role in preventing drugs from entering the brain. Non-invasive intranasal drug delivery routes that bypass the BBB are increasing in popularity because of their ability to shorten the journey and reduce the loss of genetic drugs such as siRNA in transit. However, the complex synthesis and quality control process of most nose-to-brain delivery carriers and the limited mass production are the main obstacles to their clinical application. Here, we constructed a siRNA delivery system with simple synthesis and quality control methods using cholesterol-modified T7 (T7-C), in which T7 can bind to the transferrin receptor (TfR) expressed on glioma cells to target gliomas. In our results, T7-C had dual functions as a glioma-targeting carrier and immune adjuvant. As a targeted delivery carrier, T7-C intranasally delivered siRNA into the mouse brain through the olfactory bulb pathway and was taken up by glioma cells by the caveolin- and transferrin-dependent pathway. As an immune adjuvant, T7-C could promote DC maturation and combined with slit2 siRNA could promote polarization of M2 subtype macrophages to M1 subtype macrophages and then increase the proportion of effector T cells to remodel the tumor environment. In conclusion, T7-C with glioma targeting as a delivery system of slit2 siRNA showed a good therapeutic effect in the treatment of glioma after intranasal administration and had potential application prospects. STATEMENT OF SIGNIFICANCE: In contrast to the existing literature that uses complex materials to deliver drugs across the blood-brain barrier (BBB) in an invasive manner for glioma treatment, we developed a simple, self-assembling siRNA delivery system (T7-C) based on brain tumor-targeted T7 peptide to treat glioma by intranasal administration. T7-C/siRNA could reach the tumor site through the olfactory bulb route and adjust the "cold" tumor microenvironment to the "hot" tumor microenvironment and non-invasive intranasal delivery route could shorten the journey and reduce the loss of genetic drugs. Therefore, our design has good application prospects and is expected to serve as a general strategy for intranasal drug delivery in the treatment of brain tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no competition of interests., (Copyright © 2022. Published by Elsevier Ltd.)

Methotrexate (MTX) is a preferred disease-modifying anti-rheumatic drug in the management of rheumatoid arthritis (RA). However, the toxicity and inefficiency of MTX limit its clinical application. Gut microbiota has been implicated in the side effects and efficacy of MTX. In this study, the analysis of the gut microbiota in RA patients revealed that the abundances of intestinal Bacteroides fragilis was reduced after MTX treatment. We observed that MTX has no obvious therapeutic effect in the absence of B. fragilis , while transplantation of B. fragilis restored the efficacy of MTX in antibiotics-pretreated collagen-induced arthritis (CIA) mice. In addition, B. fragilis gavage was accompanied by an increase in butyrate. Supplementation of butyrate restored the response to MTX in gut microbiota-deficient mice, to a similar level achieved by B. fragilis gavage. These results show that gut microbiota-regulated butyrate plays an essential role in the efficacy of MTX, which will provide new strategies to improve the effectiveness of methotrexate in RA treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Dong, Zhao, Lin, Tian, Zhang, Zhu, Xu and Yang.)

Dendritic cell (DC)-based cancer vaccines have so far achieved good therapeutic effects in animal experiments and early clinical trials for certain malignant tumors. However, the overall objective response rate in clinical trials rarely exceeds 15%. The poor efficiency of DC migration to lymph nodes (LNs) (< 5%) is one of the main factors limiting the effectiveness of DC vaccines. Therefore, increasing the efficiency of DC migration is expected to further enhance the efficacy of DC vaccines. Here, we used DP7-C (cholesterol modified VQWRIRVAVIRK), which can promote DC migration, as a medium. Through multiomics sequencing and biological experiments, we found that it is the metabolite pantothenic acid (PA) that improves the migration and effectiveness of DC vaccines. We clarified that both DP7-C and PA regulate DC migration by regulating the chemokine receptor CXCR2 and inhibiting miR-142a-3p to affect the NF-κB signaling pathway. This study will lay the foundation for the subsequent use of DP7-C as a universal substance to promote DC migration, further enhance the antitumor effect of DC vaccines, and solve the bottleneck problem of the low migration efficiency and unsatisfactory clinical response rate of DC vaccines., (© 2021. The Author(s).)

Rituximab (RTX) is a widely used anticancer drug with gastrointestinal side effects, such as nausea, vomiting, and diarrhea. The reason for these side effects is still poorly understood. Previous studies have reported that the intestinal microbiota is associated with the occurrence of disease and the therapeutic effect of drugs. In this study, we observed mucosal damage, inflammatory cell infiltration and increased intestinal inflammatory factor expression in RTX-treated mice. RTX also changed the diversity of the intestinal microbiota in mice, and decreased abundance of Lactobacillus reuteri was observed in RTX-treated mice. Further experiments revealed that intragastric administration of L. reuteri in RTX-treated mice attenuated the intestinal inflammatory response induced by RTX and regulated the proportion of helper T (Th) cells. In conclusion, our data characterize the effect of the intestinal microbiota on RTX-induced intestinal inflammation, suggesting that modifying the gut microbiota may represent a positive strategy for managing adverse reactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Zhou, Dong, Zhang, Xie, Tian and Yang.)

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in humans. The inhibition of peptidyl-prolyl cis/trans isomerase (Pin1) gene expression may have great potential in the treatment of HCC. N-Acetylgalactosamine (GalNAc) was used to target the liver. Cholesterol-modified antimicrobial peptide DP7 (DP7-C) acts as a carrier, the GalNAc-siRNA/DP7-C complex increases the uptake of GalNAc-siRNA and the escape of endosomes in hepatocytes. In addition, DP7-C nanoparticles and hydrogel-assisted GalNAc-Pin1 siRNA delivery can effectively enhance the stability and prolong the silencing effects of Pin1 siRNA. In an orthotopic liver cancer model, the GalNAc-Pin1 siRNA/DP7-C/hydrogel complex can potentially regulate Pin1 expression in hepatocellular carcinoma cells and effectively inhibit tumor progression. Our study proves that Pin1 siRNA is an efficient method for the treatment of HCC and provides a sustainable and effective drug delivery system for the suppression of liver cancer., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

MicroRNAs can regulate a variety of physiological and pathological processes and are increasingly recognized as being involved in regulating the malignant progression of cancer, which is an important direction for the study and treatment of cancer. In addition, the tumor microenvironment has gradually become an important direction of study for combating cancer. Researchers can inhibit tumor growth by remodeling and suppressing an immunosuppressive phenotype in the tumor microenvironment. Therefore, the combination of microRNA delivery and tumor microenvironment remodeling may be a potential research direction. In a previous study, we developed a novel cationic and hydrophilic antimicrobial peptide, DP7, by computer simulation. It was found that cholesterol-modified DP7 (DP7-C) has dual functions as a carrier and an immune adjuvant. In this experiment, we used DP7-C to deliver microRNAs or inhibitors intratumorally, where it played a dual role as a carrier and an immune adjuvant. As a delivery vector, DP7-C has more advantages in terms of transfection efficiency and cytotoxicity than Lipo2000 and PEI25K. Components of the DP7-C/RNA complex can effectively escape endosomes after uptake via caveolin- and clathrin-dependent pathways. As an immune adjuvant, DP7-C can activate dendritic cells and promote macrophage polarization. Moreover, it can transform the immunosuppressive tumor microenvironment into an immune-activated tumor microenvironment, indicating its potential as an anticancer therapy. In conclusion, this study identifies a novel microRNA and inhibitor delivery system that can remodel the tumor microenvironment and introduces an alternative scheme for antitumor treatment.

Background: Antimicrobial peptides are promising alternative antimicrobial agents to combat MDR. DP7, an antimicrobial peptide designed in silico, possesses broad-spectrum antimicrobial activities and immunomodulatory effects. However, the effects of DP7 against Pseudomonas aeruginosa and biofilm infection remain largely unexplored., Objectives: To assess (i) the antimicrobial activity of DP7 against MDR P. aeruginosa; and (ii) the antibiofilm activity against biofilm infection. Also, to preliminarily investigate the possible antimicrobial mode of action., Methods: The MICs of DP7 for 104 clinical P. aeruginosa strains (including 57 MDR strains) and the antibiofilm activity were determined. RNA-Seq, genome sequencing and cell morphology were conducted. Both acute and chronic biofilm infection mouse models were established. Two mutants, resulting from point mutations associated with LPS and biofilms, were constructed to investigate the potential mode of action., Results: DP7, at 8-32 mg/L, inhibited the growth of clinical P. aeruginosa strains and, at 64 mg/L, reduced biofilm formation by 43% to 68% in vitro. In acute lung infection, 0.5 mg/kg DP7 exhibited a 70% protection rate and reduced bacterial colonization by 50% in chronic infection. DP7 mainly suppressed gene expression involving LPS and outer membrane proteins and disrupted cell wall structure. Genome sequencing of the DP7-resistant strain DP7R revealed four SNPs controlling LPS and biofilm production. gshA44 and wbpJ139 mutants displayed LPS reduction and motility deficiency, conferring the reduction of LPS and biofilm biomass of strain DP7R and indicating that LPS was a potential target of DP7., Conclusions: These results demonstrate that DP7 may hold potential as an effective antimicrobial agent against MDR P. aeruginosa and related infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Obesity has been recognized as a low-grade, chronic inflammatory disease that leads to an increase in obesity-associated disorders, including type 2 diabetes (T2D), fatty liver diseases and cancer. Glucagon-like peptide-1 (GLP-1) is an effective drug for T2D, and it not only has glucose-regulating effects but also has anti-inflammatory effects in obesity. In our previous study, we designed a novel GLP-1 analogue, (E X -4) 2 -Fc, which has been shown to reduce body weight and improve glucose tolerance in vivo. In this study, we observed that (E X -4) 2 -Fc also has anti-inflammatory functions in adipose tissue. After the treatment of diet-induced obesity (DIO) mice with (E X -4) 2 -Fc, we found that the inflammatory response in adipose tissue was significantly attenuated. (Ex-4) 2 -Fc can reduce obesity-associated proinflammatory cytokine levels and macrophage numbers in DIO mice. In addition, (E X -4) 2 -Fc treatment resulted in proinflammatory M1-type macrophages beginning to transform into anti-inflammatory M2-type macrophages. The inflammatory mitogen-activated protein kinase (MAPK) signalling pathway and nuclear factor kappa B (NF-κB) were altered in adipose tissue after (E X -4) 2 -Fc treatment. Leptin has been proven to be closely related to immunity, and we demonstrated that the effect of (E X -4) 2 -Fc on adipocyte inflammation was related to leptin. The data suggested that (E X -4) 2 -Fc could modulate the inflammatory response by inhibiting the expression of leptin in adipose tissue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

As a widely used cancer drug, carboplatin often results in serious side effects, such as gut toxicity. In this study, we examined the effects of gut microbiota on mice with carboplatin-induced intestinal mucosal damage. Carboplatin resulted in intestinal mucositis, as indicated by weight loss, diarrhoea, and infiltration of inflammatory cells. It markedly increased the expression of inflammatory cytokines/chemokines in intestine. Carboplatin also altered the diversity and composition of the gut microbiota. A significantly higher abundance of Prevotella copri (P. copri) was observed in carboplatin-treated mice. Moreover, the content of P. copri was positively correlated with the severity of intestinal mucositis. Pretreatment with metronidazole reduced the content of P. copri and relieved the intestinal mucosal injury and inflammation that was induced by carboplatin. Further study revealed that supplementation with P. copri in carboplatin-treated mice resulted in more severe tissue damage, lower tight junction protein expression and higher cytokine expression, and it enhanced both local and systemic immune responses. These data demonstrated that P. copri was involved in the pathological process of carboplatin-induced intestinal mucositis, suggesting a potential attenuation of carboplatin-induced intestinal mucositis by targeting P. copri.