Lyotropic liquid crystals (LLC) have received increasing attention as a drug delivery system. In this study, a novel intra-canal disinfectant based on the glycerol monooleate (GMO) LLC precursor incorporation with chlorhexidine (CHX) and silver nanoparticles (Ag-NPs) was designed and evaluated. The LLC precursor with excellent fluidity was able to penetrate deeply into the complex tiny collateral branch root canals. The transformation of cubic LLC in root canals upon coming into contact with water provided long-lasting disinfection against multidrug-resistant bacteria to avoid the endodontic reinfection and follow-up visits. The GMO-ethanol-water (48% : 12% : 40%, w/w) formulation containing 0.5% CHX and 0.02% Ag-NPs was selected for further studies. The low viscosity of the precursor presented excellent injectability and flowabilities. From the in vitro release test, the release behaviours were found to be influenced by CHX and Ag-NP contents, allowing the optimized precursor to obtain a 28-day release profile. The CHX-Ag-NP containing LLC precursor exhibited an excellent and sustained sterilization effect on Enterococcus faecalis for more than one month with a bacterial inactivation rate of ≥98.5%, which was far more than the minimum clinical requirement (7 days). Furthermore, no in vitro toxicity was observed in the cytotoxicity evaluation. The CHX-Ag-NP containing LLC precursor was proved to be a promising intra-canal disinfectant in our study.

Eliminating the latent HIV reservoir remains a difficult problem for creating an HIV functional cure or achieving remission. The “block-and-lock” strategy aims to steadily suppress transcription of the viral reservoir and lock the HIV promoter in deep latency using latency-promoting agents (LPAs). However, to date, most of the investigated LPA candidates are not available for clinical trials, and some of them exhibit immune-related adverse reactions. The discovery and development of new, active, and safe LPA candidates for an HIV cure are necessary to eliminate residual HIV-1 viremia through the “block-and-lock” strategy. In this study, we demonstrated that a new small-molecule compound, Q308, silenced the HIV-1 provirus by inhibiting Tat-mediated gene transcription and selectively downregulating the expression levels of the facilitated chromatin transcription (FACT) complex. Strikingly, Q308 induced the preferential apoptosis in HIV-1 latently infected cells, indicating that Q308 may reduce the size of the viral reservoir and thus further prevent viral rebound. These findings highlight that Q308 is a novel and safe anti-HIV-1 inhibitor candidate for a functional cure.

The failure of highly active antiretroviral therapy (HAART) has been largely responsible for the existence of latent human immunodeficiency virus type 1 (HIV-1) reservoirs. The “shock and kill” strategy was confirmed to reactivate HIV-1 latent reservoirs by latency-reversing agents (LRAs) for accelerated HIV-1 clearance. However, a single LRA might be insufficient to induce HIV-1 reactivation from latency due to the complexity of the multiple signaling regulatory pathways that establish the HIV-1 latent reservoir. Therefore, combinations of LRAs or dual-mechanism LRAs are urgently needed to purge the latent reservoirs. We demonstrate here for the first time that a dual-target inhibitor with a specific suppressive effect on both BRD4 and TIP60, CPI-637, could reactivate latent HIV-1 in vitro by permitting Tat to bind positive transcription elongation factor b (P-TEFb) and assembling Tat-super-elongation complex (SEC) formation. In addition, CPI-637-mediated TIP60 downregulation further stimulated BRD4 dissociation from the HIV-1 long terminal repeat (LTR) promoter, allowing Tat to more effectively bind P-TEFb compared to BRD4 inhibition alone. Much more importantly, CPI-637 exerted a potent synergistic effect but alleviated global T cell activation and blocked viral spread to uninfected bystander CD4+ T cells with minimal cytotoxicity. Our results indicate that CPI-637 opens up the prospect of novel dual-target inhibitors for antagonizing HIV-1 latency and deserves further investigation for development as a promising LRA with a “shock and kill” strategy.

No abstract

Rationale: There is an increasing tendency for case reports to reveal anatomical aberrances in mandibular first molars, such as the lateral and accessory canals. Thus, clinicians should pay special attention to anatomic variances when dealing with mandibular first molars requiring endodontic treatment to prevent reinfection within the root canal system, which is responsible for the failure of root canal treatment. Patient concerns: This article presents the clinical report and successful root canal treatment of a 24-year-old healthy female patient with an extensive periapical lesion in a 6-canal first mandibular molar. The patient was admitted to the endodontic department because of a periapical abscess found 1 month ago in her left mandibular first molar. Diagnosis: Chronic apical periodontitis was diagnosed based on clinical examination coupled with radiographic and cone-beam computed tomography images. Interventions: The treatment plan was to first perform root canal therapy and then perform clinical observation. Outcomes: During 1-year follow-up period, the treated tooth was asymptomatic, and complete resolution of the extensive apical lesion was eventually achieved, as shown in the postoperative cone-beam computed tomography images and clinical examination. Lessons: The present case emphasizes the importance of a comprehensive understanding of root canal morphology, especially rare anatomical variations, to ensure successful root canal treatment. Additionally, the case report adds to the library of previously reported cases of extensive periapical lesions with a direct connection to the root canal system, which demonstrates the potential clinical advantages of root canal therapy as a conservative nonsurgical approach in these cases.