Allosteric Activation of Protein Phosphatase 5 with Small Molecules.

The activation of PP5 is essential for a variety of cellular processes, as it participates in a variety of biological pathways by dephosphorylating substrates. However, activation of PP5 by small molecules has been a challenge due to its native "self-inhibition" mechanism, which is controlled by the N-terminal TPR domain and the C-terminal αJ helix. Here, we reported the discovery of DDO-3733, a well-identified TPR-independent PP5 allosteric activator, which facilitates the dephosphorylation process of downstream substrates. Considering the negative regulatory effect of PP5 on heat shock transcription factor HSF1, pharmacologic activation of PP5 by DDO-3733 was found to reduce the HSP90 inhibitor-induced heat shock response. These results provide a chemical tool to advance the exploration of PP5 as a potential therapeutic target and highlight the value of pharmacological activation of PP5 to reduce heat shock toxicity of HSP90 inhibitors.

Nonantibiotic prophylaxis for urinary tract infections: a network meta-analysis of randomized controlled trials.

OBJECTIVE: Recent guidelines indicated that, in addition to antibiotics, nonantibiotic interventions serve as available preventive options for urinary tract infections (UTIs). This study aimed to compare the efficacy and safety of various nonantibiotic interventions in preventing UTIs. METHODS: The authors systematically searched databases for eligible studies. The inclusion criteria encompassed randomized controlled trials (RCTs) focusing on one or more nonantibiotic interventions for UTI prevention, with the incidence of UTIs being a key outcome measure. Subgroup analyses were performed according to age, sex, and follow-up. RESULTS: 50 RCTs comprising 10,495 subjects and investigating 14 interventions, were included. Nearly 80% of the RCTs utilized double-blind or triple-blind designs. In the whole group, D-mannose (risk ratio [RR] 0.34, 0.21 to 0.56), vaccine (RR 0.65, 0.52 to 0.82), probiotics (RR 0.69, 0.50 to 0.94), cranberry (RR 0.72, 0.60 to 0.87), and triple therapy (cranberry plus probiotics plus vitamin A) (RR 0.27, 0.09 to 0.87), exhibited a significant reduction in UTI incidence compared to the placebo. Probiotics (RR 0.50, 0.28 to 0.89) were the most effective in the nonadult group, while vitamin D (RR 0.46, 0.27 to 0.81) showed the highest efficacy in the long follow-up group (≥ 1 year). There was no significant difference in the incidence of adverse events between the interventions and the placebo group. CONCLUSIONS: D-mannose, triple therapy, vaccine, probiotics, and cranberry serve as potential nonantibiotic intervention options for clinical UTI prevention.

Acetyl-11-keto-ß-boswellic acid restrains the progression of synovitis in osteoarthritis via the Nrf2/HO-1 pathway.

Synovial inflammation plays a key role in osteoarthritis (OA) pathogenesis. Fibroblast-like synoviocytes (FLSs) represent a distinct cell subpopulation within the synovium, and their unique phenotypic alterations are considered significant contributors to inflammation and fibrotic responses. The underlying mechanism by which acetyl-11-keto-ß-boswellic acid (AKBA) modulates FLS activation remains unclear. This study aims to assess the beneficial effects of AKBA through both in vitro and in vivo investigations. Network pharmacology evaluation is used to identify potential targets of AKBA in OA. We evaluate the effects of AKBA on FLSs activation in vitro and the regulatory role of AKBA on the Nrf2/HO-1 signaling pathway. ML385 (an Nrf2 inhibitor) is used to verify the binding of AKBA to its target in FLSs. We validate the in vivo efficacy of AKBA in alleviating OA using anterior cruciate ligament transection and destabilization of the medial meniscus (ACLT+DMM) in a rat model. Network pharmacological analysis reveals the potential effect of AKBA on OA. AKBA effectively attenuates lipopolysaccharide (LPS)-induced abnormal migration and invasion and the production of inflammatory mediators, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) in FLSs, contributing to the restoration of the synovial microenvironment. After treatment with ML385, the effect of AKBA on FLSs is reversed. In vivo studies demonstrate that AKBA mitigates synovial inflammation and fibrotic responses induced by ACLT+DMM in rats via activation of the Nrf2/HO-1 axis. AKBA exhibits theoretical potential for alleviating OA progression through the Nrf2/HO-1 pathway and represents a viable therapeutic candidate for this patient population.

Injectable porous microspheres for articular cartilage regeneration through in situ stem cell recruitment and macrophage polarization.

In situ mesenchymal stem cells (MSCs) regenerative therapy holds promising potential for treating osteoarthritis. However, MSCs engraftment and intra-articular inflammation limit the therapeutic efficacy of this approach. This study introduces porous microspheres (PMs) composed of aldehyde-modified poly(lactic-co-glycolic acid), that encapsulate platelet derived growth factor-AB and kartogenin. Metformin (Met) is also incorporated onto the microsphere through a Schiff base reaction to create PMs@Met. In vitro, in vivo and ex experiments revealed that PMs@Met can be injected into the joint cavity, effectively recruiting endogenous MSCs in situ. This approach creates a favorable environment for MSCs proliferation. It also controls the intra-articular inflammatory environment by modulating the polarization of synovial macrophages, ultimately promoting cartilage repair. In summary, our study presents an innovative tissue engineering strategy for the treatment of osteoarthritis-induced articular cartilage injuries. STATEMENT OF SIGNIFICANCE: Cell therapy using autologous mesenchymal stem cells (MSCs) has potential to slow the progression of osteoarthritis (OA). Nonetheless, there are some disadvantages to adopting in situ MSCs therapy, including difficulties with MSC engraftment into cartilage-deficient regions, the effect of intra-articular inflammation on MSC therapeutic efficacy, and attaining selective chondrogenic MSC differentiation. We created injectable PLGA microspheres (PMs) that were loaded with PDGF-AB and KGN. Metformin was bonded to the surface of microspheres using a Schiff base reaction. The microspheres can recruit intra-articular MSCs and encourage their development into chondrocytes. The microspheres actively modulate the inflammatory joint environment by altering synovial macrophage polarization, thereby supporting MSCs in effective cartilage treatment. To summarize, microspheres hold great potential in the treatment of OA.

Programmed Cascade Polydopamine Nanoclusters for Pyroptosis-Based Tumor Immunotherapy.

Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti-tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti-tumor immunotherapy. Herein, a pH-responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo-arginine (R8)-1-Hexadecylamine (He)-porphyrin (Por)@PDA-gambogic acid (GA)-cRGD (R-P@PDA-GC), is rationally design to augment phototherapy-induced pyroptosis and boost anti-tumor immunity through a two-input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R8 linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R-P@PDA-GC nanoplatforms (NPs). The pH-responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two-input programmed irradiation, R-P@PDA-GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase-1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8+ T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti-tumor immunity.

[Review of clinical effects of disk-up sinus reamer(DSR)-based internal sinus floor elevation with implantation in 10 years].

PURPOSE: To analyze the bone remodeling around the implant 10 years after disk-up sinus reamer(DSR)-based internal sinus floor elevation with implantation and to investigate the influence of different factors on implant retention. METHODS: The clinical and imaging data of patients undergoing DSR-based sinus floor elevation with simultaneous implantation were collected from the Department of Dental Implantology, Affiliated Hospital of Qingdao University from January 2008 to December 2011. Panoramic film and CBCT were used to measure the changes of bone mass around implant in different periods. Kaplan-Meier and Log-rank tests were used to analyze the effects of different factors on implant retention with SPSS 26.0 software package. RESULTS: The study included 98 patients with a total of 128 implants. During the follow-up of 0-168 months, 7 implants failed, and the remaining formed good osseointegration and functioned, with a 10-year cumulative retention rate of 94.53%. The height of bone formation was (0.29±0.15) mm at the top and (2.74±0.66) mm in the sinus of 75 implant sites with complete imaging data obtained ten years after surgery. Kaplan-Meier and Log-rank tests showed that 8 factors including initial bone height, elevated bone height, mucosal perforation, implant length, implant torsion, diabetes, smoking and periodontitis had significant effects on implant retention. CONCLUSIONS: The DSR-based internal sinus floor elevation with implantation is a reliable and stable bone augmentation operation for vertical bone defect in maxillary posterior region, with a 10-year cumulative retention rate of no less than 94%. Initial bone height, elevated bone height, mucosal perforation, implant length, implant torsion, diabetes, smoking and periodontitis are the important factors affecting the long-term retention rate of implants.

A pH-responsive nanoplatform with dual-modality imaging for enhanced cancer phototherapy and diagnosis of lung metastasis.

To address the limitations of traditional photothermal therapy (PTT)/ photodynamic therapy (PDT) and real-time cancer metastasis detection, a pH-responsive nanoplatform (NP) with dual-modality imaging capability was rationally designed. Herein, 1 H,1 H-undecafluorohexylamine (PFC), served as both an oxygen carrier and a 19F magnetic resonance imaging (MRI) probe, and photosensitizer indocyanine green (ICG) were grafted onto the pH-responsive peptide hexahistidine (H6) to form H6-PFC-ICG (HPI). Subsequently, the heat shock protein 90 inhibitor, gambogic acid (GA), was incorporated into hyaluronic acid (HA) modified HPI (HHPI), yielding the ultimate HHPI@GA NPs. Upon self-assembly, HHPI@GA NPs passively accumulated in tumor tissues, facilitating oxygen release and HA-mediated cell uptake. Once phagocytosed by lysosomes, protonation of H6 was triggered due to the low pH, resulting in the release of GA. With near-infrared laser irradiation, GA-mediated decreased HSP90 expression and PFC-mediated increased ROS generation amplified the PTT/PDT effect of HHPI@GA, leading to excellent in vitro and in vivo anticancer efficacies. Additionally, the fluorescence and 19F MRI dual-imaging capabilities of HHPI@GA NPs enabled effective real-time primary cancer and lung metastasis monitoring. This work offers a novel approach for enhanced cancer phototherapy, as well as precise cancer diagnosis.

In Situ Remodeling of Efferocytosis via Lesion-Localized Microspheres to Reverse Cartilage Senescence.

Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging-related diseases, such as osteoarthritis (OA). In this study, cartilage lesion-localized hydrogel microspheres are developed to remodel the in situ efferocytosis to reverse cartilage senescence and recruit endogenous stem cells to accelerate cartilage repair. Specifically, aldehyde- and methacrylic anhydride (MA)-modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro-apoptotic liposomes (liposomes encapsulating ABT263, A-Lipo) and PDGF-BB, namely A-Lipo/PAHM, are prepared by microfluidic and photo-cross-linking techniques. By a degraded porcine cartilage explant OA model, the in situ cartilage lesion location experiment illustrated that aldehyde-functionalized microspheres promote affinity for degraded cartilage. In vitro data showed that A-Lipo induced apoptosis of senescent chondrocytes (Sn-chondrocytes), which can then be phagocytosed by the efferocytosis of macrophages, and remodeling efferocytosis facilitated the protection of normal chondrocytes and maintained the chondrogenic differentiation capacity of MSCs. In vivo experiments confirmed that hydrogel microspheres localized to cartilage lesion reversed cartilage senescence and promoted cartilage repair in OA. It is believed this in situ efferocytosis remodeling strategy can be of great significance for tissue regeneration in aging-related diseases.

Transformaer-based model for lung adenocarcinoma subtypes.

BACKGROUND: Lung cancer has the highest morbidity and mortality rate among all types of cancer. Histological subtypes serve as crucial markers for the development of lung cancer and possess significant clinical values for cancer diagnosis, prognosis, and prediction of treatment responses. However, existing studies only dichotomize normal and cancerous tissues, failing to capture the unique characteristics of tissue sections and cancer types. PURPOSE: Therefore, we have pioneered the classification of lung adenocarcinoma (LAD) cancer tissues into five subtypes (acinar, lepidic, micropapillary, papillary, and solid) based on section data in whole-slide image sections. In addition, a novel model called HybridNet was designed to improve the classification performance. METHODS: HybridNet primarily consists of two interactive streams: a Transformer and a convolutional neural network (CNN). The Transformer stream captures rich global representations using a self-attention mechanism, while the CNN stream extracts local semantic features to optimize image details. Specifically, during the dual-stream parallelism, the feature maps of the Transformer stream as weights are weighted and summed with those of the CNN stream backbone; at the end of the parallelism, the respective final features are concatenated to obtain more discriminative semantic information. RESULTS: Experimental results on a private dataset of LAD showed that HybridNet achieved 95.12% classification accuracy, and the accuracy of five histological subtypes (acinar, lepidic, micropapillary, papillary, and solid) reached 94.5%, 97.1%, 94%, 91%, and 99% respectively; the experimental results on the public BreakHis dataset show that HybridNet achieves the best results in three evaluation metrics: accuracy, recall and F1-score, with 92.40%, 90.63%, and 91.43%, respectively. CONCLUSIONS: The process of classifying LAD into five subtypes assists pathologists in selecting appropriate treatments and enables them to predict tumor mutation burden (TMB) and analyze the spatial distribution of immune checkpoint proteins based on this and other clinical data. In addition, the proposed HybridNet fuses CNN and Transformer information several times and is able to improve the accuracy of subtype classification, and also shows satisfactory performance on public datasets with some generalization ability.

Diagnostic accuracy of interleukin-6 in multiple diseases: An umbrella review of meta-analyses.

Objective: This review aims to conduct a comprehensive study of the diagnostic accuracy of interleukin-6 (IL-6) for multiple diseases by utilizing existing systematic reviews and meta-analyses. Methods: We performed a thorough search of Embase, Web of Science, PubMed, and Cochrane Database of Systematic Reviews up to April 2023 to gather meta-analyses that investigate the diagnostic accuracy of IL-6. To assess the methodological quality of the studies, we employed the Assessing the Methodological Quality of Systematic Reviews-2 and Grading of Recommendations, Assessment, Development and Evaluation criteria. Results: We included 34 meta-analyses out of the 3024 articles retrieved from the search. These meta-analyses covered 9 categories of diseases of the International Classification of Diseases-11. Studies rated as "Critically Low" or "Very Low" in the quality assessment process were excluded, resulting in a total of 6 meta-analyses that encompassed sepsis, colorectal cancer, tuberculous pleural effusion (TPE), endometriosis, among others. Among these diseases, IL-6 demonstrated a relatively high diagnostic potential in accurately identifying TPE and endometriosis. Conclusions: IL-6 exhibited favorable diagnostic accuracy across multiple diseases, suggesting its potential as a reliable diagnostic biomarker in the near future. Substantial evidence supported its high diagnostic accuracy, particularly in the cases of TPE and endometriosis.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

BACKGROUND AND OBJECTIVE: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. METHODS: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. RESULTS: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. CONCLUSIONS: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

Efficacy and Safety of Adeno-Associated Virus-Based Clinical Gene Therapy for Hemophilia: A Systematic Review and Meta-Analysis.

Clinical trials of adeno-associated virus (AAV)-based gene therapy have made remarkable progress in recent years. We aimed to perform a systematic review and meta-analysis of the literature to assess the efficacy and safety of AAV-based gene therapy for hemophilia. We systematically searched the Web of Science, Embase, PubMed, and the Cochrane Database of Systematic Reviews databases, for clinical trials involving patients diagnosed with hemophilia and treated with AAV-mediated gene therapy. Data on the annualized bleeding rate (ABR), annualized infusion rate (AIR), the incidence of treatment-related adverse events (TRAEs), severe adverse events (SAEs), and alanine aminotransferase (ALT) elevation were extracted as our outcomes. A total of 12 articles from 11 clinical trials were selected from 868 articles for meta-analysis. Pooled analyses showed that AAV-based gene therapy in hemophilia patients reduced the number of bleeding events and the number of factor infusion events by an approximate average of 7 per year and 103 per year, respectively. Eighty percent, 18%, and 63% of hemophilia patients had elevated TRAE, SAE, and ALT levels, respectively. Moreover, subgroup analysis found a significant reduction in ABR and AIR 2-3 years after the therapy. Additional findings that were not pooled including coagulation factor activity are presented in the accompanying tables. Our analysis supported the efficacy and safety of AAV-mediated gene therapy for hemophilia, providing evidence for its application as a therapeutic option for widespread clinical use in hemophilia patients in the future.

Accuracy of the Yakebot dental implant robotic system versus fully guided static computer-assisted implant surgery template in edentulous jaw implantation: A preliminary clinical study.

AIMS: To compare the accuracy of the Yakebot dental implant robotic system with that of fully guided static computer-assisted implant surgery (CAIS) template in edentulous implantation. MATERIALS AND METHODS: Thirteen patients with edentulous were recruited and divided into two groups: the Yake robotic system group (experimental) (n = 5) and the CAIS group (control) (n = 8). Postoperative cone-beam computed tomography (CBCT) was performed immediately, and the 3-dimensional positions of implants were obtained and compared with that in the preoperative design. The comparison showed platform, apical, depth, and angular deviations. A value of p < 0.05 was considered statistically significant. RESULTS: A total of 84 implants (36 in the robotic group and 48 in the CAIS group) were placed. The mean deviation at the implant platform, apex, depth, and angle in the CAIS group was 1.37 ± 0.72 mm, 1.28 ± 0.68 mm, 0.88 ± 0.47 mm, and 3.47 ± 2.02°, respectively. However, the mean deviation at the implant platform, apex, depth, and angle in the robotic group was 0.65 ± 0.25 mm, 0.65 ± 0.22 mm, 0.49 ± 0.24 mm, and 1.43 ± 1.18°, respectively. Significant differences in the four types of deviation (p < 0.05) between the two groups were observed. CONCLUSION: The accuracy of robotic system in edentulous implant placement was superior to that of the CAIS template, suggesting that robotic system is more accurate, safe, and flexible, can be considered a promising treatment in clinical practice.

Stem Cells Expansion Vector via Bioadhesive Porous Microspheres for Accelerating Articular Cartilage Regeneration.

Stem cell tissue engineering is a potential treatment for osteoarthritis. However, the number of stem cells that can be delivered, loss of stem cells during injection, and migration ability of stem cells limit applications of traditional stem cell tissue engineering. Herein, kartogenin (KGN)-loaded poly(lactic-co-glycolic acid) (PLGA) porous microspheres is first engineered via emulsification, and then anchored with chitosan through the amidation reaction to develop a new porous microsphere (PLGA-CS@KGN) as a stem cell expansion vector. Following 3D co-culture of the PLGA-CS@KGN carrier with mesenchymal stem cells (MSCs), the delivery system is injected into the capsule cavity in situ. In vivo and in vitro experiments show that PLGA-CS microspheres have a high cell-carrying capacity up to 1 × 104 mm-3 and provide effective protection of MSCs to promote their controlled release in the osteoarthritis microenvironment. Simultaneously, KGN loaded inside the microspheres effectively cooperated with PLGA-CS to induce MSCs to differentiate into chondrocytes. Overall, these findings indicate that PLGA-CS@KGN microspheres held high cell-loading ability, adapt to the migration and expansion of cells, and promote MSCs to express markers associated with cartilage repair. Thus, PLGA-CS@KGN can be used as a potential stem cell carrier for enhancing stem cell therapy in osteoarthritis treatment.