Flexocatalysis Enhances Tumor Photodynamic Therapy.

Photodynamic therapy (PDT) is long-standing suffered from elevated tumor interstitial fluid pressure (TIFP) and prevalent hypoxic microenvironment within the solid malignancies. Herein, sound-activated flexocatalysis is developed to overcome the dilemma of PDT through both enhancing tumor penetration of photosensitizers by reducing TIFP and establishing an oxygen-rich microenvironment. In detail, a Schottky junction is constructed by flexocatalyst MoSe2 nanoflowers and Pt. Subsequently, the Schottky junction is loaded with the photosensitizer indocyanine green (ICG) and encapsulated within tumor cytomembrane to constitute a bionic-flexocatalytic nanomedicine (MPI@M). After targeting the tumor, MPI@M orchestrates flexocatalytic water splitting in tumor interstitial fluid under acoustic stimulation to lower TIFP, which boosted the tumor penetration of ICG. Concurrently, the oxygen released from the flexocatalytic water splitting overcomes the limitation of hypoxia against PDT. Furthermore, superfluous singlet oxygen generated by PDT can induce mitochondrial dysfunction for further tumor cell apoptosis. After 60 min of flexocatalysis, both the 30% decrease of TIFP and the relieved tumor hypoxia are observed, significantly promoting the therapeutic effect of PDT. Consequently, MoSe2/Pt junction nanoflowers, with the excellent flexocatalytic performance, hold significant potential for future applications in biocatalytic cancer therapies.

Diet-related diseases mediate the effect of masticatory function on premature death in older adults.

AIM: Although poor oral health has been a potentially modifiable risk for mortality, the precise association between functional tooth units (FTUs) and premature death as well as the underlying mechanisms remains unclear. METHODS: This study used data from the National Health and Nutrition Examination Survey (NHANES) 2009-2018. Mortality details were obtained from the National Death Index (NDI). The number of FTUs was defined as pairs of opposing natural and artificial teeth in the premolar and molar area. Weighted logistic regression models were employed to assess the relationship between FTU and premature death. Demographic characteristics, lifestyle habits, and disease histories were adjusted as confounding factors. The propensity score matching (PSM) was conducted to further assess the association between FTU and premature death. Mediation analyses were conducted to assess the role of diet-related diseases in the association between FTU and premature death. RESULTS: The analysis included 4169 individuals aged between 60 and 74 years. Participants with 0 ≤ FTUs ≤ 3 had a significantly higher odds of premature death compared to the 10 ≤ FTUs ≤ 12 group (OR = 2.142, 95% CI 1.091-4.208). After missing data imputation, 0 ≤ FTUs ≤ 3 was still significantly associated with increased odds of premature death (OR = 2.115, 95% CI 1.125-3.975). The relationship between 0 ≤ FTUs ≤ 3 and reference group persisted (OR = 2.196, 95% CI 1.296-3.721) after PSM analyses. For mechanism, mediation analysis showed that diet-related diseases, including diabetes and hypertension, partially mediated the association between FTU and premature death with proportions of 5.089% and 8.437%, respectively. CONCLUSION: The findings revealed a link between impairment of masticatory function and a heightened odds of premature death among older adults. Notably, 0 ≤ FTUs ≤ 3 is significantly correlated to premature death among this demographic, with diabetes and hypertension partially mediating the effect of FTU on premature death. Further longitudinal studies are required to validate the findings.

Association between masticatory function and depression in older adults: Results from NHANES 2009 to 2018.

AIM: Depression is prevalent among older adults. Although the number of missing teeth is considered to be associated with depression, the relationship between masticatory function, which is usually indicated by functional tooth units (FTUs), and depression in older adults remains unclear. MATERIALS AND METHODS: This study used data from the National Health and Nutrition Examination Survey (NHANES) 2009-2018. The number of FTUs was defined as pairs of opposing natural and artificial teeth. Depression was accessed using the Patient Health Questionnaire (PHQ-9), and participants who scored ≥10 on PHQ-9 were diagnosed with depression. Logistic regression analyses, propensity score matching (PSM) analyses and subgroup analyses were conducted to assess the association between FTU and depression. RESULTS: The analysis included 5764 individuals over 60 years. An association between FTU and the risk of depression among older adults was detected (odds ratio [OR] = 0.951, 95% confidence interval [CI] 0.915-0.989), suggesting protective roles of more FTUs. Significant increase in the risk of depression in 0 ≤ FTUs ≤ 3 was observed compared with 10 ≤ FTUs ≤ 12 (OR = 1.819, 95% CI 1.157-2.858). However, no significant increase in the risk of depression in 4 ≤ FTUs ≤ 9 was found. After PSM, significant increase in the risk of depression in 0 ≤ FTUs ≤ 3 was still detected compared with 4 ≤ FTUs ≤ 12 (OR = 1.484, 95% CI 1.030-2.136). Subgroup analyses demonstrated consistent results in all subgroups, except for individuals aged 76-80 and drinking regularly. CONCLUSIONS: The findings suggested the association between impaired masticatory function and the risk of depression among older adults. Longitudinal studies are needed to elucidate the role of masticatory function impairment in the development of depression further.

Impact of periodontitis on type 2 diabetes: a bioinformatic analysis.

BACKGROUND: Periodontitis is strongly associated with type 2 diabetes (T2D) that results in serious complications and mortality. However, the pathogenic role of periodontitis in the development of T2D and the underlain mechanism have not been fully elucidated. METHODS: A Mendelian randomization (MR) was performed to estimate the causality between two diseases. Bioinformatics tools, including gene ontology and pathway enrichment analyses, were employed to analyze the common differentially expressed genes (DEGs) in periodontitis and T2D. MR and colocalization analyses were then utilized to investigate the causal associations between potential pathogenic gene expression and the risk of T2D. Single cell-type expression analysis was further performed to detect the cellular localization of these genes. RESULTS: Genetically predicted periodontitis was associated with a higher risk of T2D (OR, 1.469; 95% CI, 1.117-1.930; P = 0.006) and insulin resistance (OR 1.034; 95%CI 1.001-1.068; P = 0.041). 79 common DEGs associated with periodontitis and T2D were then identified and demonstrated enrichment mainly in CXC receptor chemokine receptor binding and interleutin-17 signaling pathway. The integration of GWAS with the expression quantitative trait locis of these genes from the peripheral blood genetically prioritized 6 candidate genes, including 2 risk genes (RAP2A, MCUR1) and 4 protective genes (WNK1, NFIX, FOS, PANX1) in periodontitis-related T2D. Enriched in natural killer cells, RAP2A (OR 4.909; 95% CI 1.849-13.039; P = 0.001) demonstrated high risk influence on T2D, and exhibited strong genetic evidence of colocalization (coloc.abf-PPH4 = 0.632). CONCLUSIONS: This study used a multi-omics integration method to explore causality between periodontitis and T2D, and revealed molecular mechanisms using bioinformatics tools. Periodontitis was associated with a higher risk of T2D. MCUR1, RAP2A, FOS, PANX1, NFIX and WNK1 may play important roles in the pathogenesis of periodontitis-related T2D, shedding light on the development of potential drug targets.

T follicular helper cells in autoimmune diseases.

T follicular helper (Tfh) cells with the phenotype of mainly expressing surface molecules C-X-C motif chemokine receptor type 5 (CXCR5), inducible co-stimulator (ICOS), secreting cytokine interleukin-21 (IL-21) and requiring the transcription factor B cell lymphoma 6 (BCL-6) have been recently defined as a new subset of CD4+ T cells. They exist in germinal centers (GCs) of lymphoid organs and in peripheral blood. With the ability to promote B cell development, GC formation and antibody production, Tfh cells play critical roles in the pathogenesis of many autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), etc. The aberrant proliferation and function of Tfh cells will cause the pathological process like autoantibody production and tissue injury. In this paper, we review the recent advances in Tfh cell biology and their roles in autoimmune diseases, with a mention of their use as therapeutic targets, which will shed more light on the pathogenesis and treatment of certain autoimmune diseases.

Microbiome-based therapies for periodontitis and peri-implantitis.

OBJECTIVES: Periodontitis and peri-implantitis are oral infectious-inflammatory diseases associated with oral microbial dysbiosis. Microbiome-based therapies, characterized by manipulation of the microbiota, are emerging as promising therapeutic approaches to resolve the microbial dysbiosis and associated dysregulation of immune system. This review aims at summarizing recent progress on microbiome-based therapies in periodontitis and peri-implantitis, promoting a further understanding of the related therapeutic mechanisms. SUBJECTS AND METHODS: Pertinent literatures focused on microbiome-based therapies for periodontitis and peri-implantitis are obtained from PubMed and Web of Science. RESULTS: In this article, we review the roles and therapeutic mechanisms of four microbiome-based therapies, including probiotics, postbiotics, predatory bacteria and phages, and microbiota transplantation, in the management of periodontitis and peri-implantitis. Challenges facing this field are also discussed, highlighting the areas that require more attention and investigation. CONCLUSIONS: Microbiome-based therapies may serve as effective treatment for periodontitis and peri-implantitis. This review presents a new viewpoint to this field.

Enhancement of Pickering effect of ovalbumin with bacterial cellulose nanofibers prepared by electron beam irradiation and encapsulation of curcumin.

In this study, the enhancement of Pickering effect of ovalbumin (OVA) with bacterial cellulose nanofibers (BCNFs) prepared by electron beam irradiation was investigated and the environmental stability of oil-in-water Pickering emulsions stabilized by OVA/BCNFs complexes was explored by varying ratios of OVA/BCNFS (1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1) and oil phase concentrations (10 %, 20 %, 30 %, 40 %, 50 %, 60 %). Droplet sizes of Pickering emulsions were decreased with the increase of the proportion of BCNFs, while the viscosity and storage modulus (G') of Pickering emulsions were increased. The gel strength of Pickering emulsions was positively correlated with the oil phase content. Pickering emulsions stabilized by OVA/BCNFs complexes were endowed excellent environmental stability under varying pH, ionic strength, and thermal conditions. Moreover, after encapsulating curcumin in Pickering emulsions, the retention rates of curcumin were improved significantly during room temperature, UV light, and thermal treatment. The present study would contribute to the advancement of novel protein/polysaccharide stabilizers and offer novel insight for investigating the stability of Pickering emulsions and delivering lipophilic bioactive compounds.

Sonocatalysis Regulates Tumor Autophagy for Enhanced Immunotherapy.

Immunotherapy stands as a groundbreaking strategy for cancer treatment, due to its ability to precisely and safely detect and eradicate tumors. However, the efficacy of immunotherapy is often limited by tumor autophagy, a natural defense mechanism that tumors exploit to resist immune attacks. Herein, we introduce a spatiotemporally controlled method to modulate tumor autophagy via sonocatalysis, aiming to improve immunotherapeutic outcomes. Specifically, we synthesized a tumor-targeting nanocatalyst based on a semiconductor heterojunction composed of Barium Titanate (BTO), Black Phosphorus (BP) integrated with Hyaluronic Acid (HA), referred to as BTO/BP-HA. Compared to traditional catalysts, the heterojunction structure enhances energy band bending and rapid electron-hole separation under ultrasonic stimulation, splitting water to generate H2. This promotes tumor cell apoptosis by inhibiting mitochondrial respiration and induces immunogenic cell death, triggering immune responses to eliminate tumor cells. However, the concurrent activation of autophagy mitigates the cytotoxic effectiveness of nanocatalysts. Within the nanocatalyst, BP undergoes lysosomal degradation to generate PO43-, which subsequently interacts with H+ to generate a conjugated acidic anion, increasing the lysosomal pH. This research ingeniously combines sonocatalysis with tumor autophagy, disrupting the activity of acidic hydrolases to inhibit autophagy, thereby enhancing the immune response and improving the effectiveness of immunotherapy.

Flexocatalytic Reduction of Tumor Interstitial Fluid/Solid Pressure for Efficient Nanodrug Penetration.

The practical efficacy of nanomedicines for treating solid tumors is frequently low, predominantly due to the elevated interstitial pressure within such tumors that obstructs the penetration of nanomedicines. This increased interstitial pressure originates from both liquid and solid stresses related to an undeveloped vascular network and excessive fibroblast proliferation. To specifically resolve the penetration issues of nanomedicines for tumor treatment, this study introduces a holistic "dual-faceted" approach. A treatment platform predicated on the WS2/Pt Schottky heterojunction was adopted, and flexocatalysis technology was used to disintegrate tumor interstitial fluids, thus producing oxygen and reactive oxygen species and effectively mitigating the interstitial fluid pressure. The chemotherapeutic agent curcumin was incorporated to further suppress the activity of cancer-associated fibroblasts, minimize collagen deposition in the extracellular matrix, and alleviate solid stress. Nanomedicines achieve homologous targeting by enveloping the tumor cell membrane. It was found that this multidimensional strategy not only alleviated the high-pressure milieu of the tumor interstitium─which enhanced the efficiency of nanomedicine delivery─but also triggered tumor cell apoptosis via the generated reactive oxygen species and modulated the tumor microenvironment. This, in turn, amplified immune responses, substantially optimizing the therapeutic impacts of nanomedicines.

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.

Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren's Syndrome.

Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren's syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT-PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS.