Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.

For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.

Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases.

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.

Trends of diabetes in Beijing, China.

BACKGROUND: The global rise in diabetes prevalence is a pressing concern. Despite initiatives like "The Healthy Beijing Action 2020-2030" advocating for increased awareness, treatment, and control, the specific situation in Beijing remains unexplored. This study aimed to analyze the trends in diabetes prevalence, awareness, treatment, and control among Beijing adults. METHODS: Through a stratified multistage probability cluster sampling method, a series of representative cross-sectional surveys were conducted in Beijing from 2005 to 2022, targeting adults aged 18-79 years. A face-to-face questionnaire, along with body measurements and laboratory tests, were administered to 111,943 participants. Data from all survey were age- and/or gender-standardized based on the 2020 Beijing census population. Annual percentage rate change (APC) or average annual percentage rate change (AAPC) was calculated to determine prevalence trends over time. Complex sampling logistic regression models were employed to explore the relationship between various characteristics and diabetes. RESULTS: From 2005 to 2022, the total prevalence of diabetes among Beijing adults aged 18-79 years increased from 9.6% (95% CI: 8.8-10.4%) to 13.9% (95% CI: 13.1-14.7%), with an APC/AAPC of 2.1% (95% CI: 1.1-3.2%, P <0.05). Significant increases were observed among adults aged 18-39 years and rural residents. Undiagnosed diabetes rose from 3.5% (95% CI: 3.2-4.0%) to 7.2% (95% CI: 6.6-7.9%) with an APC/AAPC of 4.1% (95% CI: 0.5-7.3%, P <0.05). However, diabetes awareness and treatment rates showed annual declines of 1.4% (95% CI: -3.0% to -0.2%, P <0.05) and 1.3% (95% CI: -2.6% to -0.2%, P <0.05), respectively. The diabetes control rate decreased from 21.5% to 19.1%, although not statistically significant (APC/AAPC = -1.5%, 95% CI: -5.6% to 1.9%). Overweight and obesity were identified as risk factors for diabetes, with ORs of 1.65 (95% CI: 1.38-1.98) and 2.48 (95% CI: 2.07-2.99), respectively. CONCLUSIONS: The prevalence of diabetes in Beijing has significantly increased between 2005 and 2022, particularly among young adults and rural residents. Meanwhile, there has been a concerning decrease in diabetes awareness and treatment rates, while control rates have remained stagnant. Regular blood glucose testing, especially among adults aged 18-59 years, should be warranted. Furthermore, being male, elderly, overweight, or obese was associated with higher diabetes risk, suggesting the needs for targeted management strategies.

Regulating nanoscale directional heat transfer with Janus nanoparticles.

Janus nanoparticles (JNPs) with heterogeneous compositions or interfacial properties can exhibit directional heating upon external excitation with optical or magnetic energy. This directional heating may be harnessed for new nanotechnology and biomedical applications. However, it remains unclear how the JNP properties (size, interface) and laser excitation method (pulsed vs. continuous) regulate the directional heating. Here, we developed a numerical framework to analyze the asymmetric thermal transport in JNP heating under photothermal stimulation. We found that JNP-induced temperature contrast, defined as the ratio of temperature increase on the opposite sides in the surrounding medium, is highest for smaller JNPs and when a low thermal resistance coating covers a minor fraction of JNP surface. Notably, we discovered up to 20-fold enhancement of the temperature contrast based on thermal confinement under pulsed heating compared with continuous heating. This work brings new insights to maximize the asymmetric thermal responses for JNP heating.

Pan-cancer analysis of CDKN2A alterations identifies a subset of gastric cancer with a cold tumor immune microenvironment.

BACKGROUND: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer. METHODS: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT). RESULTS: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response. CONCLUSIONS: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.

Twisted splitting and propagation factor of superimposed twisted Hermite-Gaussian Schell-model beams in turbulent atmosphere.

We believe this to be a new superposition twisted Hermite-Gaussian Schell-model (STHGSM) beam hat is proposed. Analytic formulas for the intensity distribution and propagation factor of the STHGSM beam in non-Kolmogorov turbulence are derived by utilizing the generalized Huygens-Fresnel principle (HFP) and the Wigner function. The evolution characteristics of STHGSM beams propagating are numerically calculated and analyzed. Our findings indicate that the light intensity of the STHGSM beam gradually undergoes splitting and rotation around the axis during propagation through non-Kolmogorov turbulence, eventually evolving into a diagonal lobe shape at a certain distance of transmission. The anti-turbulence capability of the beam strengthens with higher beam order or twist factor values.

Liguzinediol potentiates the metabolic remodeling by activating the AMPK/SIRT3 pathway and represses Caspase-3/GSDME-mediated pyroptosis to ameliorate cardiotoxicity.

BACKGROUND: Liguzinediol (Lig) has emerged as a promising candidate for mitigating Doxorubicin (DOX)-induced cardiotoxicity, a significant limitation in the clinical application of this widely used antineoplastic drug known for its efficacy. This study aimed to explore the effects and potential mechanisms underlying Lig's protective role against DOX-induced cardiotoxicity. METHODS: C57BL/6 mice were treated with DOX. Cardiac function changes were observed by echocardiography. Cardiac structure changes were observed by HE and Masson staining. Immunofluorescence was applied to visualize the cardiomyocyte apoptosis. Western blotting was used to detect the expression levels of AMP-activated protein kinase (AMPK), sirtuin 3 (SIRT3), Caspase-3 and gasdermin E N-terminal fragment (GSDME-N). These experiments confirmed that Lig had an ameliorative effect on DOX-induced cardiotoxicity in mice. RESULTS: The results demonstrated that Lig effectively countered myocardial oxidative stress by modulating intracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Lig reduced levels of creatine kinase (CK) and lactate dehydrogenase (LDH), while ameliorating histopathological changes and improving electrocardiogram profiles in vivo. Furthermore, the study revealed that Lig activated the AMPK/SIRT3 pathway, thereby enhancing mitochondrial function and attenuating myocardial cell apoptosis. In experiments with H9C2 cells treated with DOX, co-administration of the AMPK inhibitor compound C (CC) led to a significant increase in intracellular ROS levels. Lig intervention reversed these effects, along with the downregulation of GSDME-N, interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), suggesting a potential role of Lig in mitigating Caspase-3/GSDME-mediated pyroptosis. CONCLUSION: The findings of this study suggest that Lig effectively alleviates DOX-induced cardiotoxicity through the activation of the AMPK/SIRT3 pathway, thereby presenting itself as a natural product with therapeutic potential for preventing DOX-associated cardiotoxicity. This novel approach may pave the way for the development of alternative strategies in the clinical management of DOX-induced cardiac complications.

Bioinformatics gene analysis for potential biomarkers and therapeutic targets of Parkinson's disease based on neutrophil extracellular traps.

Introduction: Neutrophil extracellular traps (NETs) provide key innate immune mechanisms, and studies have shown innate immunity and adaptive immunity are directly linked to Parkinson's disease (PD) pathology. However, limited research has been conducted on NETs in the context of PD. Methods: A differential analysis was implemented to acquire differentially expressed genes (DEGs) between PD and control as well as between high- and low-score groups determined by a gene set variation analysis (GSVA). Then, the genes within the critical module, obtained through a weighted gene co-expression network analysis (WGCNA), were intersected with the DEGs to identify the overlapping genes. Then, five kinds of algorithms in the protein-protein interaction (PPI) were performed to identify potential biomarkers. Subsequently, a nomogram for forecasting PD probability was created. An enrichment analysis and an immune infiltration analysis were performed on the identified biomarkers. qRT-PCR was performed to validate the expression trends of three biomarkers. Results: We revealed 798 DEGs between PD and control groups as well as 168 DEGs between high- and low-score groups obtained by differential analyses. The pink module containing 926 genes was identified as the critical module. According to the intersection of these gene sets, a total of 43 overlapping genes were screened out. Furthermore, GPR78, CADM3, and CACNA1E were confirmed as biomarkers. Moreover, we found that biomarkers mainly participated in pathways, such as the 'hydrogen peroxide catabolic process', and 'cell cycle'; five kinds of differential immune cells between PD and control groups were identified. Finally, the qRT-PCR analysis demonstrated the up-regulation of GPR78, CADM3, and CACNA1E in the PD group. Discussion: Our study authenticated GPR78, CADM3, and CACNA1E as the biomarkers associated with PD. These findings provide an original reference for the diagnosis and treatment of PD.

Qingzhuan dark tea polysaccharides-zinc alleviates dextran sodium sulfate-induced ulcerative colitis.

BACKGROUND: Qingzhuan dark tea polysaccharides (QDTP) have been complexed with Zinc (Zn) to form the Qingzhuan dark tea polysaccharides-Zinc (QDTP-Zn) complex. The present study investigated the protective effects of QDTP-Zn on ulcerative colitis (UC) in mice. The UC mouse model was induced using dextran sodium sulfate (DSS), followed by oral administration of QDTP-Zn (0.2 and 0.4 g kg-1 day-1). RESULTS: QDTP-Zn demonstrated alleviation of UC symptoms in mice, as evidenced by a decrease in disease activity index scores. QDTP-Zn also regulated colon tissue injury by upregulating ZO-1 and occludin protein expression, at the same time as downregulating tumor necrosis factor-α and interleukin-6ß levels. Furthermore, QDTP-Zn induced significant alterations in the abundance of bacteroidetes and firmicutes and notably increased levels of short-chain fatty acids (SCFAs), particularly acetic acid, propionic acid, and butyric acid. CONCLUSION: In summary, QDTP-Zn exhibits therapeutic potential in alleviating enteritis by fortifying the colonic mucosal barrier, mitigating inflammation and modulating intestinal microbiota and SCFAs levels. Thus, QDTP-Zn holds promise as a functional food for both the prevention and treatment of UC. © 2024 Society of Chemical Industry.

PDE4D and miR-203 are promising biomarkers for canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (CAD) is a common genetically predisposed, inflammatory, and pruritic skin disorder that affects dogs globally. To date, there are no specific biomarkers available to diagnose CAD, and the current diagnosis is based on a combination of criteria including patient history, clinical signs, and exclusion of other relevant differential diagnoses. METHODS AND RESULTS: We examined the gene expression of phosphodiesterase 4D (PDE4D) in peripheral blood mononuclear cells (PBMCs), as well as miR-203 and miR-483 in plasma, in three groups: healthy dogs, CAD dogs, and other inflammatory pruritic skin diseases (OIPSD) such as pemphigus foliaceus, scabies, cutaneous lymphoma, and dermatophytosis. Our results showed that PDE4D gene expression in the CAD group is statistically higher compared to those in the healthy and OIPSD groups, suggesting PDE4D may be a specific marker for CAD. Nevertheless, no correlation was found between PDE4D gene expression levels and the lesion severity gauged by CAD severity index-4 (CADESI-4). We also showed that miR-203 is a generic marker for clinical dermatitis and differentiates both CAD and OIPSD inflammatory conditions from healthy controls. CONCLUSIONS: We show that PDE4D is a potential marker to differentiate CAD from non-atopic healthy and OIPSD while miR-203 may be a potential marker for general dermatologic inflammation. Future study of PDE4D and miR-203 on a larger scale is warranted.

The impact of Yoga on patients with knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The objective of this review is to conduct a comprehensive and systematic assessment of the efficacy of Yoga as an intervention for knee osteoarthritis (KOA). METHODS: We searched PubMed, Cochrane Library, Embase, Web of Science, and PEDro as of January 3, 2024. Retrieved a total of 200 articles. Standardised mean differences (SMDs) and 95% confidence intervals (CI) were calculated. RESULTS: The study included a total of 8 trials and involved 756 KOA patients. The results indicated that compared to the control group, Yoga exercise showed significant improvements in alleviating pain (SMD = -0.92; 95% CI = -1.64 ~ - 0.20; P = 0.01, I2 = 94%), stiffness (SMD = -0.51; 95% CI = -0.91 ~ -0.12; P = 0.01; I2 = 66%) and physical function (SMD = -0.53; 95% CI = -0.89 ~ -0.17; P = 0.004; I2 = 59%) among KOA patients. However, there was no significant improvement observed in terms of activities of activity of daily living (ADL) (SMD = 1.03; 95% CI = -0.01 ~ 2.07; P = 0.05; I2 = 84%), and quality of life (QOL) (SMD = 0.21; 95% CI = -0.33 ~ 0.74; P = 0.44; I2 = 83%) with the practice of Yoga. CONCLUSIONS: In general, Yoga has been found to be effective in reducing pain and stiffness in KOA patients, it can also improve the physical function of patients. However, there is limited evidence to suggest significant improvements in terms of ADL and QOL.

Methylation in cornea and corneal diseases: a systematic review.

Corneal diseases are among the primary causes of blindness and vision loss worldwide. However, the pathogenesis of corneal diseases remains elusive, and diagnostic and therapeutic tools are limited. Thus, identifying new targets for the diagnosis and treatment of corneal diseases has gained great interest. Methylation, a type of epigenetic modification, modulates various cellular processes at both nucleic acid and protein levels. Growing evidence shows that methylation is a key regulator in the pathogenesis of corneal diseases, including inflammation, fibrosis, and neovascularization, making it an attractive potential therapeutic target. In this review, we discuss the major alterations of methylation and demethylation at the DNA, RNA, and protein levels in corneal diseases and how these dynamics contribute to the pathogenesis of corneal diseases. Also, we provide insights into identifying potential biomarkers of methylation that may improve the diagnosis and treatment of corneal diseases.

Facile Peptide Macrocyclization and Multifunctionalization via Cyclen Installation.

Cyclen-peptide bioconjugates are usually prepared in multiple steps that require individual preparation and purification of the cyclic peptide and hydrophilic cyclen derivatives. An efficient strategy is discovered for peptide cyclization and functionalization toward lanthanide probe via three components intermolecular crosslinking on solid-phase peptide synthesis with high conversion yield. Multifunctionality can be conferred by introducing different modular parts or/and metal ions on the cyclen-embedded cyclopeptide. As a proof-of-concept, a luminescent Eu3+ complex and a Gd3+-based contrasting agent for in vitro optical imaging and in vivo magnetic resonance imaging, respectively, are demonstrated through utilizing this preparation of cyclen-embedded cyclic arginylglycylaspartic acid (RGD) peptide.

FLOURY ENDOSPERM24, a heat shock protein 101 (HSP101), is required for starch biosynthesis and endosperm development in rice.

Endosperm is the main storage organ in cereal grain and determines grain yield and quality. The molecular mechanisms of heat shock proteins in regulating starch biosynthesis and endosperm development remain obscure. Here, we report a rice floury endosperm mutant flo24 that develops abnormal starch grains in the central starchy endosperm cells. Map-based cloning and complementation test showed that FLO24 encodes a heat shock protein HSP101, which is localized in plastids. The mutated protein FLO24T296I dramatically lost its ability to hydrolyze ATP and to rescue the thermotolerance defects of the yeast hsp104 mutant. The flo24 mutant develops more severe floury endosperm when grown under high-temperature conditions than normal conditions. And the FLO24 protein was dramatically induced at high temperature. FLO24 physically interacts with several key enzymes required for starch biosynthesis, including AGPL1, AGPL3 and PHO1. Combined biochemical and genetic evidence suggests that FLO24 acts cooperatively with HSP70cp-2 to regulate starch biosynthesis and endosperm development in rice. Our results reveal that FLO24 acts as an important regulator of endosperm development, which might function in maintaining the activities of enzymes involved in starch biosynthesis in rice.

Plasmonic-Driven Regulation of Biomolecular Activity In Situ.

Selective and remote manipulation of activity for biomolecules, including protein, DNA, and lipids, is crucial to elucidate their molecular function and to develop biomedical applications. While advances in tool development, such as optogenetics, have significantly impacted these directions, the requirement for genetic modification significantly limits their therapeutic applications. Plasmonic nanoparticle heating has brought new opportunities to the field, as hot nanoparticles are unique point heat sources at the nanoscale. In this review, we summarize fundamental engineering problems such as plasmonic heating and the resulting biomolecular responses. We highlight the biological responses and applications of manipulating biomolecules and provide perspectives for future directions in the field.

Theabrownin from Qingzhuan tea prevents high-fat diet-induced MASLD via regulating intestinal microbiota.

The aim of this study was to investigate whether the therapeutic effect of theabrownin extracted from Qingzhuan tea (QTB) on metabolic dysfunction-associated steatosis liver disease (MASLD) is related to the regulation of intestinal microbiota and its metabolite short-chain fatty acids (SCFAs). Mice were divided into four groups and received normal diet (ND), high-fat diet (HFD) and HFD+QTB (180, 360 mg/kg) for 8 weeks. The results showed that QTB significantly reduced the body weight of HFD mice, ameliorated liver lipid and dyslipidemia, and increased the level of intestinal SCFAs in HFD mice. The results of 16 S rRNA showed that the relative abundance of Bacteroides, Blautia and Lachnoclostridium and their main metabolites acetate and propionate were significantly increased after QTB intervention. The relative abundance of Colidextribacter, Faecalibaculum and Lactobacillus was significantly reduced. QTB can also significantly up-regulate the expression of ATGL, PPARα, FFAR2 and FFAR3, and inhibit the expression of LXRα, SREBP-1c, FAS and HMGCR genes. This makes it possible to act as a prebiotic to prevent MASLD.

Potential targets for the treatment of MI: GRP75-mediated Ca2+ transfer in MAM.

After myocardial infarction (MI), there is a notable disruption in cellular calcium ion homeostasis and mitochondrial function, which is believed to be intricately linked to endoplasmic reticulum (ER) stress. This research endeavors to elucidate the involvement of glucose regulated protein 75 (GRP75) in post-MI calcium ion homeostasis and mitochondrial function. In MI rats, symptoms of myocardial injury were accompanied by an increase in the activation of ER stress. Moreover, in oxygen-glucose deprivation (OGD)-induced cardiomyocytes, it was confirmed that inhibiting ER stress exacerbated intracellular Ca2+ disruption and cell apoptosis. Concurrently, the co-localization of GRP75 with IP3R and VDAC1 increased under ER stress in cardiomyocytes. In OGD-induced cardiomyocytes, knockdown of GRP75 not only reduced the Ca2+ levels in both the ER and mitochondria and improved the ultrastructure of cardiomyocytes, but it also increased the number of contact points between the ER and mitochondria, reducing mitochondria associated endoplasmic reticulum membrane (MAM) formation, and decreased cell apoptosis. Significantly, knockdown of GRP75 did not affect the protein expression of PERK and hypoxia-inducible factor 1α (HIF-1α). Transcriptome analysis of cardiomyocytes revealed that knockdown of GRP75 mainly influenced the molecular functions of sialyltransferase and IP3R, as well as the biosynthesis of glycosphingolipids and lactate metabolism. The complex interaction between the ER and mitochondria, driven by the GRP75 and its associated IP3R1-GRP75-VDAC1 complex, is crucial for calcium homeostasis and cardiomyocyte's adaptive response to ER stress. Modulating GRP75 could offer a strategy to regulate calcium dynamics, diminish glycolysis, and thereby mitigate cardiomyocyte apoptosis.

Therapeutic Effect of a Novel M1 Macrophage-Targeted Nanodrug in Chronic Periodontitis Mice.

Chronic periodontitis is a chronic, progressive, and destructive disease. Especially, the large accumulation of advanced glycation end products (AGEs) in a diseased body will aggravate the periodontal tissue damage, and AGEs induce M1 macrophages. In this project, the novel nanodrugs, glucose-PEG-PLGA@MCC950 (GLU@MCC), are designed to achieve active targeting with the help of glucose transporter 1 (GLUT1) which is highly expressed in M1 macrophages induced by AGEs. Then, the nanodrugs release MCC950, which is a kind of NLRP3 inhibitor. These nanodrugs not only can improve the water solubility of MCC950 but also exhibit superior characteristics, such as small size, stability, innocuity, etc. In vivo experiments showed that GLU@MCC could reduce periodontal tissue damage and inhibit cell apoptosis in periodontitis model mice. In vitro experiments verified that its mechanism of action might be closely related to the inhibition of the NLRP3 inflammatory factor in M1 macrophages. GLU@MCC could effectively reduce the damage to H400 cells caused by AGEs, decrease the expression of NLRP3, and also obviously reduce the M1-type macrophage pro-inflammatory factors such as IL-18, IL-1ß, caspase-1, and TNF-α. Meanwhile, the expression of anti-inflammatory factor Arg-1 in the M2 macrophage was increased. In brief, GLU@MCC would inhibit the expression of inflammatory factor NLRP3 and exert antiperiodontal tissue damage in chronic periodontitis via GLUT1 in the M1 macrophage as the gating target. This study provides a novel nanodrug for chronic periodontitis treatment.

Microfluidic Synthesis of CuH Nanoparticles for Antitumor Therapy through Hydrogen-Enhanced Apoptosis and Cuproptosis.

Cuproptosis has drawn enormous attention in antitumor material fields; however, the responsive activation of cuproptosis against tumors using nanomaterials with high atom utilization is still challenging. Herein, a copper-based nanoplatform consisting of acid-degradable copper hydride (CuH) nanoparticles was developed via a microfluidic synthesis. After coating with tumor-targeting hyaluronic acid (HA), the nanoplatform denoted as HA-CuH-PVP (HCP) shows conspicuous damage toward tumor cells by generating Cu+ and hydrogen (H2) simultaneously. Cu+ can induce apoptosis by relying on Fenton-like reactions and lead to cuproptosis by causing mitochondrial protein aggregation. Besides, the existence of H2 can enhance both cell death types by causing mitochondrial dysfunction and intracellular redox homeostatic disorders. In vivo experimental results further exhibit the desirable potential of HCP for killing tumor cells and inhibiting lung metastases, which will broaden the horizons of designing copper-based materials triggering apoptosis and cuproptosis for better antitumor efficacy.

Molecular Engineering of Activatable NIR-II Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Inflammatory Bowel Disease.

Molecular imaging in the second near-infrared window (NIR-II) provides high-fidelity visualization of biopathological events in deep tissue. However, most NIR-II probes produce "always-on" output and demonstrate poor signal specificity toward biomarkers. Herein, we report a series of hemicyanine reporters (HBCs) with tunable emission to NIR-II window (715-1188 nm) and structurally amenable to constructing activatable probes. Such manipulation of emission wavelengths relies on rational molecular engineering by integrating benz[c,d]indolium, benzo[b]xanthonium, and thiophene moieties to a conventional hemicyanine skeleton. In particular, HBC4 and HBC5 possess bright and record long emission over 1050 nm, enabling improved tissue penetration depth and superior signal to background ratio for intestinal tract mapping than NIR-I fluorophore HC1. An activatable inflammatory reporter (AIR-PE) is further constructed for pH-triggered site-specific release in colon. Due to minimized background interference, oral gavage of AIR-PE allows clear delineation of irritated intestines and assessment of therapeutic responses in a mouse model of inflammatory bowel disease (IBD) through real-time NIRF-II imaging. Benefiting from its high fecal clearance efficiency (>90%), AIR-PE can also detect IBD and evaluate the effectiveness of colitis treatments via in vitro optical fecalysis, which outperforms typical clinical assays including fecal occult blood testing and histological examination. This study thus presents NIR-II molecular scaffolds that are not only applicable to developing versatile activatable probes for early diagnosis and prognostic monitoring of deeply seated diseases but also hold promise for future clinical translations.