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Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.

Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation. Consistently, liver-specific Ggpps deficient mice have reduced fat adipose deposition. The levels of several EV-derived miRNAs in the plasma of non-alcoholic fatty liver disease (NAFLD) patients are positively correlated with body mass index (BMI), and these miRNAs enhance adipocyte lipid accumulation. Thus, we highlight an inter-organ mechanism whereby the liver senses different metabolic states and sends corresponding signals to remodel adipose tissue to adapt to metabolic changes in response to lipid overload. Extracellular vesicles (EVs) containing miRNAs or proteins can coordinate metabolic responses between tissues. Here the authors demonstrate that during lipid overload, the liver secretes miRNA-containing EVs through a Ggpps-Rab27 dependent mechanism, which controls adipose tissue lipid storage capacity.

Background Relevant studies focusing on epidemiological of profiles hypertensive disorders of pregnancy from global data that report the cause-specific prevalence and trends of hypertensive disorders of pregnancy at global, regional and national levels from 1990 to 2019 by age and sociodemographic index are still limited. Methods For hypertensive disorders of pregnancy, point prevalence, annual incidence, and years lived with disability numbers and age standardized rates per 100,000 population were compared at regional and national levels by age and sociodemographic index using data from the global Burden of Disease 2019 Study, covering populations from 204 countries and territories. Estimates are reported with uncertainty intervals to exhibit the changing trends during a specific period. Results The incidence of hypertensive disorders of pregnancy increased from 16.30 million to 18.08 million globally, with a total increase of 10.92 % from 1990 to 2019. The age-standardized incidence rate decreased, with an estimated annual percent change of -0.68 (95 % confidence interval [CI] -0.49 to -0.86). The number of deaths due to hypertensive disorders of pregnancy was approximately 27.83 thousand in 2019, representing a 30.05 % decrease from 1990. Based on the incidence and prevalence, the number of deaths and years lived with disability were highest in the group aged 25–29 years, followed by the groups aged 30–34 and 20–24 years, while the lowest estimated incidence rate was observed in the group aged 25–29 years and higher incidence rates were observed in the youngest and oldest groups. Positive associations between incidence rates and the sociodemographic index and human development index were found for all countries and regions in 2019. Age-standardized incidence rates were higher in countries/regions with lower sociodemographic indices and human development indices. Conclusions Our study provides a comprehensive overview of the global burden of hypertensive disorders of pregnancy. The death and incidence rates are decreasing in most countries and all regions except for those with low sociodemographic and human development indexes. This difference is mainly due to the increasing attention to prenatal examinations and health education. Further investigations should focus on forecasting the global disease burden of specific hypertensive disorders of pregnancy and modifiable risk factors.

Solar-powered water evaporation — the extraction of vapour from liquid water using solar energy — provides the basis for the development of eco-friendly and cost-effective freshwater production. Liquid water consumes and carries energy, and, thus, plays an essential role in this process. As such, extensive experimental and theoretical studies have been focused on water management to achieve efficient solar vapour generation. Many innovative materials have been proposed to enable highly controllable and efficient solar-to-thermal energy conversion to address the challenges in the energy–water nexus from the microscale to the molecular level. In this Review, we summarize the fundamental principles of materials design for efficient solar-to-thermal energy conversion and vapour generation. We discuss how to integrate photothermal materials, nanostructures/microstructures and water–material interactions to improve the performance of the evaporation system via in situ utilization of solar energy. Focusing on materials science and engineering, we overview the key challenges and opportunities for nanostructured and microstructured materials in both fundamental research and practical water-purification applications. Materials engineering enables the control of water–material interactions in solar vapour generators, which aim to efficiently utilize solar energy for the cost-effective production of clean water. This Review discusses material-design principles for solar evaporators, spanning from macrostructures to molecular configurations.

DNA end resection has a key role in double-strand break repair and DNA replication. Defective DNA end resection can cause malfunctions in DNA repair and replication, leading to greater genomic instability. DNA end resection is initiated by MRN-CtIP generating short, 3′-single-stranded DNA (ssDNA). This newly generated ssDNA is further elongated by multiple nucleases and DNA helicases, such as EXO1, DNA2, and BLM. Effective DNA end resection is essential for error-free homologous recombination DNA repair, the degradation of incorrectly replicated DNA and double-strand break repair choice. Because of its importance in DNA repair, DNA end resection is strictly regulated. Numerous mechanisms have been reported to regulate the initiation, extension, and termination of DNA end resection. Here, we review the general process of DNA end resection and its role in DNA replication and repair pathway choice.DNA repair: tying up loose endsCarefully regulated enzymatic processing of the ends of DNA strands is essential for efficient replication and damage repair while also minimizing the risk of genomic instability. Replication and repair depend on a mechanism known as DNA resection, in which enzymes trim back double-stranded DNA ends to leave single-stranded overhangs. Zhenkun Lou and colleagues at the Mayo Clinic in Rochester, USA, have reviewed the various steps involved in the initiation and control of DNA resection. There are multiple different DNA repair processes, and the manner in which resection occurs can determine which of these processes subsequently takes place. The authors note that cancer cells rely heavily on these repair pathways to survive radiotherapy and chemotherapy, and highlight research opportunities that might reveal therapeutically useful vulnerabilities in the resection mechanism.

Sarcomas (SARC) are a highly heterogeneous cancer type that is prone to recurrence and metastasis. Numerous studies have confirmed that Siglecs are involved in immune signaling and play a key role in regulating immune responses in inflammatory diseases and various cancers. However, studies that systematically explore the therapeutic and prognostic value of Siglecs in SARC patients are very limited. The online databases GEPIA, UALCAN, TIMER, The Kaplan–Meier Plotter, GeneMANIA, cBioPortal, and STING were used in this study. IHC staining was performed on the collected patient tissues, and clinical data were statistically analyzed. The transcript levels of most Siglec family members showed a high expression pattern in SARC. Compared with normal tissues, Siglec-5 , Siglec-10 , and Siglec-12 were abnormally highly expressed in tumor tissues. Importantly, Siglec-15 was significantly associated with poor prognosis. Functional enrichment analysis showed that the Siglec family was mainly enriched in hematopoietic cell lineages. The genes associated with molecular mutations in the Siglec family were mainly TP53 and MUC16, among which Siglec-2 and Siglec-15 were significantly associated with the survival of patients. The expression levels of all Siglec family members were significantly correlated with various types of immune cells (B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils and dendritic cells). Furthermore, a significant correlation was found between the somatic copy number changes of all Siglec molecules and the abundance of immune infiltrates. Our study paints a promising vision for the development of immunotherapy drugs and the construction of prognostic stratification models by investigating the therapeutic and prognostic potential of the Siglec family for SARC.

Background Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. Methods Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). Results Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. Conclusion LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

To develop the platelet inflammation hypothesis and propose the concept of platelets as the central hub regulating inflammation. We employed a narrative review design. Based on platelets being the source of cellular fragments shed from megakaryocytes, we traced the active molecules within platelet granules to infer platelet regulatory roles in aseptic inflammation, infectious inflammation, cancer, and neuroinflammation. Furthermore, we visually mapped the central regulatory mechanisms of platelets in the aforementioned inflammatory contexts. Platelets not only mediate hemostasis and thrombosis through the coagulation pathway but also dynamically regulate inflammatory responses through interactions between bioactive substances in platelet granules, leukocytes, vasculature, and immune signaling. This regulatory role applies across a broad spectrum of pathological inflammations. Platelets influence vascular integrity in aseptic inflammatory injury, participate in pathogen recognition and containment during infectious inflammation, and regulate immune cell recruitment and inflammatory outcomes in tumor/cancer and neuroinflammation. The central principle of platelet-mediated inflammation regulation is dual control of immune thrombogenesis through damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), thereby influencing disease outcomes. Platelets serve as the central hub in the microcirculatory-damaged tissue-immune inflammatory interaction network. Their immunoregulatory functions play a pivotal role in diverse inflammatory pathologies. The platelet-driven mechanism-disease-immune inflammatory regulation framework provides clinically translatable insights for diagnostic evaluation of inflammatory and thrombotic conditions, as well as for developing antiplatelet therapeutic strategies targeting diseases such as cancer and epilepsy.

Purpose To investigate the clinical indicators that can predict myocardial damage in children with mycoplasma pneumoniae pneumonia (MPP) to help early identification and management. Methods The clinical data of 123 MPP children admitted from December 2023 to February 2024 in the affiliated Changzhou Children’s Hospital of Nantong University were analyzed retrospectively. According to the creatine kinase isoenzyme (CK-MB) level, the children were divided into 61 cases without myocardial damage group and 62 cases with myocardial damage group. Clinical manifestations and laboratory parameters were compared between the two groups. The factors affecting myocardial damage in children with MPP were analyzed by logistic regression. The ROC curve analyzed the predictive value of relevant indicators for myocardial damage in children with MPP. Results The incidence of abnormal electrocardiogram (ECG), extrapulmonary manifestations (except myocardial damage), white blood cell count (WBC), neutrophil/lymphocyte ratio (NLR), erythrocyte sedimentation rate (ESR), albumin and other myocardial enzyme parameters in the myocardial damage group were higher than those in the group without myocardial damage ( P  < 0.05), and the median age and platelet/neutrophil ratio (PNR) were lower than those in the group without myocardial damage ( P  < 0.05); there was no significant difference in general data such as gender, duration of fever, length of hospital stay, the incidence of severe pneumonia between the two groups ( P  > 0.05); multivariate logistic regression analysis showed that median age, NLR level and extrapulmonary manifestations (except myocardial damage) were the main factors affecting myocardial damage in children with MPP ( P  < 0.05); considering the interaction between NLR and PNR. We also performed ROC curve analysis for PNR. Among the univariate factors, PNR had the highest predictive value, and the specificity was as high as 86.9%. The combined area under the curve of the four indicators was 0.747, higher than that of the univariate factor ( P  < 0.001), with a predictive sensitivity of 83.9% and a specificity of 63.9%. Conclusion Children with MPP younger than 6.79 years have extrapulmonary manifestations (acute sinusitis, acute otitis media, etc.), NLR > 2.41, and PNR < 44.74 in blood routine are more likely to develop myocardial damage. Clinical trial number Not applicable.

The pathogenesis of senile osteoporosis involves immune cell imbalance, inflammaging, and dysregulation of the RANKL/OPG bone-immune axis, collectively defining the concept of immunoporosis. These interrelated processes mutually reinforce one another, leading to a 2-3-fold prolongation of bone healing time, while conventional single-target therapies fail to achieve coordinated regulation of bone regeneration and the immune microenvironment. Black phosphorus (BP) nanomaterials, as an emerging class of biomaterials, represent a paradigm shift from \"passive scaffolds\" to \"active immuno-bone synergistic regulators.\" BP exerts multifunctional effects by restoring macrophage M1/M2 polarization balance, scavenging reactive oxygen species (ROS) to disrupt inflammatory feedback loops, and modulating the RANKL/OPG axis, thereby promoting a transition from a pro-inflammatory, destructive state to an anti-inflammatory, reparative phenotype. Experimental evidence indicates that BP can reduce pro-inflammatory cytokine expression by approximately 60% and achieve bone defect bridging rates of up to 93%. However, the clinical translation of BP remains challenged by the complexity of aging-related immune mechanisms, insufficient long-term safety data, and unclear translational pathways. This Perspective systematically discusses the regulatory mechanisms of BP in the aged osteoimmune microenvironment, the current limitations, and future research directions.