Nature of epigenetic aging from a single-cell perspective.

Age-related changes in DNA methylation (DNAm) form the basis of the most robust predictors of age-epigenetic clocks-but a clear mechanistic understanding of exactly which aspects of aging are quantified by these clocks is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the dynamics of tissue and single-cell DNAm in mice. We compare these changes during early development with those observed during adult aging in mice, and corroborate our analyses with a single-cell RNA sequencing analysis within the same multiomics dataset. We show that epigenetic aging involves co-regulated changes as well as a major stochastic component, and this is consistent with transcriptional patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns. Together, our analyses increase our understanding of the basis of epigenetic clocks and highlight potential opportunities for targeting aging and evaluating longevity interventions.

A unified classification system for HIV-1 5' long terminal repeats.

The HIV-1 provirus mainly consists of internal coding region flanked by 1 long terminal repeats (LTRs) at each terminus. The LTRs play important roles in HIV-1 reverse transcription, integration, and transcription. However, despite of the significant study advances of the internal coding regions of HIV-1 by using definite reference classification, there are no systematic and phylogenetic classifications for HIV-1 5' LTRs, which hinders our elaboration on 5' LTR and a better understanding of the viral origin, spread and therapy. Here, by analyzing all available resources of 5' LTR sequences in public databases following 4 recognized principles for the reference classification, 83 representatives and 14 consensus sequences were identified as representatives of 2 groups, 6 subtypes, 6 sub-subtypes, and 9 CRFs. To test the reliability of the supplemented classification system, the constructed references were applied to identify the 5' LTR assignment of the 22 clinical isolates in China. The results revealed that 16 out of 22 tested strains showed a consistent subtype classification with the previous LTR-independent classification system. However, 6 strains, for which recombination events within 5' LTR were demonstrated, unexpectedly showed a different subtype classification, leading a significant change of binding sites for important transcription factors including SP1, p53, and NF-κB. The binding change of these transcriptional factors would probably affect the transcriptional activity of 5' LTR. This study supplemented a unified classification system for HIV-1 5' LTRs, which will facilitate HIV-1 characterization and be helpful for both basic and clinical research fields.

Androgen levels in autism spectrum disorders: a systematic review and meta-analysis.

Background: Accumulating evidence suggests that the autism spectrum disorder (ASD) population exhibits altered hormone levels, including androgens. However, studies on the regulation of androgens, such as testosterone and dehydroepiandrosterone (DHEA), in relation to sex differences in individuals with ASD are limited and inconsistent. We conducted the systematic review with meta-analysis to quantitatively summarise the blood, urine, or saliva androgen data between individuals with ASD and controls. Methods: A systematic search was conducted for eligible studies published before 16 January 2023 in six international and two Chinese databases. We computed summary statistics with a random-effects model. Publication bias was assessed using funnel plots and heterogeneity using I2 statistics. Subgroup analysis was performed by age, sex, sample source, and measurement method to explain the heterogeneity. Results: 17 case-control studies (individuals with ASD, 825; controls, 669) were assessed. Androgen levels were significantly higher in individuals with ASD than that in controls (SMD: 0.27, 95% CI: 0.06-0.48, P=0.01). Subgroup analysis showed significantly elevated levels of urinary total testosterone, urinary DHEA, and free testosterone in individuals with ASD. DHEA level was also significantly elevated in males with ASD. Conclusion: Androgen levels, especially free testosterone, may be elevated in individuals with ASD and DHEA levels may be specifically elevated in males.

Highly-solvating Electrolyte Enables Mechanically Stable and Inorganic-rich Cathode Electrolyte Interphase for High-performing Potassium-ion Batteries.

Cathode-electrolyte interphase (CEI) is crucial for the reversibility of rechargeable batteries, yet receives less attention compared to solid-electrolyte interphase (SEI). The prevalent weakly-solvating electrolyte is usually proposed from the standing point of obtaining robust SEI, however, the resultant weak ion-solvent interaction gives rise to excessive free solvents and forms thick CEI with high kinetic barriers, which is disadvantageous for interfacial stability at the high working voltage. Herein, we report a highly-solvating electrolyte to immobilize free solvents by generating stable ternary complexes and facilitate the growth of homogeneous and ultrathin CEI to boost the electrochemical performances of potassium-ion batteries (PIBs). Through time-of-flight secondary ion mass spectrometry and cryogenic transmission electron microscopy, we reveal that the deliberately coordinated complexes are the key to forming mechanically stable and inorganic-rich CEI with superior diffusion kinetics for high-performing PIBs. Coupling with a K0.5MnO2 cathode and a soft carbon (SC) anode, we achieve a high energy density (202.3 Wh kg-1) with an exceptional cycle lifespan (92.5% capacity retention after 500 cycles) in a SC||K0.5MnO2 full cell, setting new performance benchmarks for PIBs. This article is protected by copyright. All rights reserved.

Major Clinical Adverse Events of Breast Implant in the Manufacturer and User Facility Device Experience Database.

OBJECTIVE: Search the Manufacturer and User Facility Device Experience database to collect information on adverse events of breast implant. We analyzed the local complications and the breast implant illness (BII) of silicone breast implants, as well as saline breast implants separately, aim to provide a reference for women who want to breast augmentation. MATERIALS AND METHODS: The Manufacturer and User Facility Device Experience database was queried for events reports related to the breast implant between July 1, 2012, and June 30, 2022. Event year and reporting year were summarized. Patient problem was collected and analyzed to distinguish between local complications and BII. RESULTS: A total of 108,728 adverse events in the past 3 years were analyzed, silicone breast implants accounted for 62.1% and saline breast implants accounted for 37.9%. The most common local complication of women receiving silicone breast implants was "Capsular Contracture," accounting for 48.73%. However, the incidence of "capsular contracture" in women who received saline breast implants was only 17.49%. The most common BII was "fatigue/weakness" in both women receiving 2 different breast implants, 17.20% in women receiving silicone breast implants and 24.71% in women receiving saline breast implants. Of note, in all the reports, there was a wide variation in the timing of reporting as compared with the timing of the adverse event. CONCLUSIONS: Although the adverse events of breast implant cannot completely be determined from this study, we provide a reference for women who want to get breast implants, so that they can choose breast implants more carefully. In addition, a better understanding of BII may allow them to think further about whether the benefits of breast implants outweigh the risks.

Polylysine-modified near-infrared-emitting carbon dots assemblies: Amplification of tumor accumulation for enhanced tumor photothermal therapy.

A key challenge to enhance the therapeutic outcome of photothermal therapy (PTT) is to improve the efficiency of passive targeted accumulation of photothermal agents at tumor sites. Carbon dots (CDs) are an ideal choice for application as photothermal agents because of their advantages such as adjustable fluorescence, high photothermal conversion efficiency, and excellent biocompatibility. Here, we synthesized polylysine-modified near-infrared (NIR)-emitting CDs assemblies (plys-CDs) through post-solvothermal reaction of NIR-emitting CDs with polylysine. The encapsulated structure of plys-CDs was confirmed by determining morphological, chemical, and luminescent properties. The particle size of CDs increased to approximately 40 ± 8 nm after polylysine modification and was within the size range appropriate for achieving superior enhanced permeability and retention effect. Plys-CDs maintained a high photothermal conversion efficiency of 54.9 %, coupled with increased tumor site accumulation, leading to a high efficacy in tumor PTT. Thus, plys-CDs have a great potential for application in photothermal ablation therapy of tumors.

Collective behavior of squirmers in thin films.

Bacteria in biofilms form complex structures and can collectively migrate within mobile aggregates, which is referred to as swarming. This behavior is influenced by a combination of various factors, including morphological characteristics and propulsive forces of swimmers, their volume fraction within a confined environment, and hydrodynamic and steric interactions between them. In our study, we employ the squirmer model for microswimmers and the dissipative particle dynamics method for fluid modeling to investigate the collective motion of swimmers in thin films. The film thickness permits a free orientation of non-spherical squirmers, but constraints them to form a two-layered structure at maximum. Structural and dynamic properties of squirmer suspensions confined within the slit are analyzed for different volume fractions of swimmers, motility types (e.g., pusher, neutral squirmer, puller), and the presence of a rotlet dipolar flow field, which mimics the counter-rotating flow generated by flagellated bacteria. Different states are characterized, including a gas-like phase, swarming, and motility-induced phase separation, as a function of increasing volume fraction. Our study highlights the importance of an anisotropic swimmer shape, hydrodynamic interactions between squirmers, and their interaction with the walls for the emergence of different collective behaviors. Interestingly, the formation of collective structures may not be symmetric with respect to the two walls. Furthermore, the presence of a rotlet dipole significantly mitigates differences in the collective behavior between various swimmer types. These results contribute to a better understanding of the formation of bacterial biofilms and the emergence of collective states in confined active matter.

Optimal power-heat-carbon scheduling strategy for interconnected heterogeneous multi-microgrid considering hydrogen fuel cell vehicles.

The scale of multi-microgrid (MMG) and hydrogen fuel cell vehicles (HFCVs) is increasing dramatically with the increase in the new energy penetration ratio, and developing an integrated energy system containing a multi-microgrid for hydrogen fuel vehicles brings great challenges to power grid operation. Focusing on the difficulties of the access of multiple microgrids for the low-carbon and economic operation of the system, this paper proposes an optimal interconnected heterogeneous multi-microgrid power-heat-carbon scheduling strategy for hydrogen-fueled vehicles. Firstly, an HFCV model is established, and then an optimal scheduling model is constructed for the cooperative trading of power-heat-carbon in a multi-microgrid, on the basis of which the low-carbon economic operation of the multi-microgrid is realized. The results of the case study show that the scheduling strategy in this paper reduces carbon emissions by about 7.12% and costs by about 3.41% compared with the independent operation of the multi-microgrid. The degrees of interaction of each multi-microgrid are also analyzed under different HFCV penetration rates.

Epigenetic modifications in the development of bronchopulmonary dysplasia: a review.

While perinatal medicine advancements have bolstered survival outcomes for premature infants, bronchopulmonary dysplasia (BPD) continues to threaten their long-term health. Gene-environment interactions, mediated by epigenetic modifications such as DNA methylation, histone modification, and non-coding RNA regulation, take center stage in BPD pathogenesis. Recent discoveries link methylation variations across biological pathways with BPD. Also, the potential reversibility of histone modifications fuels new treatment avenues. The review also highlights the promise of utilizing mesenchymal stem cells and their exosomes as BPD therapies, given their ability to modulate non-coding RNA, opening novel research and intervention possibilities. IMPACT: The complexity and universality of epigenetic modifications in the occurrence and development of bronchopulmonary dysplasia were thoroughly discussed. Both molecular and cellular mechanisms contribute to the diverse nature of epigenetic changes, suggesting the need for deeper biochemical techniques to explore these molecular alterations. The utilization of innovative cell-specific drug delivery methods like exosomes and extracellular vesicles holds promise in achieving precise epigenetic regulation.

The association between psychological distress, abusive experiences, and help-seeking among people with intimate partner violence.

BACKGROUND: Intimate partner violence (IPV) is a serious public health problem associated with countless adverse physical and mental health outcomes. It places an enormous economic and public health burden on communities. The aim of this study was to examine the associations between psychological states (such as depression or hopeless) and help-seeking experiences of IPV survivors after experiencing IPV, based on the Allegheny County Health Survey (ACHS). METHODS: Data from 2015 to 2016 Allegheny County Health Survey with N = 8,012 adults were analyzed. The 6-item version of the Kessler Psychological Stress Scale, located in Module 11 of the ACHS questionnaire, was used to measure psychological stress in participants. Module 12 of the ACHS questionnaire collected information on participants' experiences of intimate partner violence and help-seeking in the past 12 months. Descriptive statistical analysis, Pearson's chi-square or two sample independent t-tests statistical analysis, and multivariate binary logistic regression models were used to analyze the relationship between IPV experience and psychological distress. RESULTS: A total of 212 of the 8,012 participants had IPV experience, with age, marital status, education, income, and race significantly different from those without IPV experience. The psychological stress of participants feeling hopeless (OR = 2.02, 95% CI = 1.37-2.99), restless or fidgety (OR = 1.83, 95% CI = 1.27-2.65), perceiving everything was an effort (OR = 1.55, 95% CI = 1.08-2.22) and worthless (OR = 1.49, 95% CI = 1.01-2.20) was associated with the IPV experience. Help-seeking behaviors of IPV survivors were associated with psychological distress, such as hopelessness (OR = 6.71, 95% CI = 1.38-32.60). CONCLUSIONS: This study explored the association between IPV experience, help-seeking and psychological distress, and the need to expand community support. It is necessary to implement targeted interventions, enhance training of professionals, and promote the identification of early IPV cases as well as collaboration between healthcare and social support departments to reduce the occurrence of IPV or psychological distress following IPV.

Mitochondrial DNA Leakage and cGas/STING Pathway in Microglia: Crosstalk Between Neuroinflammation and Neurodegeneration.

Neurodegenerative diseases, characterized by abnormal deposition of misfolded proteins, often present with progressive loss of neurons. Chronic neuroinflammation is a striking hallmark of neurodegeneration. Microglia, as the primary immune cells in the brain, is the main type of cells that participate in the formation of inflammatory microenvironment. Cytoplasmic free mitochondrial DNA (mtDNA), a common component of damage-associated molecular patterns (DAMPs), can activate the cGas/stimulator of interferon genes (STING) signalling, which subsequently produces type I interferon and proinflammatory cytokines. There are various sources of free mtDNA in microglial cytoplasm, but mitochondrial oxidative stress accumulation plays the vital role. The upregulation of cGas/STING pathway in microglia contributes to the abnormal and persistent microglial activation, accompanied by excessive secretion of neurotoxic inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which exacerbates the damage of neurons and promotes the development of neurodegeneration. Currently, novel therapeutic approaches need to be found to delay the progression of neurodegenerative disorders, and regulation of the cGas/STING signaling in microglia may be a potential target.

Near Full-Length Genome Characterization of Two Novel Unique Recombinants (CRF01_AE/CRF07_BC) in Beijing, China.

With the prevalence of human immunodeficiency virus type 1 (HIV-1) CRF01_AE and CRF07_BC subtypes in China, the co-circulation of multiple subtypes in the HIV-1-positive population may result in dual infection or superinfection in the population, leading to the emergence of unique recombinant forms (URFs) of the HIV-1 virus. In this study, two second-generation unique recombinant strains, BI0114 and BI0116, were identified, and their near full-length genome sequences were obtained. Recombination analysis showed that both sequences were isoforms of URF_0107, and they were second-generation unique recombinant strains formed by the recombination of CRF01_AE and CRF07_BC, with the isoforms being CRF01_AE and CRF0107_BC, respectively. The continued emergence of novel CRF01_AE/CRF07_BC recombinant strains suggests that the epidemiological, preventive, and control situation of HIV-1 is complex and that the relevant health authorities urgently need to establish responses to the challenges posed by changes in the pattern of strain recombination.

Clinical features and surgical treatments of scoliosis in neurofibromatosis type 1: a systemic review and meta-analysis.

BACKGROUND: Neurofibromatosis type 1 (NF 1) is an autosomal-dominant tumor predisposition genetic disease affecting approximately 1 in 3000 live births. The condition could present various manifestations ranging from skin abnormalities to neurological tumors. The musculoskeletal system could also be frequently affected, and scoliosis is the most common orthopedic manifestation. Characterized by the early-onset and rapid progression tendency, NF 1-related dystrophic scoliosis presented discrepancies from idiopathic scoliosis in terms of natural history, clinical features, and management outcomes and thus required special attention. In the current study, the authors conducted a systemic review to outline the body of evidence of the natural history, clinical characteristics, surgical outcomes, and surgical complications of NF 1-induced scoliosis, aiming to provide an elucidative insight into this condition. METHOD: Systemic review and meta-analysis were conducted according to the latest Preferred Reporting Items for Systematic Reviews Meta-Analyses (PRISMA) guidelines. The search was performed in Medline, Embase, and Web of Science Core Collection up to December 27, 2022, using related keywords. Clinical features such as frequencies, segmental involvement, and hereditary information were summarized and described qualitatively. Meta-analysis was conducted using R software and the 'meta' package to yield an overall outcome of efficacy and safety of surgical management, precisely, spinal fusion procedure and growing rods procedure. Corrective rate of Cobb angle, sagittal kyphosis angle, and T1-S1 length post-operative and at the last follow-up was used to evaluate the efficacy, and the occurrence of surgery-related complications was used to evaluate the safety. RESULT: A total of 37 articles involving 1023 patients were included. Approximately 26.6% of the NF 1 patients would present with scoliosis. Patients tend to develop scoliosis at an earlier age. The thoracic part turned out to be the most affected segment. No obvious correlation between scoliosis and genotype or hereditary type was observed. Both spinal fusion and growing rod surgery have shown acceptable treatment outcomes, with spinal fusion demonstrating better performance in terms of effectiveness and safety. The growing rods technique seemed to allow a better lengthening of the spine. The mainstay post-operative complications were implant-related complications but could be managed with limited revision surgery. Severe neurological deficits were rarely reported. CONCLUSION: Scoliosis, especially the subtype characterized by dystrophic bony changes, is a significant orthopedic manifestation of NF1. It has an early onset, a tendency to persistently and rapidly progress, and is challenging to deal with. The current review outlines the available evidence from the perspective of natural history, clinical features, and the treatment efficacy and safety of the mainstay surgical options. Patients with NF1 scoliosis will benefit from a better understanding of the disease and evidence based treatment strategies.

Machine learning-based exosome profiling of multi-receptor SERS sensors for differentiating adenocarcinoma in situ from early-stage invasive adenocarcinoma.

Exosomes, extracellular vesicles released by cells, hold potential as diagnostic markers for the early detection of lung cancer. Despite their clinical promise, current technologies lack rapid and effective means to discriminate between exosomes derived from adenocarcinoma in situ (AIS) and early-stage invasive adenocarcinoma (IAC). This challenge arises from the intrinsic structural heterogeneity of exosomes, necessitating the development of advanced methodologies for precise differentiation. Here, we demonstrate a novel approach for plasma exosome detection utilizing multi-receptor surface-enhanced Raman spectroscopy (SERS) technology to differentiate between AIS and early-stage IAC. To accomplish this, we synthesized a stable and uniform two-dimensional SERS substrate (BC/Au NPs film) by fabricating gold nanoparticles onto bacterial cellulose. We then enhanced its capabilities by introducing multi-receptor SERS functionality via modifying the substrate with both low-specificity and physicochemical-selective molecules. Furthermore, by strategically combining all capturer-exosome SERS spectra, comprehensive "combined-SERS spectra" are reconstructed to enhance spectral variations of the exosome. Combining these features with partial least squares regression-discriminant analysis (PLS-DA) modeling significantly improved discriminatory accuracy, achieving 90% sensitivity and 95% specificity in distinguishing AIS from early-stage IAC. Our developed SERS sensor provides an effective method for early detection of lung cancer, thereby paving a new way for innovative advancements in diagnosing lung cancer.

Comprehensive characterization of ERV-K (HML-8) in the chimpanzee genome revealed less genomic activity than humans.

Endogenous retroviruses (ERVs) originate from ancestral germline infections caused by exogenous retroviruses. Throughout evolution, they have become fixed within the genome of the animals into which they were integrated. As ERV elements coevolve with the host, they are normally epigenetically silenced and can become upregulated in a series of physiological and pathological processes. Generally, a detailed ERV profile in the host genome is critical for understanding the evolutionary history and functional performance of the host genome. We previously characterized and cataloged all the ERV-K subtype HML-8 loci in the human genome; however, this has not been done for the chimpanzee, the nearest living relative of humans. In this study, we aimed to catalog and characterize the integration of HML-8 in the chimpanzee genome and compare it with the integration of HML-8 in the human genome. We analyzed the integration of HML-8 and found that HML-8 pervasively invaded the chimpanzee genome. A total of 76 proviral elements were characterized on 23/24 chromosomes, including detailed elements distribution, structure, phylogeny, integration time, and their potential to regulate adjacent genes. The incomplete structure of HML-8 proviral LTRs will undoubtedly affect their activity. Moreover, the results indicated that HML-8 integration occurred before the divergence between humans and chimpanzees. Furthermore, chimpanzees include more HML-8 proviral elements (76 vs. 40) and fewer solo long terminal repeats (LTR) (0 vs. 5) than humans. These results suggested that chimpanzee genome activity is less than the human genome and that humans may have a better ability to shape and screen integrated proviral elements. Our work is informative in both an evolutionary and a functional context for ERVs.

Generating single-cell gene expression profiles for high-resolution spatial transcriptomics based on cell boundary images.

In spatially resolved transcriptomics, Stereo-seq facilitates the analysis of large tissues at the single-cell level, offering subcellular resolution and centimeter-level field-of-view. Our previous work on StereoCell introduced a one-stop software using cell nuclei staining images and statistical methods to generate high-confidence single-cell spatial gene expression profiles for Stereo-seq data. With advancements allowing the acquisition of cell boundary information, such as cell membrane/wall staining images, we updated our software to a new version, STCellbin. Using cell nuclei staining images, STCellbin aligns cell membrane/wall staining images with spatial gene expression maps. Advanced cell segmentation ensures the detection of accurate cell boundaries, leading to more reliable single-cell spatial gene expression profiles. We verified that STCellbin can be applied to mouse liver (cell membranes) and Arabidopsis seed (cell walls) datasets, outperforming other methods. The improved capability of capturing single-cell gene expression profiles results in a deeper understanding of the contribution of single-cell phenotypes to tissue biology. Availability & Implementation: The source code of STCellbin is available at https://github.com/STOmics/STCellbin.

Preparation of cellulose-based flexible SERS and its application for rapid and ultra-sensitive detection of thiram on fruits and vegetables.

In response to the prevalent issue of thiram as a common pesticide residue on the surface of fruits and vegetables, our research team employed an acidic hydrated metal salt low co-fusion solvent to dissolve cellulose lysis slurry. Subsequently, a regenerated cellulose membrane (RCM) was successfully prepared via sol-gel method. Uniformly sized Ag nanoparticles (NPs) were deposited on RCM utilizing the continuous ion layer adsorption and reaction (SILAR) technique. The resulting Ag NPs/RCM flexible surface-enhanced Raman spectroscopy (SERS) substrates exhibited a minimum detection limit of 5 × 10-9 M for Rhodamine 6G (R6G), demonstrating good uniformity (RSD = 4.86 %) and reproducibility (RSD = 3.07 %). Moreover, the substrate displayed a remarkable sensitivity of 10-10 M toward thiram standard solution. Given its inherent flexibility, the substrate proves advantageous for the detection of three-dimensional environments such as fruit and vegetable surfaces, and its practicality has been confirmed in the detection of thiram residue on apples, tomatoes, pears, and other fruits and vegetables.

2'-Hydroxychalcone Induces Autophagy and Apoptosis in Breast Cancer Cells via the Inhibition of the NF-κB Signaling Pathway: In Vitro and In Vivo Studies.

2'-Hydroxychalcone is a hydroxyl derivative of chalcones, which are biosynthetic precursors of flavonoids and rich in the human diet. The anticancer activity of 2'-hydroxychalcone has been reported in several cancers but remains to be investigated in breast cancer. In the current study, 2'-hydroxychalcone showed significant cytotoxicity against breast cancer cell lines MCF-7 and CMT-1211. It could inhibit breast cancer cell proliferation, migration, and invasion in vitro and suppress tumor growth and metastasis in vivo. Mechanistic investigation revealed that the NF-κB pathway was significantly inhibited by 2'-hydroxychalcone treatment accompanied by an excessive intracellular accumulation of reactive oxygen species, induction of endoplasmic reticulum stress, and activation of JNK/MAPK. In addition, 2'-hydroxychalcone elevated the autophagic levels in breast cancer cells equipped with increasing numbers of autophagy vesicles and complete autophagic flux. Finally, autophagy-dependent apoptosis was observed in 2'-hydroxychalcone-induced cell death. In conclusion, 2'-hydroxychalcone enhances the autophagic levels and induces apoptosis in breast cancer cells, which could be contributed to the inhibition of the pro-survival NF-κB signaling, indicating a promising potential for 2'-hydroxychalcone in future anticancer drug development.

3-N-butylphthalide attenuates neuroinflammation in rotenone-induced Parkinson's disease models via the cGAS-STING pathway.

Neuroinflammation is crucial in the onset and progression of dopaminergic neuron loss in Parkinson's disease (PD). We aimed to determine whether 3-N-Butylphthalide (NBP) can protect against PD by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and the inflammatory response of microglia. MitoSOX/MitoTracker/Hoechst staining was used to detect the levels of mitochondrial reactive oxygen species (ROS) in BV2 cells. Quantitative Real-Time Polymerase Chain Reaction was used to measure the levels of free cytoplasmic mitochondrial DNA (mtDNA) in BV2 cells and mouse brain tissues. Behavioral impairments were assessed using rotarod, T-maze, and balance beam tests. Dopaminergic neurons and microglia were observed using immunohistochemical staining. Expression levels of cGAS, STING, nuclear factor kappa-B (NfκB), phospho- NfκB (p-NfκB), inhibitor of NfκBα (IκBα), and phospho-IκBα (p-IκBα) proteins in the substantia nigra and striatum were detected using Western Blot. NBP decreased mitochondrial ROS levels in rotenone-treated BV2 cells. NBP alleviated behavioral impairments and protected against rotenone-induced microgliosis and damage to dopaminergic neurons in the substantia nigra and striatum of rotenone-induced PD mice. NBP decreased rotenone-induced mtDNA leakage and mitigated neuroinflammation by inhibiting cGAS-STING pathway activation. NBP exhibited a protective effect in rotenone-induced PD models by significantly inhibiting the cGAS-STING pathway. Moreover, NBP can alleviate neuroinflammation, and is a potential therapeutic drug for alleviating clinical symptoms and delaying the progression of PD. This study provided insights for the potential role of NBP in PD therapy, potentially mitigating neurodegeneration, and consequently improving the quality of life and lifespan of patients with PD. The limitations are that we have not confirmed the exact mechanism by which NBP decreases mtDNA leakage, and this study was unable to observe the actual clinical therapeutic effect, so further cohort studies are required for validation.

TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression.

TNFα and IFNγ (TNF/IFNγ) synergistically induce caspase-8 activation and cancer cell death. However, the mechanism of IFNγ in promoting TNF-initiated caspase-8 activation in cancer cells is poorly understood. Here, we found that in addition to CASP8, CYLD is transcriptionally upregulated by IFNγ-induced transcription factor IRF1. IRF1-mediated CASP8 and CYLD upregulation additively mediates TNF/IFNγ-induced cancer cell death. Clinically, the expression levels of TNF, IFNγ, CYLD, and CASP8 in melanoma tumors are increased in patients responsive to immune checkpoint blockade (ICB) therapy after anti-PD-1 treatment. Accordingly, our genetic screen revealed that ELAVL1 (HuR) is required for TNF/IFNγ-induced caspase-8 activation. Mechanistically, ELAVL1 binds CASP8 mRNA and extends its stability to sustain caspase-8 expression both in IFNγ-stimulated and in basal conditions. Consequently, ELAVL1 determines death receptors-initiated caspase-8-dependent cell death triggered from stimuli including TNF and TRAIL by regulating basal/stimulated caspase-8 levels. As caspase-8 is a master regulator in cell death and inflammation, these results provide valuable clues for tumor immunotherapy and inflammatory diseases.