Mutual regulation of microglia and astrocytes after Gas6 inhibits spinal cord injury.

JOURNAL/nrgr/04.03/01300535-202502000-00032/figure1/v/2024-05-28T214302Z/r/image-tiff Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury. Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction. However, the mechanisms involved remain unclear. In this study, we found that after spinal cord injury, resting microglia (M0) were polarized into pro-inflammatory phenotypes (MG1 and MG3), while resting astrocytes were polarized into reactive and scar-forming phenotypes. The expression of growth arrest-specific 6 (Gas6) and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury. In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia, and even inhibited the cross-regulation between them. We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway. This, in turn, inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways. In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord, thereby promoting tissue repair and motor function recovery. Overall, Gas6 may play a role in the treatment of spinal cord injury. It can inhibit the inflammatory pathway of microglia and polarization of astrocytes, attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment, and thereby alleviate local inflammation and reduce scar formation in the spinal cord.

Perilipin-2 mediates ferroptosis in oligodendrocyte progenitor cells and myelin injury after ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202507000-00024/figure1/v/2024-09-09T124005Z/r/image-tiff Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination. Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage. Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation, and plays an important role in the pathological process of ischemic stroke. However, there are few studies on oligodendrocyte progenitor cell ferroptosis. We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia. Bioinformatics analysis suggested that perilipin-2 (PLIN2) was involved in oligodendrocyte progenitor cell ferroptosis. PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation. For further investigation, we established a mouse model of cerebral ischemia/reperfusion. We found significant myelin damage after cerebral ischemia, as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area. The ferroptosis inhibitor, ferrostatin-1, rescued oligodendrocyte progenitor cell death and subsequent myelin injury. We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells. Plin2 knockdown rescued demyelination and improved neurological deficits. Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.

Targeted/untargeted metabolomics and antioxidant properties distinguish Citrus reticulata 'Chachi' from Citrus reticulata Blanco.

Dried citrus peel (DCP), also called "Chen Pi", has edible and medicinal value. However, the specific differences among various sources remain unknown. Herein, we collected six DCP species, namely, one Citrus reticulata 'Chachi' (CZG) and five Citrus reticulata Blanco (CRB). Targeted high-performance liquid chromatography and untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry were employed to comprehensively compare the phenolic compounds and metabolites in DCP. Interestingly, 13 different phenolic compounds were noted in DCP. The total phenolic compound content in all CRB samples (58.86-127.65 mg/g) was higher than that of CZG (39.47 mg/g). Untargeted metabolomic revealed 1495 compounds, with 115 differentially expressed metabolites for CRBs and CZG, particularly flavonoids (38), terpenoids (15), and phenolic acids and derivatives (9). Lastly, antioxidant assays revealed that all CRB samples exhibited higher antioxidant activities compared with CZG. Therefore, our study results provide a theoretical basis for the high-value utilization of citrus peels and their metabolites.

Dissolved organic matter characteristics linked to bacterial community succession and nitrogen removal performance in woodchip bioreactors.

Woodchip bioreactors are an eco-friendly technology for removing nitrogen (N) pollution. However, there needs to be more clarity regarding the dissolved organic matter (DOM) characteristics and bacterial community succession mechanisms and their association with the N removal performance of bioreactors. The laboratory woodchip bioreactors were continuously operated for 360 days under three influent N level treatments, and the results showed that the average removal rate of TN was 45.80 g N/(m3·day) when the influent N level was 100 mg N/L, which was better than 10 mg N/L and 50 mg N/L. Dynamic succession of bacterial communities in response to influent N levels and DOM characteristics was an important driver of TN removal rates. Medium to high N levels enriched a copiotroph bacterial module (Module 1) detected by network analysis, including Phenylobacterium, Xanthobacteraceae, Burkholderiaceae, Pseudomonas, and Magnetospirillaceae, carrying N-cycle related genes for denitrification and ammonia assimilation by the rapid consumption of DOM. Such a process can increase carbon limitation to stimulate local organic carbon decomposition to enrich oligotrophs with fewer N-cycle potentials (Module 2). Together, this study reveals that the compositional change of DOM and bacterial community succession are closely related to N removal performance, providing an ecological basis for developing techniques for N-rich effluent treatment.

Interpersonal interactions, sense of loneliness and perceived depressive emotions among older adults: A cultural-psychological perspective from heterogeneous roles of different relationships.

In the context of the "Chinese Differential Mode of Association" in traditional Chinese culture, this paper examines the heterogeneous effects of interpersonal interactions in different relationships on older adults' depressive emotions from a cultural-psychological perspective. Results using data from Chinese General Social Survey demonstrate that: interactions with children are the most helpful in reducing perceived depression for the elderly, followed by communications with siblings and relatives. However, interactions with friends and other fellows do not significantly reduce older people's perceived depression. This reflects the "Chinese Differential Mode of Association" in interpersonal relationships. When using different perceived depression measures, and Double Debiased Machine Learning (DDML) approaches for robustness and endogeneity tests, above findings are very robust. The impact mechanism is that interactions with children and siblings reduce depressive emotions by decreasing older adults' sense of loneliness, while communications with others do not have such a significant effect. This paper further discusses the roles of different types of interactions with adult children. It is found that receiving and providing emotional support can prominently decrease depressive emotions for older people, whereas the effects of monetary support and non-material assistance are less pronounced. In addition, interpersonal interactions' impacts are more significant for those who are female, older than 75 and with poorer health, as well as older people who exercise less frequently, have higher social status, and hold more traditional beliefs. In the current context of active promotion of healthy aging, findings of this paper have important implications for a deeper understanding and scientific management of depressive emotions among the elderly.

Semi-synthetic chondroitin sulfate CS-semi5 upregulates miR-122-5p, conferring a therapeutic effect on osteoarthritis via the p38/MMP13 pathway.

Osteoarthritis (OA) is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage. Traditional treatments for OA are limited to alleviating various OA symptoms. There is a lack of drugs available in clinical practice that can truly repair cartilage damage. Here, we developed the chondroitin sulfate analog CS-semi5, semi-synthesized from chondroitin sulfate A. In vivo, CS-semi5 alleviated inflammation, provided analgesic effects, and protected cartilage in the modified Hulth OA rat model and papain-induced OA rat model. A bioinformatics analysis was performed on samples from OA patients and an exosome analysis on papain-induced OA rats, revealing miR-122-5p as the key regulator associated with CS-semi5 in OA treatment. Binding prediction revealed that miR-122-5p acted on the 3'-untranslated region of p38 mitogen-activated protein kinase, which was related to MMP13 regulation. Subsequent in vitro experiments revealed that CS-semi5 effectively reduced cartilage degeneration and maintained matrix homeostasis by inhibiting matrix breakdown through the miR-122-5p/p38/MMP13 axis, which was further validated in the articular cartilage of OA rats. This is the first study to investigate the semi-synthesized chondroitin sulfate CS-semi5, revealing its cartilage-protecting, anti-inflammatory, and analgesic properties that show promising therapeutic effects in OA via the miR-122-5p/p38/MMP13 pathway.

Integrating network analysis and experimental validation to reveal the mechanism of si-jun-zi decoction in the treatment of renal fibrosis.

Treating kidney diseases from the perspective of spleen is an important clinical method in traditional Chinese medicine (TCM) for anti-renal fibrosis (RF). Si-jun-zi decoction (SJZD), a classic formula for qi-invigorating and spleen-invigorating, has been reported to alleviate RF. This study aims to investigate the potential mechanism by which SJZD attenuates RF. The results demonstrated notable improvements in renal function levels, inflammation and fibrosis indices in UUO-mice following SJZD intervention. The main active ingredients identified were Quercetin, Kaempferol, Naringenin and 7-Methoxy-2-methyl isoflavone. Furthermore, STAT3, MAPK3, MYC were confirmed as key targets. Additionally, GO enrichment analysis demonstrated that SJZD delayed RF primarily by regulating oxidative stress and other biological mechanisms. KEGG enrichment analysis revealed the involvement of pathways such as Lipid and atherosclerosis signaling pathway, MAPK signaling pathway and other pathways in the reno-protective effects of SJZD. The molecular docking results revealed that the active ingredients of SJZD were well-bound and stable to the core targets. The experiments results revealed that Quercetin, Kaempferol, and Naringenin not only improved the morphology of TGF-ß-induced HK-2 cells but also reversed the expression of α-SMA, COL1A1 and MAPK, thereby delaying the progression of RF. The anti-RF effects of SJZD were exerted through multi-components, multi-targets and multi-pathways.

Prediction of water level at Huayuankou station based on rating curve.

The construction of large reservoirs has modified the process of water and sediment transport downstream, resulting in changes in the morphology of the river cross-section. Changes in water and sand transport and cross-sectional morphology are reflected in the rating curve at the cross-section. This study analyzed the variations in the rating curve at the Huayuankou (HYK) section and their influencing factors, and conducted water level predictions based on this relationship. The findings revealed that while the annual mean water level has shown a declining tendency over the past 20 years, the annual mean discharge has shown a constant pattern. The rating curve at this stretch narrowed from a rope-loop type curve in its natural condition to a more stable single curve as a result of the construction of the dam upstream of the HYK section. The effect of pre-flood section morphology and the water-sediment process on the scattering degree of the rating curve is inverse; increasing roughness and hydraulic radius decreases scattering degree, while increasing sand content and sand transport rate increases scattering degree. Using the measured data from 2020 as an example, the feasibility of predicting cross-sectional water levels using the rating curve was verified. The prediction results were accurate when the flow was between 1000 and 2800 m3/s; However, when the flow was between 2800 and 4000 m3/s, the forecast results were typically slightly lower than the measured values. Overall, the method demonstrates good predictive accuracy. Insight from the method can be used to predict water levels to better inform decision making about water resources management, and flood emergency response in the lower Yellow River.

Development of Neural Cells and Spontaneous Neural Activities in Engineered Brain-Like Constructs for Transplantation.

Stem cell transplantation has demonstrated efficacy in treating neurological disorders by generating functional cells and secreting beneficial factors. However, challenges remain for current cell suspension injection therapy, including uncontrollable cell distribution, the potential for tumor formation, and limited ability to treat spatial defects. Therefore, implants with programmable cell development, tailored 3D structure, and functionalized biomaterials have the potential to both control cell distribution and reduce or heal spatial defects. Here, a biomimetic material system comprising gelatin, alginate, and fibrinogen has been developed for neural progenitor cell constructs using 3D printing. The resulting constructs exhibit excellent formability, stability, and developmental functions in vitro, as well as biocompatibility and integration into the hippocampus in vivo. The controllability, reproducibility, and material composition of the constructs show potential for use in personalized stem cell-based therapies for defective neurological disorders, neural development research, disease modeling, and organoid-derived intelligent systems.

The mechanism of action and chemical synthesis of FDA newly approved drug molecules.

In 2023, the U.S. Food and Drug Administration has approved 29 small molecule drugs. These newly approved small molecule drugs possess the distinct scaffolds, thereby exhibiting diverse mechanisms of action and binding modalities. Moreover, the marketed drugs have always been an important source of new drug development and creative inspiration, thereby fostering analogous endeavors in drug discovery that potentially extend to the diverse clinical indications. Therefore, conducting a comprehensive evaluation of drug approval experience and associated information will facilitate the expedited identification of highly potent drug molecules. In this review, we comprehensively summarized the relevant information regarding the clinical applications, mechanisms of action and chemical synthesis of 29 small molecule drugs, with the aim of providing a promising structural basis and design inspiration for pharmaceutical chemists.

Immunogenomic features of radiologically distinctive nodules in multiple primary lung cancer.

OBJECTIVES: To provide molecular and immunological attributes mechanistic insights for the management of radiologically distinctive multiple primary lung cancer (MPLC). METHODS: The Bulk RNA-seq data of MPLC were obtained from our center. The Bulk RNA-seq data and CT images of patients with single primary lung cancer (SPLC) were obtained from GSE103584. Immune infiltration algorithms were performed to investigate the disparities in the immunological microenvironment between the two groups. Single-cell gene analysis was used to explore immune cells composition and communication relationships between cells in MPLC. RESULTS: In MPLC, 11 pure ground-glass opacity nodules (pGGN) and 10 mixed GGN (mGGN) were identified, while in SPLC, the numbers were 18 pGGN and 22 mGGN, respectively. In MPLC, compared to pGGN, mGGN demonstrated a significantly elevated infiltration of CD8+ T cells. Single-cell gene analysis demonstrated that CD8+ T cells play a central role in the signaling among immune cells in MPLC. The transcription factors including MAFG, RUNX3, and TBX21 may play pivotal roles in regulation of CD8+ T cells. Notably, compared to SPLC nodules for both mGGN and pGGN, MPLC nodules demonstrated a significantly elevated degree of tumor-infiltrating immune cells, with this difference being particularly pronounced in mGGN. There was a positive correlation between the proportion of immune cells and consolidation/tumor ratio (CTR). CONCLUSIONS: Our findings provided a comprehensive description about the difference in the immune microenvironment between pGGN and mGGN in early-stage MPLC, as well as between MPLC and SPLC for both mGGN and pGGN. The findings may provide evidence for the design of immunotherapeutic strategies for MPLC.

Induced pluripotent stem cell-derived mesenchymal stem cells enhance acellular nerve allografts to promote peripheral nerve regeneration by facilitating angiogenesis.

Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells. However, adult tissue-derived mesenchymal stem cells encounter various obstacles, including limited tissue sources, invasive acquisition methods, cellular heterogeneity, purification challenges, cellular senescence, and diminished pluripotency and proliferation over successive passages. In this study, we used induced pluripotent stem cell-derived mesenchymal stem cells, known for their self-renewal capacity, multilineage differentiation potential, and immunomodulatory characteristics. We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury. Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation. Furthermore, the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats. Additionally, our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization. Collectively, our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats, offering promising therapeutic strategies for clinical translation.

Continuous Oral Administration of the Superantigen Staphylococcal Enterotoxin C2 Activates Intestinal Immunity and Modulates the Gut Microbiota in Mice.

Staphylococcal Enterotoxin C2 (SEC2), a classical superantigen, is an antitumor immunotherapy agent. However, the injectable formulation of SEC2 limits its clinical application. Here, it is reported that oral administration of SEC2 activates the intestinal immune system and benefits intestinal health in a mouse model. These results indicate that intact SEC2 is detected in the stomach, intestine, and serum after oral administration. Continuous oral administration of SEC2 activates immune cells in gut-associated lymphoid tissues, promoting extensive differentiation and proliferation of CD4+ and CD8+ T cells and CD19+ B cells, leading to increased production of cytokines and secretory immunoglobulin A. SEC2 also enhances intestinal barrier function, as demonstrated by an increased villus length/crypt depth ratio and elevated expression of mucins and tight junction proteins. Additionally, SEC2 indirectly influenced gut microbiota, reinforcing potential probiotics and short-chain fatty acid synthesis. Enhanced differentiation of T and B cells in the spleen, coupled with elevated serum interleukin-2 levels, suggests systemic immune enhancement following oral administration of SEC2. These findings provide a scientific basis for the development of SEC2 as an oral immunostimulant for immune enhancement and anti-tumor immunotherapy.

MYB Transcription Factor CDC5 Activates CBF3 Expression to Positively Regulates Freezing Tolerance via Cooperating With ICE1 and Histone Modification in Arabidopsis.

The freezing temperature greatly limits the growth, development and productivity of plants. The C-repeat/DRE binding factor (CBF) plays a major role in cold acclimation, enabling plants to increase their freezing tolerance. Notably, the INDUCER OF CBF EXPRESSION1 (ICE1) protein has garnered attention for its pivotal role in bolstering plants' resilience against freezing through transcriptional upregulation of DREB1A/CBF3. However, the research on the interaction between ICE1 and other transcription factors and its function in regulating cold stress tolerance is largely inadequate. In this study, we found that a R2R3 MYB transcription factor CDC5 interacts with ICE1 and regulates the expression of CBF3 by recruiting RNA polymerase II, overexpression of ICE1 can complements the freezing deficient phenotype of cdc5 mutant. CDC5 increases the expression of CBF3 in response to freezing. Furthermore, CDC5 influences the expression of CBF3 by altering the chromatin status through H3K4me3 and H3K27me3 modifications. Our work identified a novel component that regulates CBF3 transcription in both ICE1-dependent and ICE1-independent manner, improving the understanding of the freezing signal transduction in plants.

Regional differences in the Association of Healthy Aging with the incidence of falls: an analysis based on the China Health and Retirement Longitudinal Study from 2011 to 2020.

Background: Falls frequently occur among the older adult population. In this study, we examined the variations in fall incidence across different regions over time, focusing on the disparities between urban and rural areas among older adult Chinese individuals, Healthy aging is comprised of five dimensions: (1) absence of chronic diseases, (2) good physical functioning, (3) normal cognitive function, (4) active social participation, and (5) absence of depression. Additionally, we explored the relationship between healthy aging and the occurrence of falls in middle-aged and older adults. Falls are defined as events that occurred within the past two years. Results: Among 9,918 participants, 33.8% lived in urban areas and 23.0% achieved healthy aging. In contrast, 66.2% resided in rural areas with 16.5% achieving healthy aging. In 2011, rural residents had a higher fall incidence rate (17% in rural vs. 13.5% in urban); by 2020, the fall rate remained higher in rural areas (19.5% in rural vs. 17.3% in urban). Unhealthy aging (HR = 1.08, 95%CI: 1.00-1.16) were risk factors for falls. Subgroup analysis revealed that in rural areas, unhealthy aging increased the risk of falls. In urban areas, the increased risk of falls associated with unhealthy aging was not significant (Rural HR = 1.11, 95%CI:1.01-1.22; Urban HR = 1.05, 95%CI: 0.93-1.18). Conclusion: Healthy aging may be more strongly associated with a lower risk of falls in rural areas, while this association might be less pronounced in urban areas due to different environmental and social factors. This highlights the need for environment-specific fall prevention strategies and targeted measures for the older adult.

Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression.

BACKGROUND: Glioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies. METHODS: We conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment. RESULTS: Our research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models. CONCLUSION: This study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.

On-site SERS analysis and intelligent multi-identification of fentanyl class substances by deep machine learning.

As the types of fentanyl class substances continue to grow, a universal SERS sensor is essential for the application of discriminant detection of fentanyl substances. A new nanomaterial SERS sensor-Ag@Au NPs-paper was developed. The SERS sensitivity and stability of Ag@Au NPs-paper were investigated by using R6G molecule, and the results showed that Ag@Au NPs-paper has excellent performance. In combination with visual analysis and machine learning methods, Ag@Au NPs-paper has been successfully applied to the analysis of fentanyl class substances and the component identification of binary fentanyl mixtures, and thus it can be effectively used in food safety, environmental toxicants and other fields.

Biomarkers differentiating regression from progression among untreated cervical intraepithelial neoplasia grade 2 lesions.

BACKGROUND: Cervical intraepithelial neoplasia grade 2 (CIN2) is one of the precursor stages before cervical lesions develop into cervical cancer. The spontaneous development of CIN2 is ambiguous. One part of CIN2 lesions will progress to cervical intraepithelial neoplasia grade 3 or worse (CIN3+), another part will regress to cervical intraepithelial neoplasia grade 1 or less (CIN1-), and the last part will persist. Although the guidelines suggest that CIN2 patients with fertility requirements can be treated conservatively to minimize the risk of infertility and obstetric complications, most CIN2 patients undergo surgical treatment to prevent the progression of the disease, which will lead to over-treatment and unnecessary complications. AIM OF REVIEW: The clinical outcome of CIN2 lesions is unpredictable and depends on histopathological examinations. Thus, it is necessary to identify the biomarkers differentiating regression lesions from progression lesions, which is conducive to supporting individualised treatment. The natural history of CIN2 is commonly regulated by the interaction of human papillomavirus (HPV) viral factors (HPV genotype and viral DNA methylation), host factors (p16/Ki-67 status, host gene methylation effects, human leukocyte antigen subtypes and immune microenvironment) and other factors (vaginal microbiota). KEY SCIENTIFIC CONCEPTS OF REVIEW: This review summarized the biomarkers predicting the spontaneous regression of CIN2, which correlated with HPV infection, the (epi)genetic change of host genes and microenvironment change. However, potential biomarkers must be validated with prospective cohort studies, which should be conducted with expanded enrollment, a longer observational period and the tracking of more patients.