Search

Background: The correlation between the triglyceride-glucose (TyG) index and mortality in the general population remains controversial, with inconsistent conclusions emerging from different studies., Objective: This study aims to investigate whether there is an association between the TyG index and mortality in the general population in the United States, and to explore whether a new index combining the TyG index with systemic inflammation indicators can better predict all-cause and cardiovascular mortality risks in the general population than using the TyG index alone., Methods: Calculate the systemic inflammation indicators and TyG index for each participant based on their complete blood count, as well as their triglyceride and glucose levels in a fasting state. TyG-inflammation indices were obtained by multiplying the TyG index with systemic inflammation indicators (TyG-NLR, TyG-MLR, TyG-lgPLR, TyG-lgSII, and TyG-SIRI). Based on the weighted Cox proportional hazards model, assess whether the TyG and TyG-Inflammation indices are associated with mortality risk in the general population. Restricted cubic splines (RCS) are used to clarify the dose-response relationship between the TyG and TyG-Inflammation indices and mortality, and to visualize the results. Time-dependent receiver operating characteristic (ROC) curves are used to evaluate the accuracy of the TyG and TyG-Inflammation indices in predicting adverse outcomes., Results: This study included 17,118 participants. Over a median follow-up period of 125 months, 2595 patients died. The TyG index was not found to be related to mortality after adjusting for potentially confounding factors. However, the TyG-inflammation indices in the highest quartile (Q4), except for TyG-lgPLR, were significantly associated with both all-cause and cardiovascular mortality, compared to those in the lowest quartile (Q1). Among them, TyG-MLR and TyG-lgSII showed the strongest correlations with all-cause mortality and cardiovascular mortality. Specifically, compared to their respective lowest quartiles (Q1), participants in the highest quartile (Q4) of TyG-MLR had a 48% increased risk of all-cause mortality (95% CI: 1.23-1.77, P for trend < 0.0001), while participants in the highest quartile (Q4) of TyG-lgSII had a 92% increased risk of cardiovascular mortality (95% CI: 1.31-2.81, P for trend < 0.001). Time-dependent ROC curve analysis showed that the TyG-MLR had the highest accuracy in predicting long-term mortality outcomes., Conclusions: The TyG-Inflammation indices constructed based on TyG and systemic inflammation indicators are closely related to mortality in the general population and can better predict the risk of adverse outcomes. However, no association between TyG and mortality in the general population was found., (© 2024. The Author(s).)

Obstructive sleep apnea syndrome (OSAS), a state of sleep disorder, is characterized by repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Previous studies have revealed that intermittent hypoxia (IH) conditions in OSAS patients elicited neuron injury (especially in the hippocampus and cortex), leading to cognitive dysfunction, a significant and extraordinary complication of OSAS patients. The repeated courses of airway collapse and obstruction in OSAS patients resulted in apnea and arousal during sleep, leading to IH and excessive daytime sleepiness (EDS) and subsequently contributing to the development of inflammation. IH-mediated inflammation could further trigger various types of cognitive dysfunction. Many researchers have found that, besides continuous positive airway pressure (CPAP) treatment and surgery, anti-inflammatory substances might alleviate IH-induced neurocognitive dysfunction. Clarifying the role of inflammation in IH-mediated cognitive impairment is crucial for potentially valuable therapies and future research in the related domain. The objective of this article was to critically review the relationship between inflammation and cognitive deficits in OSAS.

Background: In this study, we sought to determine the cellular source of inducible nitric oxide synthase (iNOS) induced in lymphatic endothelial cells (LECs) in response to tumor necrosis factor (TNF), the effects of iNOS on lymphatic smooth muscle cell (LSMC) function and on the development of arthritis in TNF-transgenic (TNF-Tg) mice, and whether iNOS inhibitors improve lymphatic function and reduce joint destruction in inflammatory erosive arthritis., Methods: We used quantitative polymerase chain reactions, immunohistochemistry, histology, and near-infrared imaging to examine (1) iNOS expression in podoplanin + LECs and lymphatic vessels from wild-type (WT) and TNF-Tg mice, (2) iNOS induction by TNF in WT LECs, (3) the effects of iNOS inhibitors on expression of functional muscle genes in LSMCs, and (4) the effects of iNOS inhibitors on lymphatic vessel contraction and drainage, as well as the severity of arthritis, in TNF-Tg mice., Results: LECs from TNF-Tg mice had eight fold higher iNOS messenger RNA levels than WT cells, and iNOS expression was confirmed immunohistochemically in podoplanin + LECs in lymphatic vessels from inflamed joints. TNF (0.1 ng/ml) increased iNOS levels 40-fold in LECs. LSMCs cocultured with LECs pretreated with TNF had reduced expression of functional muscle genes. This reduction was prevented by ferulic acid, which blocked nitric oxide production. Local injection of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide into inflamed paws of TNF-Tg mice resulted in recovery of lymphatic vessel contractions and drainage. Treatment of TNF-Tg mice with ferulic acid reduced synovial inflammation as well as cartilage and bone erosion, and it also restored lymphatic contraction and drainage., Conclusions: iNOS is produced primarily by LECs in lymphatic vessel efferent from inflamed joints of TNF-Tg mice in response to TNF and inhibits LSMC contraction and lymph drainage. Ferulic acid represents a potential new therapy to restore lymphatic function and thus improve inflammatory arthritis by inhibiting local production of nitric oxide by LSMCs.

Background: Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Diverse cellular stimuli create a wide variety of transcription factor activities through signal transduction pathways, resulting in different gene expression patterns. Understanding the relationship between external stimuli and the corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach is needed to integrate experimental data and theoretical hypotheses to identify the physiological consequences of environmental stimuli., Results: We proposed a systematic approach that combines forward and reverse engineering to link the signal transduction cascade with the gene responses. To demonstrate the feasibility of our strategy, we focused on linking the NF-kappaB signaling pathway with the inflammatory gene regulatory responses because NF-kappaB has long been recognized to play a crucial role in inflammation. We first utilized forward engineering (Hybrid Functional Petri Nets) to construct the NF-kappaB signaling pathway and reverse engineering (Network Components Analysis) to build a gene regulatory network (GRN). Then, we demonstrated that the corresponding IKK profiles can be identified in the GRN and are consistent with the experimental validation of the IKK kinase assay. We found that the time-lapse gene expression of several cytokines and chemokines (TNF-alpha, IL-1, IL-6, CXCL1, CXCL2 and CCL3) is concordant with the NF-kappaB activity profile, and these genes have stronger influence strength within the GRN. Such regulatory effects have highlighted the crucial roles of NF-kappaB signaling in the acute inflammatory response and enhance our understanding of the systemic inflammatory response syndrome., Conclusion: We successfully identified and distinguished the corresponding signaling profiles among three microarray datasets with different stimuli strengths. In our model, the crucial genes of the NF-kappaB regulatory network were also identified to reflect the biological consequences of inflammation. With the experimental validation, our strategy is thus an effective solution to decipher cross-talk effects when attempting to integrate new kinetic parameters from other signal transduction pathways. The strategy also provides new insight for systems biology modeling to link any signal transduction pathways with the responses of downstream genes of interest.

Background: Elderly rheumatoid arthritis (ERA) population faces multiple treatment dilemma. Here we aim to investigate if Gancao Nourishing-Yin decoction (GCNY) added to methotrexate (MTX) exhibit better effects in an ERA mice model. Methods: ERA mice model was established by adding D-galactose (Dgal) to collagen-induced arthritis (CIA) mice. The model was then assigned into control group (CIA + Dgal), MTX treatment group (MTX), GCNY treatment group (GCNY), and integrative treatment group (MTX + GCNY). Pathological scoring was performed to evaluate the severity between the groups. Proteomic analysis was applied to investigate the secretory phenotype of the ERA mouse model and the underlying mechanism of GCNY, MTX and their combination. Representative cytokines related to proteomic results were further validated by ELISAs. Results: CIA + Dgal mice showed more aggressive joints damage than the CIA mice. Besides changes in the inflammatory pathway such as Pi3k-Akt signaling pathway in both model, differential expressed proteins (DEPs) indicated metabolism-related pathways were more obvious in CIA + Dgal mice. Low-dose MTX failed to show pathological improvement in CIA + Dgal mice, while GCNY improved joints damage significantly. Besides down-regulated inflammation-related targets, GCNY-regulated DEPs (such as Apoc1 ~ 3, Grk2 and Creb3l3) were broadly enriched in metabolism-related pathways. MTX + GCNY showed the best therapeutic effect, and the DEPs enriched in a variety of inflammatory,metabolism and osteoclast differentiation signaling pathway. Notably, MTX + GCNY treatment up-regulated Dhfr, Cbr1, Shmt1 involved in folic acid biosynthesis and anti-folate resistance pathways indicated a coincidence synergic action. ELISAs confirmed CPR and Akt that elevated in CIA + Dgal mice were significantly ameliorated by treatments, and adding on GCNY elevated folic acid levels and its regulator Dhfr. Conclusion: Aging aggravated joints damage in CIA, which probably due to metabolic changes rather than more severe inflammation. GCNY showed significant effects in the ERA mice model especially when integrated with MTX to obtain a synergic action. [ABSTRACT FROM AUTHOR]

Background: The transcription factor Sox2 plays important roles in the developmental processes of multiple organs and tissues. However, whether Sox2 can protect mature or terminally differentiated cells against injury is still unknown.Methods: We investigated the roles of Sox2 in cochlear hair cells, which are terminally differentiated cells, using conditional transgenic mice and several hearing loss models.Results: Sox2 overexpression dramatically mitigated the degree of cochlear hair cell loss when exposed to ototoxic drugs. Noise-induced apoptosis of cochlear hair cells and hearing loss were also significantly alleviated by Sox2 overexpression. Notably, noise-induced upregulation of pro-inflammatory factors such as TNF-α and IL6 was inhibited by Sox2 overexpression. Then we used lipopolysaccharide to clarify the effect of Sox2 on cochlear inflammation, and Sox2 overexpression significantly inhibited lipopolysaccharide-induced upregulation of pro-inflammatory factors and alleviated inflammation-related cochlear hair cell death.Conclusions: These results demonstrate a novel protective role of Sox2 in mature and terminally differentiated cochlear hair cells by inhibiting inflammation. [ABSTRACT FROM AUTHOR]

Reference 1 Zhang X, Akhtar M, Chen Y. Chicken jejunal microbiota improves growth performance by mitigating intestinal inflammation. B Correction: Microbiome 10, 107 (2022) b B https://doi.org/10.1186/s40168-022-01299-8 b Following the publication of the original article, the author reported that an incorrect video abstract is attached to the article. [Extracted from the article]

Background: Cerebral blood flow (CBF) is known to be dysregulated in persons with human immunodeficiency virus 1 (HIV-1), for uncertain reasons. This is an important issue because impaired vasoreactivity has been associated with increased risk of ischemic stroke, elevated overall cardiovascular risk and cognitive impairment. Methods: To test whether dysregulation of CBF might be due to virally-induced neuroinflammation, we used a well-defined animal model (GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic (Tat-tg) mice). We then exposed the mice to a brief hypercapnic stimulus, and assessed cerebrovascular reactivity by measuring 1) changes in cerebral blood flow, using laser Doppler flowmetry and 2) changes in vascular dilation, using in vivo two-photon imaging. Results: Exposure to brief hypercapnia revealed an underlying cerebrovascular pathology in Tat-tg mice. In control animals, brief hypercapnia induced a brisk increase in cortical flow (20.8% above baseline) and vascular dilation, as measured by laser Doppler flowmetry and in vivo two-photon microscopy. These responses were significantly attenuated in Tat-tg mice (11.6% above baseline), but cortical microvascular morphology and capillary density were unaltered, suggesting that the functional pathology was not secondary to vascular remodeling. To examine the mechanistic basis for the diminished cerebrovascular response to brief hypercapnia, Tat-tg mice were treated with 1) gisadenafil, a phosphodiesterase 5 (PDE5) inhibitor and 2) tetrahydrobiopterin (BH4). Gisadenafil largely restored the normal increase in cortical flow following hypercapnia in Tat-tg mice (17.5% above baseline), whereas BH4 had little effect. Gisadenafil also restored the dilation of small (<25 μm) arterioles following hypercapnia (19.1% versus 20.6% diameter increase in control and Tat-tg plus gisadenafil, respectively), although it failed to restore full dilation of larger (>25 μm) vessels. Conclusions: Taken together, these data show that HIV-associated neuroinflammation can cause cerebrovascular pathology through effects on cyclic guanosine monophosphate (cGMP) metabolism and possibly on PDE5 metabolism. [ABSTRACT FROM AUTHOR]