Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

BACKGROUND: Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood. METHODS: This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRT‒PCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions. RESULTS: (1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression. CONCLUSIONS: Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

cGAS-STING, an important signaling pathway in diseases and their therapy.

Since cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism of cGAS-STING signaling pathway in the past decade. Meanwhile, the triggering and transduction mechanisms have been continuously illuminated. cGAS-STING plays a key role in human diseases, particularly DNA-triggered inflammatory diseases, making it a potentially effective therapeutic target for inflammation-related diseases. Here, we aim to summarize the ancient origin of the cGAS-STING defense mechanism, as well as the triggers, transduction, and regulating mechanisms of the cGAS-STING. We will also focus on the important roles of cGAS-STING signal under pathological conditions, such as infections, cancers, autoimmune diseases, neurological diseases, and visceral inflammations, and review the progress in drug development targeting cGAS-STING signaling pathway. The main directions and potential obstacles in the regulating mechanism research and therapeutic drug development of the cGAS-STING signaling pathway for inflammatory diseases and cancers will be discussed. These research advancements expand our understanding of cGAS-STING, provide a theoretical basis for further exploration of the roles of cGAS-STING in diseases, and open up new strategies for targeting cGAS-STING as a promising therapeutic intervention in multiple diseases.

Cisplatin and doxorubicin chemotherapy alters gut microbiota in a murine osteosarcoma model.

The gut microbiota is closely associated with tumor progression and treatment in a variety of cancers. However, the alteration of the gut microbiota during the progression and chemotherapy of osteosarcoma remains poorly understood. This study aimed to explore the relationship between dysbiosis in the gut microbiota during osteosarcoma growth and chemotherapy treatment. We used BALB/c nude mice to establish osteosarcoma xenograft tumor models and administered cisplatin (CDDP) or doxorubicin (DOX) intraperitonially once every 2 days for a total of 5 times to establish effective chemotherapy models. Fecal samples were collected and processed for 16S rRNA sequencing to analyze the composition of the gut microbiota. We observed that the abundances of Colidextribacter, Lachnospiraceae_NK4A136_group, Lachnospiraceae_UCG-010, Lachnospiraceae_UCG-006, and Lachnoclostridium decreased, and the abundances of Alloprevotella and Enterorhabdus increased in the osteosarcoma mouse model group compared to those in the control group. In addition, genera, such as Lachnoclostridium and Faecalibacterium were more abundant in chemotherapy-treated mice than those in saline-treated mice. Additionally, we observed that alterations in some genera, including Lachnoclostridium and Colidextribacter in the osteosarcoma animal model group returned to normal after CDDP or DOX treatment. Furthermore, the function of the gut microbiota was inferred through PICRUSt2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States), which indicated that metabolism-related microbiota was highly enriched and significantly different in each group. These results indicate correlations between dysbiosis of the gut microbiota and osteosarcoma growth and chemotherapy treatment with CDDP or DOX and may provide novel avenues for the development of potential adjuvant therapies.

Emerging trends and focus of research on the relationship between traumatic brain injury and gut microbiota: a visualized study.

Background: Traumatic brain injury (TBI) is one of the most serious types of trauma and imposes a heavy social and economic burden on healthcare systems worldwide. The development of emerging biotechnologies is uncovering the relationship between TBI and gut flora, and gut flora as a potential intervention target is of increasing interest to researchers. Nevertheless, there is a paucity of research employing bibliometric methodologies to scrutinize the interrelation between these two. Therefore, this study visualized the relationship between TBI and gut flora based on bibliometric methods to reveal research trends and hotspots in the field. The ultimate objective is to catalyze progress in the preclinical and clinical evolution of strategies for treating and managing TBI. Methods: Terms related to TBI and gut microbiota were combined to search the Scopus database for relevant documents from inception to February 2023. Visual analysis was performed using CiteSpace and VOSviewer. Results: From September 1972 to February 2023, 2,957 documents published from 98 countries or regions were analyzed. The number of published studies on the relationship between TBI and gut flora has risen exponentially, with the United States, China, and the United Kingdom being representative of countries publishing in related fields. Research has formed strong collaborations around highly productive authors, but there is a relative lack of international cooperation. Research in this area is mainly published in high-impact journals in the field of neurology. The "intestinal microbiota and its metabolites," "interventions," "mechanism of action" and "other diseases associated with traumatic brain injury" are the most promising and valuable research sites. Targeting the gut flora to elucidate the mechanisms for the development of the course of TBI and to develop precisely targeted interventions and clinical management of TBI comorbidities are of great significant research direction and of interest to researchers. Conclusion: The findings suggest that close attention should be paid to the relationship between gut microbiota and TBI, especially the interaction, potential mechanisms, development of emerging interventions, and treatment of TBI comorbidities. Further investigation is needed to understand the causal relationship between gut flora and TBI and its specific mechanisms, especially the "brain-gut microbial axis."

[Status Quo and Prospects of Research on Precision Nursing of Life-Cycle Health and Disease].

With the changing lifestyle and spectrum of diseases among Chinese people, the life-cycle approach to health has been given national strategic importance. Over the past decade, global nursing researchers have gradually started to pay more attention to the research related to precision nursing at different stages of the life cycle. Researchers have applied multi-omics to explore the pathogenesis and novel biomarkers of relevant symptoms in tumor patients or patients with chronic diseases in order to manage symptoms with better precision. However, systematic theories of precision nursing of life-cycle health and disease have not yet been developed, and the research field and its implications still need to be continuously expanded and innovated. In the nursing discipline, the advantages of interdisciplinary integration should be given full play and the precise and effective resolution of life-cycle health problems should be taken as its goal. Through accurately defining key quantitative objective indicators of nursing care, the nursing discipline will be able to achieve early identification of life-cycle health problems, clarify the occurrence and patterns of change in life-cycle health problems, and gain a better understanding of the regulatory mechanisms. Precise and effective nursing-related technologies and products of non-medication and non-surgery nature should be developed to achieve better precision in nursing interventions, thereby effectively promoting recovery from diseases and improving the overall health of the people.

Investigation of long-term symptoms and influencing factors in patients with mild traumatic brain injury: A cross-sectional study.

BACKGROUND: Traumatic brain injury is the leading cause of death and disability in individuals under the age of 45, which places a heavy disease burden on patients and society. However, the prevalence of long-term symptoms in individuals who suffered from mild traumatic brain injury and how psychosocial factors affect their long-term symptoms remain unclear. OBJECTIVE: To determine howpsychosocial factors influence long-term symptomsin individuals who suffered from mild traumatic brain injury as well as the prevalence of long-term symptoms. METHODS: A demographic characteristics questionnaire, adapted self-report questionnaire of family relationship quality, revised Chinese version of the disease perception questionnaire, Rivermead postconcussion syndrome symptom questionnaire, Glasgow Outcome Scale-Extended, and Brief Symptoms Inventory 18 were used to collect data anonymously. Psychosocial factors associated with long-term symptoms in individuals who suffered from mild traumatic brain injury weremeasuredusingmultiple linear regression. RESULTS: More than half of individuals who suffered from mild traumatic brain injury showed at least 1 long-term symptom after injury. Our results indicated that family relationship quality, disease perception, and demographic characteristics were related to the long-term symptoms of individuals who suffered from mild traumatic brain injury. CONCLUSIONS: Our study shows that theprevalence of long-term symptomsfollowingmild traumatic brain injuryishigh. Psychosocial factors are related to patients' long-term symptoms. The findings indicate that healthcare administrators ought to adopt a robust health promotion strategy that prioritizes familial support and health education of diseases to ameliorate long-term symptoms in individuals who suffered from mild traumatic brain injury.

Study on the application effect of the family doctor contract service mode of 'basic package+personalised package' in elderly hypertension management in Chengdu, China: a retrospective observational study.

OBJECTIVES: We conducted this study to assess the application effect of the family doctor contract service mode of 'basic package+personalised package' in the management of hypertension patients. DESIGN: Observational study. SETTING: The study was conducted at a community health centre in Southwest China. Data were collected from 1 January 2018 to 31 December 2020. PARTICIPANTS: From 1 January 2018 to 31 December 2020, hypertensive patients (age ≥65 years) who participated in the contract services of family doctors at a community health service centre in Chengdu, Southwest China, were selected as the study subjects. MAIN OUTCOME MEASURES: The primary outcomes included mean blood pressure (systolic, diastolic) and the rate of blood pressure control, secondary outcomes included the level of cardiovascular disease risk and self-management ability. Assessments of baseline and 6 months after signing up were conducted on all outcomes. The major statistical analysis methods included two independent sample t-tests, paired t-tests, Pearson's χ2 test, McNemar's test, two independent sample Mann-Whitney U tests and paired sample marginal homogeneity tests. RESULTS: Of the 10 970 patients screened for eligibility, 968 (8.8%) were separated into an observation group (receiving 'basic package+personalised package (hypertension)' service) (n=403) and a control group (receiving 'basic package' service) (n=565) according to the type of service package they received. In comparison to the control group, the observation group had lower mean systolic blood pressure (p=0.023), higher blood pressure control rate (p<0.001), lower cardiovascular disease risk level (p<0.001) and higher self-management ability level (p<0.001) at 6 months after signing up. The mean diastolic blood pressure of the two groups was not significantly different (p=0.735). CONCLUSIONS: The family doctor contract service model of 'basic package+personalised package (hypertension)' has a good application effect in the management of elderly hypertension, which can improve the average blood pressure, the rate of blood pressure control, the level of cardiovascular disease risk and self-management ability of the elderly with hypertension.

Research progress of plant-derived natural products in thyroid carcinoma.

Thyroid carcinoma (TC) is a prevalent malignancy of the endocrine system, with a notable rise in its detection rate in recent decades. The primary therapeutic approaches for TC now encompass thyroidectomy and radioactive iodine therapy, yielding favorable prognoses for the majority of patients. TC survivors may necessitate ongoing surveillance, remedial treatment, and thyroid hormone supplementation, while also enduring the adverse consequences of thyroid hormone fluctuations, surgical complications, or side effects linked to radioactive iodine administration, and encountering enduring physical, psychosocial, and economic hardships. In vitro and in vivo studies of natural products against TC are demonstrating the potential of these natural products as alternatives to the treatment of thyroid cancer. This therapy may offer greater convenience, affordability, and acceptability than traditional therapies. In the early screening of natural products, we mainly use a combination of database prediction and literature search. The pharmacological effects on TC of selected natural products (quercetin, genistein, apigenin, luteolin, chrysin, myricetin, resveratrol, curcumin and nobiletin), which hold promise for therapeutic applications in TC, are reviewed in detail in this article through most of the cell-level evidence, animal-level evidence, and a small amount of human-level evidence. In addition, this article explores possible issues, such as bioavailability, drug safety.

Effect of Hypothermia Therapy on Children with Traumatic Brain Injury: A Meta-Analysis of Randomized Controlled Trials.

Hypothermia therapy is a promising therapeutic strategy for traumatic brain injury (TBI); however, some trials have shown that hypothermia therapy has a negative effect on patients with TBI. The treatment of hypothermia in children with TBI remains controversial. We conducted a search of six online databases to validate the literature on comparing hypothermia with normal therapy for children with TBI. Eight randomized controlled trials (514 patients) were included. The meta-analysis indicated that hypothermia therapy may increase the Glasgow Outcome Scale (GOS) scores. However, in terms of improving the rate of complications, intracranial pressure (ICP), mortality, cerebral perfusion pressure (CPP), and length of stay both in hospital as well as pediatric ICU, the difference was not statistically significant. Hypothermia therapy may have clinical advantages in improving the GOS scores in children with TBI compared with normothermic therapy, but hypothermia therapy may have no benefit in improving the incidence of complications, ICP, mortality, CPP, and length of stay both in pediatric ICU as well as hospital. The decision to implement hypothermia therapy for children with TBI depends on the advantages and disadvantages from many aspects and these must be considered comprehensively.

An Endogenous H2S-Activated Nanoplatform for Triple Synergistic Therapy of Colorectal Cancer.

Overproduced hydrogen sulfide (H2S) is a highly potential target for precise colorectal cancer (CRC) therapy; herein, a novel 5-Fu/Cur-P@HMPB nanomedicine is developed by coencapsulation of the natural anticancer drug curcumin (Cur) and the clinical chemotherapeutic drug 5-fluorouracil (5-Fu) into hollow mesoporous Prussian blue (HMPB). HMPB with low Fenton-catalytic activity can react with endogenous H2S and convert into high Fenton-catalytic Prussian white (PW), which can generate in situ a high level of •OH to activate chemodynamic therapy (CDT) and meanwhile trigger autophagy. Importantly, the autophagy can be amplified by Cur to induce autophagic cell death; moreover, Cur also acted as a specific chemosensitizer of the chemotherapy drug 5-Fu, achieving a good synergistic antitumor effect. Such a triple synergistic therapy based on a novel nanomedicine has been verified both in vitro and in vivo to have high efficacy in CRC treatment, showing promising potential in translational medicine.

Long noncoding RNA PVT1 regulates the proliferation and apoptosis of ARPE-19 cells in vitro via the miR-1301-3p/KLF7 axis.

Diabetic retinopathy (DR) as a frequent diabetic microvascular complication shows signs in one-third of diabetic patients. Long non-coding RNAs (lncRNAs) have drawn increasing attention because of their regulatory roles in DR. LncRNA plasmacytoma variant translocation 1 (PVT1) is documented to be upregulated in diabetes-related diseases, while its effects in DR remains unexplored. ARPE-19 cells under the treatment of high-glucose (HG) were used as DR cell models. The gene expression in ARPE-19 cells was examined using RT-qPCR. The viability and apoptosis of ARPE-19 cells were determined by MTT and TUNEL assays. The levels of inflammation-associated proteins or mRNA were measured using western blot. Luciferase reporter assay and RNA pull down assay were conducted for the exploration of the underlying mechanism of PVT1. PVT1 was revealed to be upregulated in DR cell models. Silencing of PVT1 promoted the viability and inhibited apoptosis of HG-stimulated ARPE-19 cells. The results revealed that PVT1 can bind with miR-1301-3p. PVT1 negatively modulated miR-1301-3p expression. Additionally, KLF7 was targeted by miR-1301-3p. PVT1 upregulated KLF7 expression by binding with miR-1301-3p. The silenced PVT1-mediated influence on cell viability and cell apoptosis was rescued by overexpression of KLF7. PVT1 suppresses proliferation and promotes apoptosis of ARPE-19 cells treated with HG in vitro by binding with miR-1301-3p to upregulate KLF7.

A metabolism-related gene signature for predicting the prognosis in thyroid carcinoma.

Metabolic reprogramming is one of the cancer hallmarks, important for the survival of malignant cells. We investigated the prognostic value of genes associated with metabolism in thyroid carcinoma (THCA). A prognostic risk model of metabolism-related genes (MRGs) was built and tested based on datasets in The Cancer Genome Atlas (TCGA), with univariate Cox regression analysis, LASSO, and multivariate Cox regression analysis. We used Kaplan-Meier (KM) curves, time-dependent receiver operating characteristic curves (ROC), a nomogram, concordance index (C-index) and restricted mean survival (RMS) to assess the performance of the risk model, indicating the splendid predictive performance. We established a three-gene risk model related to metabolism, consisting of PAPSS2, ITPKA, and CYP1A1. The correlation analysis in patients with different risk statuses involved immune infiltration, mutation and therapeutic reaction. We also performed pan-cancer analyses of model genes to predict the mutational value in various cancers. Our metabolism-related risk model had a powerful predictive capability in the prognosis of THCA. This research will provide the fundamental data for further development of prognostic markers and individualized therapy in THCA.

Circular Ribonucleic Acid circFTO Promotes Angiogenesis and Impairs Blood-Retinal Barrier Via Targeting the miR-128-3p/Thioredoxin Interacting Protein Axis in Diabetic Retinopathy.

Background: Increasing attention has been attracted by the role of circular RNAs (circRNAs) in ocular diseases. Previous study has revealed that circ_0005941 (also known as circFTO, an alpha-ketoglutarate-dependent dioxygenase) was upregulated in the vitreous humor of diabetic retinopathy (DR), while its underlying mechanism in DR remains unknown. Methods: Retinal vascular endothelial cells (RVECs) treated with high glucose (HG) were used to establish the DR cell model. The in vivo assays were conducted using streptozotocin-induced diabetic mice. The circular structure and stability of circFTO were identified by Sanger sequencing and RNase R treatment. RT-qPCR analysis was used to detect the RNA expression. The levels of the mRNA-encoded protein thioredoxin-interacting protein (TXNIP) or angiogenesis-associated proteins (VEGFA, PDGF, and ANG2) and blood-retinal barrier (BRB)-related proteins (ZO-1, Occludin, and Claudin-5) were measured by Western blot. The viability of RVECs was measured using CCK-8 assays. The angiogenesis of RVECs was assessed using tube formation assays in vitro. Endothelial permeability assays were conducted to examine the function of the BRB. The binding between genes was explored using RNA pulldown and luciferase reporter assays. Results: CircFTO was upregulated in HG-treated RVECs. CircFTO deficiency reversed the HG-induced increase in the viability and angiogenesis of RVECs and alleviated HG-mediated impairment of the BRB. MiR-128-3p bound with circFTO and was downregulated in HG-treated RVECs. TXNIP was a downstream target gene of miR-128-3p. TXNIP was highly expressed in the DR cell model. Rescue assays revealed that circFTO promoted angiogenesis and impaired the blood-retinal barrier by upregulating TXNIP. In the DR mouse model, circFTO silencing inhibited angiogenesis and promoted BRB recovery in vivo. Conclusion: CircFTO promotes angiogenesis and impairs the blood-retinal barrier in vitro and in vivo by binding with miR-128-3p to upregulate TXNIP in DR.