Remnant cholesterol is superior to other lipid-related parameters for the prediction of cardiometabolic disease risk in individuals with hypertension: The Kailuan study.

BACKGROUND: It is uncertain which lipid-related parameter is most suitable for predicting the risk of cardiometabolic disease (CMD) in individuals with hypertension. AIMS: To explore which lipid-related parameter is most suitable for predicting the risk of CMD. METHODS AND RESULTS: We studied 30,378 patients with hypertension who completed the 2006-2007 Kailuan health examination and followed up until December 31, 2021. In the constructed model, the utilities of lipid-related parameters for the prediction of CMD were compared using the C-index, NRI, and IDI. The best predictor (remnant cholesterol, RC) was identified and the participants were grouped according to RC quartile. Cox proportional hazard analysis was then used to evaluate the relationship between RC and the risk of CMD. During a median follow-up period of 14.7 years (IQR 5.3-15.1), 9502 (31.27 %) participants with hypertension developed CMD. The C-index, NRI, and IDI values for RC were higher than those for the other lipid parameters. After adjustment for multiple potential confounding factors, compared with the quartile (Q)1 RC group, the adjusted hazard ratios for CMD of the Q2-Q4 groups were 1.09 (1.03-1.16), 1.17 (1.11-1.24), and 1.25 (1.18-1.33) (P < 0.0001). Restrictive cubic spline analysis revealed dose-dependent relationships of lipid parameters with the risk of CMD. CONCLUSIONS: RC is superior to other lipid parameters for the prediction of the risk of CMD in individuals with hypertension. As the concentration of RC increases, the risk of CMD in such individuals also increases.

A modified hyaluronic acid hydrogel with strong bacterial capture and killing capabilities for drug-resistant bacteria-infected diabetic wound healing.

Management of diabetic wounds becomes increasingly challenging as bacterial infections intensify the inflammation. Employing polysaccharide hydrogels with inherent antibacterial qualities can significantly reduce the need for antibiotics to manage infections in diabetic wounds. The typical approach to achieving antibacterial outcomes with hydrogels relies on the penetration of bacteria into their porous architecture. Such penetration not only takes time but can also prolong inflammation, thus impeding the healing of wounds. Hence, the quick capture and eradication of bacteria are essential for optimizing the hydrogel's antibacterial performance. Herein, we introduce a multifunctional polysaccharide hydrogel dressing-designated as HAQ-created for managing bacterial infections in diabetic wounds. This dressing is based on hyaluronic acid, which is modified with methacrylic anhydride, and special functional groups are added to the modified hyaluronic acid matrix: phenylboronic acid for capturing bacteria and quaternary ammonium chitosan for bacterial destruction. As expected, the HAQ system exhibits robust antibacterial effectiveness against both methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa in vitro and in vivo. Consequently, HAQ stands as a promising hydrogel dressing with intrinsic antibacterial capabilities and offers significant potential for managing diabetic wounds infected by drug-resistant bacteria.

Update on the intriguing roles of AQP4 expression and redistribution in the progression and treatment of glioma.

Aquaporin 4 (AQP4) is abundant in the human brain and has an important role in brain homeostasis and diseases. AQP4 expression has been found to be associated with glioma malignancies. However, the complete understanding of the biological processes and curative importance of AQP4 in glioma remains unclear. The impact of AQP4 subcellular mislocalization on glioma progression and the precise mechanisms regarding AQP4 translocation in glioma need further investigation. In this review, we update recent findings about disturbed AQP4 expression in glioma and explore targeting AQP4 to modulate the glioma progression. Thereafter we discuss some possible mechanisms of action of AQP4 translocations in glioma. The present article offers an appropriate introduction to the potential involvement of AQP4 in the emergence and progression of glioma. Both comprehensive research into the mechanisms and systematically intervention studies focusing on AQP4 are essential. By embracing this strategy, we can obtain a new and insightful outlook on managing cancerous glioma. Although the observations summarized in this review should be confirmed with more studies, we believe that they could provide critical information for the design of more focused research that will allow for systematic and definitive evaluation of the role of AQP4 in glioma treatments.

Relationship of the trajectory of the triglyceride-glucose index with heart failure: the Kailuan study.

BACKGROUND: A high triglyceride-glucose index (TyG) is associated with a higher risk of incident heart failure. However, the effects of longitudinal patterns of TyG index on the risk of heart failure remain to be characterized. Therefore, in the present study, we aimed to characterize the relationship between the trajectory of TyG index and the risk of heart failure. METHODS: We performed a prospective study of 56,149 participants in the Kailuan study who attended three consecutive surveys in 2006-2007, 2008-2009, and 2010-2011 and had no history of heart failure or cancer before the third wave survey (2010-2011). The TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2], and we used latent mixture modeling to characterize the trajectory of the TyG index over the period 2006-2010. Additionally, Cox proportional risk models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for incident heart failure for the various TyG index trajectory groups. RESULTS: From 2006 to 2010, four different TyG trajectories were identified: low-stable (n = 13,554; range, 7.98-8.07), moderate low-stable (n = 29,435; range, 8.60-8.65), moderate high-stable (n = 11,262; range, 9.31-9.30), and elevated-stable (n = 1,898; range, 10.04-10.25). A total of 1,312 new heart failure events occurred during a median follow-up period of 10.04 years. After adjustment for potential confounders, the hazard ratios (HRs) and 95% confidence intervals (CIs) for incident heart failure for the elevated-stable, moderate high-stable, and moderate low-stable groups were 1.55 (1.15, 2.08), 1.32 (1.08, 1.60), and 1.17 (0.99, 1.37), respectively, compared to the low-stable group. CONCLUSIONS: Higher TyG index trajectories were associated with a higher risk of heart failure. This suggests that monitoring TyG index trajectory may help identify individuals at high risk for heart failure and highlights the importance of early control of blood glucose and lipids for the prevention of heart failure.

Association between the atherogenic index of plasma trajectory and risk of heart failure among hypertensive patients: a prospective cohort study.

BACKGROUND: The atherogenic index of plasma (AIP) has been shown to be positively correlated with cardiovascular events. However, it remains unclear whether hypertensive patients with long-term high AIP levels are at greater risk of developing heart failure (HF). Therefore, the aim of this study was to investigate the association between AIP trajectory and the incidence of HF in hypertensive patients. METHODS: This prospective study included 22,201 hypertensive patients from the Kailuan Study who underwent three waves of surveys between 2006 and 2010. Participants were free of HF or cancer before or during 2010. The AIP was calculated as the logarithmic conversion ratio of triglycerides to high-density lipoprotein cholesterol. Latent mixed modeling was employed to identify different trajectory patterns for AIP during the exposure period (2006-2010). Cox proportional hazard models were then used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for incident HF among different trajectory groups. RESULTS: Four distinct trajectory patterns were identified through latent mixture modeling analysis: low-stable group (n = 3,373; range, -0.82 to -0.70), moderate-low stable group (n = 12,700; range, -0.12 to -0.09), moderate-high stable group (n = 5,313; range, 0.53 to 0.58), and elevated-increasing group (n = 815; range, 1.22 to 1.56). During a median follow-up period of 9.98 years, a total of 822 hypertensive participants experienced HF. After adjusting for potential confounding factors, compared with those in the low-stable group, the HR and corresponding CI for incident HF in the elevated-increasing group, moderate-high stable group, and moderate-low stable group were estimated to be 1.79 (1.21,2.66), 1.49 (1.17,1.91), and 1.27 (1.02,1.58), respectively. These findings remained consistent across subgroup analyses and sensitivity analyses. CONCLUSION: Prolonged elevation of AIP in hypertensive patients is significantly associated with an increased risk of HF. This finding suggests that regular monitoring of AIP could aid in identifying individuals at a heightened risk of HF within the hypertensive population.

Physical Activity Modifies the Risk of Incident Cardiac Conduction Disorders Upon Inflammation: A Population-Based Cohort Study.

BACKGROUND: Emerging evidence suggests a central role for inflammation in cardiac conduction disorder (CCD). It is unknown whether habitual physical activity could modulate the inflammation-associated risks of incident CCD in the general population. METHODS AND RESULTS: This population-based cohort was derived from the China Kailuan study, including a total of 97 192 participants without prior CCD. The end points included incident CCD and its subcategories (atrioventricular block and bundle-branch block). Systemic inflammation was indicated by the monocyte-to-lymphocyte ratio (MLR). Over a median 10.91-year follow-up, 3747 cases of CCD occurred, with 1062 cases of atrioventricular block and 2697 cases of bundle-branch block. An overall linear dose-dependent relationship was observed between MLR and each study end point (all P-nonlinearity≥0.05). Both higher MLR and physical inactivity were significantly associated with higher risks of conduction block. The MLR-associated risks of developing study end points were higher in the physically inactive individuals than in those being physically active, with significant interactions between MLR levels and physical activity for developing CCD (P-interaction=0.07) and bundle-branch block (P-interaction<0.05) found. Compared with those in MLR quartile 2 and being physically active, those in the highest MLR quartile and being physically inactive had significantly higher risks for all study end points (1.42 [95% CI, 1.24-1.63], 1.62 [95% CI, 1.25-2.10], and 1.33 [95% CI, 1.13-1.56], respectively, for incident CCD, atrioventricular block, and bundle-branch block). CONCLUSIONS: MLR should be a biomarker for the risk assessment of incident CCD. Adherence to habitual physical activity is favorable for reducing the MLR-associated risks of CCD.

Photothermal-enhanced in situ supramolecular hydrogel promotes bacteria-infected wound healing in diabetes.

Bacterial infection can impede the healing of chronic wounds, particularly diabetic wounds. The high-sugar environment of diabetic wounds creates a favorable condition for bacterial growth, posing a challenge to wound healing. In clinical treatment, the irregular shape of the wound and the poor mechanical properties of traditional gel adjuvants make them susceptible to mechanical shear and compression, leading to morphological changes and fractures, and difficult to adapt to irregular wounds. Traditional gel adjuvants are prepared in advance, while in situ gel is formed at the site of administration after drug delivery in a liquid state, which can better fit the shape of the wound. Therefore, this study developed an in situ HA/GCA/Fe2+-GOx gel using a photothermal-enhanced Fenton reaction to promote the generation of hydroxyl radicals (·OH). The generation of ·OH has an antibacterial effect while promoting the formation of the gel, achieving a dual effect. The addition of double-bonded adamantane (Ada) interacts with the host-guest effect of graphene oxide and the double-bond polymerization of HAMA gel, making the entire gel system more complete. At the same time, the storage modulus (G') of the gel increased from 130 to 330 Pa, enhancing the mechanical properties of the gel. This enables the gel to have better injectability and self-healing effects. The addition of GOx can consume glucose at the wound site, providing a good microenvironment for the repair of diabetic wounds. The gel has good biocompatibility and in a diabetic rat wound model infected with S. aureus, it can effectively kill bacteria at the wound site and promote wound repair. Meanwhile, the inflammation of wounds treated with HA/GCA/Fe2+-GOx + NIR was lighter compared to untreated wounds. Therefore, this study provides a promising strategy for treating bacterial-infected diabetic wounds.

Dual-trajectory of TyG levels and lifestyle scores and their associations with ischemic stroke in a non-diabetic population: a cohort study.

BACKGROUND: The Triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, has been implicated in the risk of ischemic stroke. However, the interplay between TyG levels, lifestyle factors, and their collective impact on stroke risk in non-diabetic populations remains inadequately explored. This study aims to evaluate the association of ischemic stroke with the joint development of the TyG index and lifestyle in the non-diabetic population. METHODS: In this prospective cohort study, data was collected across three consecutive biennial surveys of the Kailuan Study from 2006 to 2011. The dual-trajectory model was used to determine the temporal development of TyG levels and lifestyle scores. Statistical analysis involved Cox regression models to evaluate the association between TyG-lifestyle trajectories and ischemic stroke risk, adjusting for potential confounders. RESULTS: A total of 44,403 participants were included, with five distinct TyG levels and lifestyle scores trajectory subtypes identified. In the multivariable-adjusted analyses, significant differences in ischemic stroke risk among the trajectory subtypes. Group 5, characterized by the highest TyG levels and moderate lifestyle scores, exhibited the greatest ischemic stroke risk (HR = 1.81, 95% CI: 1.51-2.18), while group 4, with moderate TyG levels and higher lifestyle scores, demonstrated the lowest risk (HR = 1.19, 95% CI: 1.04-1.37), compared with group 3. Participants with elevated TyG levels were at an increased risk of ischemic stroke in cases of pronounced insulin resistance, even with a healthy lifestyle. CONCLUSIONS: This study reveals the significant associations between the identified TyG and lifestyle trajectories and the stratification of ischemic stroke risk among non-diabetics. The TyG index is a valuable indicator for assessing insulin resistance. However, the potential benefits of lifestyle changes for those with significantly high TyG levels need to be clarified by more research to develop more effective stroke prevention strategies.

A cuttlefish ink nanoparticle-reinforced biopolymer hydrogel with robust adhesive and immunomodulatory features for treating oral ulcers in diabetes.

Oral ulcers can be managed using a variety of biomaterials that deliver drugs or cytokines. However, many patients experience minimal benefits from certain medical treatments because of poor compliance, short retention times in the oral cavity, and inadequate drug efficacy. Herein, we present a novel hydrogel patch (SCE2) composed of a biopolymer matrix (featuring ultraviolet-triggered adhesion properties) loaded with cuttlefish ink nanoparticles (possessing pro-healing functions). Applying a straightforward local method initiates the formation of a hydrogel barrier that adheres to mucosal injuries under the influence of ultraviolet light. SCE2 then demonstrates exceptional capabilities for near-infrared photothermal sterilization and neutralization of reactive oxygen species. These properties contribute to the elimination of bacteria and the management of the oxidation process, thus accelerating the healing phase's progression from inflammation to proliferation. In studies involving diabetic rats with oral ulcers, the SCE2 adhesive patch significantly quickens recovery by altering the inflamed state of the injured area, facilitating rapid re-epithelialization, and fostering angiogenesis. In conclusion, this light-sensitive hydrogel patch offers a promising path to expedited wound healing, potentially transforming treatment strategies for clinical oral ulcers.

Increased Risk of Cardiometabolic Disease in Ideal Weight Adults With History of Overweight/Obesity in China: A Prospective Cohort Study.

BACKGROUND: Overweight and obesity represent critical modifiable determinants in the prevention of cardiometabolic disease (CMD). However, the long-term impact of prior overweight/obesity on the risk of CMD in later life remains unclear. We aimed to investigate the association between longitudinal transition of body mass index (BMI) status and incident CMD. METHODS AND RESULTS: This prospective cohort study included 57 493 CMD-free Chinese adults from the Kailuan Study. BMI change patterns were categorized according to the BMI measurements obtained during the 2006 and 2012 surveys. The primary end point was a composite of myocardial infarction, stroke, and type 2 diabetes. Cox regression models were used to evaluate the associations of transitions in BMI with overall CMD events and subtypes, with covariates selected on the basis of the directed acyclic graph. During a median follow-up of 7.62 years, 8412 participants developed CMD. After considering potential confounders, weight gain pattern (hazard ratio [HR], 1.34 [95% CI, 1.23-1.46]), stable overweight/obesity (HR, 2.12 [95% CI, 2.00-2.24]), and past overweight/obesity (HR, 1.73 [95% CI, 1.59-1.89]) were associated with the incidence of CMD. Similar results were observed in cardiometabolic multimorbidity, cardiovascular disease, and type 2 diabetes. Additionally, triglyceride and systolic blood pressure explained 8.05% (95% CI, 5.87-10.22) and 12.10% (95% CI, 9.19-15.02) of the association between past overweight/obesity and incident CMD, respectively. CONCLUSIONS: A history of overweight/obesity was associated with an increased risk of CMD, even in the absence of current BMI abnormalities. These findings emphasize the necessity for future public health guidelines to include preventive interventions for CMD in individuals with past overweight/obesity.

Analysis of the sodium pump subunit ATP1A3 in glioma patients: Potential value in prognostic prediction and immunotherapy.

The ATP1A3 gene is associated with the development and progression of neurological diseases. However, the pathological function and therapeutic value of ATP1A3 in glioblastoma (GBM) remains unknown. In this study, we tried to explore the correlation between the ATP1A3 gene expression and immune features in GBM samples. We found that ATP1A3 gene expression levels showed significant negative correlation with immune checkpoints such as PD-L1, CTLA-4 and IDO1. Next, ATP1A3 gene expression levels showed significant negative correlation with the anti-cancer immune cell process, the immune score and stromal score. By grouping ATP1A3 expression levels, we found that that immunomodulator-related genes and tumor-associated immune cell effector gene expression levels were associated with lower ATP1A3 expression. In addition, immunotherapy prediction pathway activity and a majority of the anti-cancer immune cell process activity levels were also showed to be correlated with lower ATP1A3 gene expression. Further, nine prognostic factors were identified by prognostic analysis, and a GBM prognostic model (risk score) was established. We applied the model to the TCGA GBM training set sample and the GSE4412 validation set sample and found that patients in the high risk score subgroup had significantly shorter survival time, demonstrating the prognostic value and prognostic efficacy of the risk score. Furthermore, ATP1A3 overexpression has also been found to sensitize cancer cells to anti-PD-1 therapy. In conclusion, we showed that ATP1A3 is a highly promising treatment target in GBM and the risk score is an independent prognostic factor for cancer and can be used to help guide the prediction of survival time in patients with GBM.

The Neuro-Inflammatory Microenvironment: An Important Regulator of Stem Cell Survival in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-ß plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no "curative" drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα, CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ, CSF1R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD.

The effect of cumulative lipid accumulation product and related long-term change on incident stroke: The Kailuan Study.

BACKGROUND AND AIMS: A single measurement lipid accumulation product (LAP) level has been shown to increase cardiovascular disease, but cumulative LAP on stroke effects is uncertain. METHODS AND RESULTS: This study included 43,089 participants, free of any cardiovascular diseases at baseline, from the Kailuan Study. The cumulative LAP was determined by multiplying the average LAP index and the time interval between two consecutive examinations, resulting in their categorization into four quartile groups. The higher LAP exposure was defined as participants with LAP values exceeding 90% of this population during each health survey. The association between cumulative LAP and stroke was assessed using multivariable Cox proportional hazard models. During a median follow-up period of 11.0 (10.6-11.3) years, 2461 participants developed stroke (of which 2220 were ischemic stroke, 320 were hemorrhagic stroke, and 79 were concurrent). After adjusting for potential confounders, the risk of stroke gradually increased in Groups Q2 to Q4 compared to Q1, with hazard ratios (HRs) ranging from 1.19 (95% CI: 1.05-1.36) to 1.50 (95% CI: 1.30-1.70). Specifically, the risk of ischemic stroke showed an increase from 1.21 (1.06-1.39) to 1.56 (1.36-1.79), while no statistically significant effect was observed for hemorrhagic stroke. The longer duration of higher LAP index exposure was also associated with increased stroke risk. Similar results were obtained in the stratification and sensitivity analyses. CONCLUSION: Cumulative LAP was positively and significantly associated with incident stroke, especially ischemic stroke, and a longer duration of exposure to higher LAP may increase the risk of stroke.

Measurement of cumulative high-sensitivity C-reactive protein and monocyte to high-density lipoprotein ratio in the risk prediction of type 2 diabetes: a prospective cohort study.

BACKGROUND: Converging data have suggested that monocytic inflammation and C-reactive protein (CRP) are biologically intertwined processes and are involved in diabetogenesis. This study aimed to investigate the association between systemic inflammation assessed by joint cumulative high-sensitivity C-reactive protein (CumCRP) and monocyte to high-density lipoprotein ratio (CumMHR) and incident type 2 diabetes (T2D) and their predictive value for T2D in a general population. METHODS: A total of 40,813 nondiabetic participants from a prospective real-life cohort (Kailuan Study, China) were followed biennially from 2010/2011 until December 31, 2020. Multivariable Cox regression analyses were conducted to evaluate the adjusted hazard ratios (aHRs) of incident diabetes. RESULTS: During a median follow-up of 7.98 (IQR: 5.74-8.87) years, 4848 T2D cases developed. CumMHR and CumCRP were alone or jointly associated with incident T2D after adjusting for potential confounders. Elevated CumMHR levels significantly increased the risk of incident diabetes in each CumCRP strata (P-interaction: 0.0278). Participants with concomitant elevations in CumMHR and CumCRP levels had the highest risk (aHR: 1.71, 95% CI 1.52-1.91) compared to both in the low strata. Notably, the coexposure-associated T2D risk was modified by age, sex, hypertension, dyslipidemia, and prediabetes status. C-statistics increased from 0.7377 to 0.7417 when CumMHR and CumCRP were added into the multivariable-adjusted model, with a net reclassification improvement (%) of 12.39 (9.39-15.37) (P < 0.0001). CONCLUSIONS: Cumulative hsCRP and MHR were both independently and jointly associated with an increased risk of T2D and their addition to established risk factors should improve risk prediction and reclassification of diabetes.

Multi-trajectories of triglyceride-glucose index and lifestyle with Cardiovascular Disease: a cohort study.

BACKGROUND: Previous studies using trajectory models focused on examining the longitudinal changes in triglyceride-glucose (TyG) levels and lifestyle scores separately, without exploring the joint evolution of these two factors. This study aimed to identify the multi-trajectories of TyG levels and lifestyle scores and assess their association with the risk of cardiovascular disease (CVD). METHODS: The study enrolled 47,384 participants from three health surveys of the Kailuan Study. The TyG index was computed as Ln [fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2], and the lifestyle scores were derived from five factors, including smoking, alcohol consumption, physical activity, sedentary behaviors, and salt intake. A group-based multi-trajectory model was adopted to identify multi-trajectories of TyG levels and lifestyle scores. The association of identified multi-trajectories with incident CVD was examined using Cox proportional hazard model. RESULTS: Five distinct multi-trajectories of TyG levels and lifestyle scores were identified. During a median follow-up period of 10.98 years, 3042 participants developed CVD events (2481 strokes, 616 myocardial infarctions, and 55 co-current stroke and myocardial infarctions). In comparison to group 3 with the lowest TyG levels and the best lifestyle scores, the highest CVD risk was observed in group 5 characterized by the highest TyG levels and moderate lifestyle scores (HR = 1.76, 95% CI: 1.50-2.05). Group 2 with higher TyG levels and the poorest lifestyle scores had a 1.45-fold (95% CI 1.26-1.66) risk of CVD, and group 1 with lower TyG levels and poorer lifestyle scores had a 1.33-fold (95% CI 1.17-1.50) risk of CVD. Group 4, with moderate TyG levels and better lifestyle scores, exhibited the lowest CVD risk (HR = 1.32, 95% CI: 1.18-1.47). CONCLUSIONS: Distinct multi-trajectories of TyG levels and lifestyle scores corresponded to differing CVD risks. The CVD risk caused by a high level TyG trajectory remained increased despite adopting healthier lifestyles. These findings underscored the significance of evaluating the combined TyG and lifestyle patterns longitudinally, and implementing early interventions to reduce CVD risk by lowering TyG levels.

Combined effect of adiposity and elevated inflammation on incident type 2 diabetes: a prospective cohort study.

BACKGROUND: Adiposity and elevated inflammation are two hallmarks of hyperglycemia. However, it is unknown whether clustering of elevated inflammation and adiposity interact act on diabetogenesis and lead to a greater risk for incident type 2 diabetes (T2D). METHODS: Adiposity was indicated by body mass index, waist circumference and ultrasonography-measured fatty liver degrees. Elevated inflammation was indicated as high-sensitivity C-reactive protein levels ≥ 2 mg/L. Time-to-event survival analyses were conducted to investigate the joint effect of adiposity and inflammation on incident T2D on both multiplicative and additive scales. RESULTS: Among 82,172 non-diabetic participants from a prospective cohort in China, 14,278 T2D occurred over a median follow-up of 11 years. In the multivariable-adjusted model, elevated inflammation [1.12 (1.08‒1.16)] and adiposity [1.76 (1.69‒1.83) for overweight/obesity, 1.49 (1.44‒1.55) for central obesity, and 2.02 (1.95‒2.09) for fatty liver] were significantly associated with incident diabetes. Higher adiposity-associated risks and incidence rates of diabetes were observed with elevated inflammation. When studying the joint effect, the adjusted HRs were 1.77 (1.69‒1.85) for overweight/obesity, 1.14 (1.06‒1.23) for elevated inflammation, and 2.08 (1.97‒2.19) for their joint effect, with a relative excess risk due to interaction of 0.17 (0.05‒0.28). The attributable proportions were 71.30% for overweight/obesity, 12.96% for elevated inflammation, and 15.74% for their interaction. Similar results were observed when adiposity was assessed as waist circumference or fatty liver. CONCLUSIONS: Adiposity and elevated inflammation synergically lead to greater risks of incident diabetes than addition of each individual exposure. Strategies simultaneously targeting both risks should produce more benefits for diabetes prevention than through initiatives directed at each separate risk.

Relationship between the cumulative exposure to atherogenic index of plasma and ischemic stroke: a retrospective cohort study.

BACKGROUND: Atherogenic index of plasma (AIP) has been demonstrated as a surrogate marker for ischemic stroke, but there is limited evidence for the effect of long-term elevation of AIP on ischemic stroke. Therefore, we aimed to characterize the relationship between cumulative exposure to AIP and the risk of ischemic stroke. METHODS: A total of 54,123 participants in the Kailuan Study who attended consecutive health examinations in 2006, 2008, and 2010 and had no history of ischemic stroke or cancer were included. The time-weighted cumulative AIP (cumAIP) was calculated as a weighted sum of the mean AIP values for each time interval and then normalized to the total duration of exposure (2006-2010). Participants were divided into four groups according to quartile of cumAIP: the Q1 group, ≤-0.50; Q2 group, - 0.50 to - 0.12; Q3 group, - 0.12 to 0.28; and Q4 group, ≥ 0.28. Cox proportional hazard models were used to evaluate the relationship between cumAIP and ischemic stroke by calculating hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: After a median follow-up of 11.03 years, a total of 2,742 new ischemic stroke events occurred. The risk of ischemic stroke increased with increasing quartile of cumAIP. After adjustment for potential confounders, Cox regression models showed that participants in the Q2, Q3, and Q4 groups had significantly higher risks of ischemic stroke than those in the Q1 group. The HRs (95% CIs) for ischemic stroke in the Q2, Q3, and Q4 groups were 1.17 (1.03, 1.32), 1.33 (1.18, 1.50), and 1.45 (1.28, 1.64), respectively. The longer duration of high AIP exposure was significantly associated with increased ischemic stroke risk. CONCLUSIONS: High cumulative AIP is associated with a higher risk of ischemic stroke, which implies that the long-term monitoring and maintenance of an appropriate AIP may help prevent such events.

Progress in cancer neuroscience.

Cancer of the central nervous system (CNS) can crosstalk systemically and locally in the tumor microenvironment and has become a topic of attention for tumor initiation and advancement. Recently studied neuronal and cancer interaction fundamentally altered the knowledge about glioma and metastases, indicating how cancers invade complex neuronal networks. This review systematically discussed the interactions between neurons and cancers and elucidates new therapeutic avenues. We have overviewed the current understanding of direct or indirect communications of neuronal cells with cancer and the mechanisms associated with cancer invasion. Besides, tumor-associated neuronal dysfunction and the influence of cancer therapies on the CNS are highlighted. Furthermore, interactions between peripheral nervous system and various cancers have also been discussed separately. Intriguingly and importantly, it cannot be ignored that exosomes could mediate the "wireless communications" between nervous system and cancer. Finally, promising future strategies targeting neuronal-brain tumor interactions were reviewed. A great deal of work remains to be done to elucidate the neuroscience of cancer, and future more research should be directed toward clarifying the precise mechanisms of cancer neuroscience, which hold enormous promise to improve outcomes for a wide range of malignancies.

Temporal relationship between triglyceride-glucose index and blood pressure and their joint cumulative effect on cardiovascular disease risk: a longitudinal cohort study.

BACKGROUND: Concurrent insulin resistance and elevated blood pressure are commonly observed in cardiovascular disease (CVD) and have long been proposed to contribute to CVD. However, the temporal relationship between them and the effect of their cumulative co-exposure on future incident CVD remains unclear. METHODS: Longitudinal analysis of data on 57,192 participants from a real-world, prospective cohort study (Kailuan Study) was performed to address the temporal relationship between Triglyceride-Glucose Index (TyG, calculated as ln [TG (mg/dL) × FBG (mg/dL)/2]) and blood pressure (BP) assessed by cross-lagged analyses in an approximately 4-year exposure period (2006/2007 to 2010/2011). After excluding 879 participants with known diabetes, 56,313 nonCVD participants were included for further analysis of the CVD outcome. Cox regression models were used to examine the hazard ratios (HRs) upon the cumulative TyG (CumTyG) and BP(CumBP) in the exposure period. RESULTS: The standard regression coefficient from baseline TyG to follow-up systolic BP was 0.0142 (95% CI 0.0059-0.0226), which was greater than the standard regression coefficient from baseline systolic BP to follow-up TyG (- 0.0390; 95% CI - 0.0469 to - 0.0311). The same results were observed in the cross-lag between TyG and diastolic blood pressure [0.0271 (0.0185 to 0.0356) vs. - 0.0372 (- 0.0451 to - 0.0293)]. During a median follow-up of 9.98 years, 3981 CVD cases occurred. Significant interactions were observed between the median CumTyG (8.61) and CumSBP thresholds (130, 140 mmHg) (P = 0.0149), the median CumTyG (8.61) and CumDBP thresholds (80, 90 mmHg) (P = 0.0441). Compared to CumTyG < 8.61 and CumSBP < 130 mmHg, after adjusting for potential confounding factors, the HR gradually increased in the high co-exposure groups. The hazard ratios (HRs) and 95% confidence intervals (CIs) for Q2-Q6 were 1.39 (1.24, 1.57), 1.94 (1.69, 2.22), 2.40 (2.12, 2.71), 2.74 (2.43, 3.10), and 3.07 (2.74, 3.45). Additionally, the CVD risks in the co-exposure were more prominent in younger participants. CONCLUSIONS: These findings suggest that elevated TyG has a greater impact on future blood pressure changes than vice versa. Dual assessment and management of insulin resistance and blood pressure contribute to the prevention of CVD, especially in younger individuals.

An Immunomodulatory Hydrogel by Hyperthermia-Assisted Self-Cascade Glucose Depletion and ROS Scavenging for Diabetic Foot Ulcer Wound Therapeutics.

Current therapeutic protocols for diabetic foot ulcers (DFUs), a severe and rapidly growing chronic complication in diabetic patients, remain nonspecific. Hyperglycemia-caused inflammation and excessive reactive oxygen species (ROS) are common obstacles encountered in DFU wound healing, often leading to impaired recovery. These two effects reinforce each other, forming an endless loop. However, adequate and inclusive methods are still lacking to target these two aspects and break the vicious cycle. This study proposes a novel approach for treating DFU wounds, utilizing an immunomodulatory hydrogel to achieve self-cascade glucose depletion and ROS scavenging to regulate the diabetic microenvironment. Specifically, AuPt@melanin-incorporated (GHM3) hydrogel dressing is developed to facilitate efficient hyperthermia-enhanced local glucose depletion and ROS scavenging. Mechanistically, in vitro/vivo experiments and RNA sequencing analysis demonstrate that GHM3 disrupts the ROS-inflammation cascade cycle and downregulates the ratio of M1/M2 macrophages, consequently improving the therapeutic outcomes for dorsal skin and DFU wounds in diabetic rats. In conclusion, this proposed approach offers a facile, safe, and highly efficient treatment modality for DFUs.