Comparison of multiple linear regression and machine learning methods in predicting cognitive function in older Chinese type 2 diabetes patients.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) has increased dramatically in recent decades, and there are increasing indications that dementia is related to T2D. Previous attempts to analyze such relationships principally relied on traditional multiple linear regression (MLR). However, recently developed machine learning methods (Mach-L) outperform MLR in capturing non-linear relationships. The present study applied four different Mach-L methods to analyze the relationships between risk factors and cognitive function in older T2D patients, seeking to compare the accuracy between MLR and Mach-L in predicting cognitive function and to rank the importance of risks factors for impaired cognitive function in T2D. METHODS: We recruited older T2D between 60-95 years old without other major comorbidities. Demographic factors and biochemistry data were used as independent variables and cognitive function assessment (CFA) was conducted using the Montreal Cognitive Assessment as an independent variable. In addition to traditional MLR, we applied random forest (RF), stochastic gradient boosting (SGB), Naïve Byer's classifier (NB) and eXtreme gradient boosting (XGBoost). RESULTS: Totally, the test cohort consisted of 197 T2D (98 men and 99 women). Results showed that all ML methods outperformed MLR, with symmetric mean absolute percentage errors for MLR, RF, SGB, NB and XGBoost respectively of 0.61, 0.599, 0.606, 0.599 and 0.2139. Education level, age, frailty score, fasting plasma glucose and body mass index were identified as key factors in descending order of importance. CONCLUSION: In conclusion, our study demonstrated that RF, SGB, NB and XGBoost are more accurate than MLR for predicting CFA score, and identify education level, age, frailty score, fasting plasma glucose, body fat and body mass index as important risk factors in an older Chinese T2D cohort.

circFNDC3B promotes esophageal squamous cell carcinoma progression by targeting MYO5A via miR-370-3p/miR-136-5p.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor worldwide. Circular RNA (circRNA) is of great value in tumorigenesis progression. However, the mechanism of circFNDC3B in ESCC remains to be clarified. METHODS: Firstly, the circular characteristics of circFNDC3B were evaluated by Actinomycin D and RNase R measurements. The functions of circFNDC3B in ESCC cells were examined by CCK-8, EdU and flow cytometry. Subsequently, the molecular mechanism of circFNDC3B was explained using luciferase reporter gene detection. Finally, we constructed xenograft model to prove the role of circFNDC3B in vivo. RESULTS: Our study revealed that circFNDC3B was more stable than its linear RNA and prominently upregulated in ESCC. Functional findings suggested that silencing of circFNDC3B reduced the proliferation and enhanced apoptosis of ESCC cells in vitro. Meanwhile, knockdown of circFNDC3B attenuated tumor progression in vivo. Next, miR-370-3p/miR-136-5p was discovered to bind circFNDC3B. miR-370-3p/miR-136-5p reversed the promotive effect on cell proliferation and the inhibitory effect on cell apoptosis of circFNDC3B. MYO5A was a downstream target of miR-370-3p/miR-136-5p. CircFNDC3B served as a sponge for miR-370-3p/miR-136-5p and alleviated the prohibitory effect of miR-370-3p/miR-136-5p on MYO5A, which accelerated ESCC progression. CONCLUSION: circFNDC3B positively adjusted the MYO5A expression via spongy miR-370-3p/miR-136-5p, hence achieving the cancer-promoting effect on ESCC. circFNDC3B was a prospective diagnosis marker for ESCC.

Treadmill Exercise Decreases Inflammation Via Modulating IL-6 Expression in the Rat Model of Middle Cerebral Artery Occlusion.

BACKGROUND: Long-term bed rest in neurointensive care (NIC) patients leads to skeletal muscle atrophy and cognitive dysfunction, which seriously affects the physical fitness and final prognosis of critically ill patients. Exercise therapy plays an increasingly important role in the treatment and rehabilitation of patients with sarcopenia. However, the therapeutic effect and mechanism of exercise therapy for patients with neurological impairment remain unclear. METHODS: Serum samples of NIC patients before and after exercise therapy and normal people were collected to detect interleukin-6 (IL-6) and interleukin-1ß levels by enzyme-linked immunosorbent assay (ELISA). Middle cerebral artery occlusion (MCAO) was used for the construction of a rat model. The Morris water maze test, exploration test, and open-field test were used to assess neurological function in rats. Western blot and quantitative real-time polymerase chain reaction were performed to evaluate the activation of IL-6/adenosine-monophosphate-activated protein kinase (AMPK) signaling. RESULTS: Exercise therapy attenuated IL-6 expression in NIC patients. Exercise therapy alleviated cognitive dysfunctions and decreased IL-6 expression in MCAO rats. Exercise therapy alleviated gastrocnemius muscle injury in rats after MCAO by modulating IL-6/AMPK signaling. CONCLUSIONS: Treadmill exercise decreases inflammation in MCAO rats via modulating IL-6/AMPK signaling.

Integration of transcriptomic and proteomic analyses reveals several levels of metabolic regulation in the excess starch and early senescent leaf mutant lses1 in rice.

BACKGROUND: The normal metabolism of transitory starch in leaves plays an important role in ensuring photosynthesis, delaying senescence and maintaining high yield in crops. OsCKI1 (casein kinase I1) plays crucial regulatory roles in multiple important physiological processes, including root development, hormonal signaling and low temperature-treatment adaptive growth in rice; however, its potential role in regulating temporary starch metabolism or premature leaf senescence remains unclear. To reveal the molecular regulatory mechanism of OsCKI1 in rice leaves, physiological, transcriptomic and proteomic analyses of leaves of osckI1 allele mutant lses1 (leaf starch excess and senescence 1) and its wild-type varieties (WT) were performed. RESULTS: Phenotypic identification and physiological measurements showed that the lses1 mutant exhibited starch excess in the leaves and an obvious leaf tip withering phenotype as well as high ROS and MDA contents, low chlorophyll content and protective enzyme activities compared to WT. The correlation analyses between protein and mRNA abundance are weak or limited. However, the changes of several important genes related to carbohydrate metabolism and apoptosis at the mRNA and protein levels were consistent. The protein-protein interaction (PPI) network might play accessory roles in promoting premature senescence of lses1 leaves. Comprehensive transcriptomic and proteomic analysis indicated that multiple key genes/proteins related to starch and sugar metabolism, apoptosis and ABA signaling exhibited significant differential expression. Abnormal increase in temporary starch was highly correlated with the expression of starch biosynthesis-related genes, which might be the main factor that causes premature leaf senescence and changes in multiple metabolic levels in leaves of lses1. In addition, four proteins associated with ABA accumulation and signaling, and three CKI potential target proteins related to starch biosynthesis were up-regulated in the lses1 mutant, suggesting that LSES1 may affect temporary starch accumulation and premature leaf senescence through phosphorylation crosstalk ABA signaling and starch anabolic pathways. CONCLUSION: The current study established the high correlation between the changes in physiological characteristics and mRNA and protein expression profiles in lses1 leaves, and emphasized the positive effect of excessive starch on accelerating premature leaf senescence. The expression patterns of genes/proteins related to starch biosynthesis and ABA signaling were analyzed via transcriptomes and proteomes, which provided a novel direction and research basis for the subsequent exploration of the regulation mechanism of temporary starch and apoptosis via LSES1/OsCKI1 in rice.

Natural variation of the BRD2 allele affects plant height and grain size in rice.

MAIN CONCLUSION: The zqdm1 identified from a rice mutant is a novel allele of BRD2 and is responsible for regulating rice plant height, grain size and appearance, which has possibilities on improving rice quality. Plant height is an important agronomic trait related to rice yield, and grain size directly determines grain yield in rice (Oryza sativa L.). With the development of molecular biotechnology and genome sequencing technology, more and more key genes associated with plant height and grain size have been cloned and identified in recent years. This study identified the zqdm1 gene from a mutant with reduced plant height and grain size. The zqdm1 gene was revealed to be a new allele of BRASSINOSTEROID DEFICIENT DWARF 2 (BRD2), encoding a FAD-linked oxidoreductase protein involved in the brassinosteroid (BR) biosynthesis pathway, and regulates plant height by reducing cell number of longitudinal sections of the internode and regulates grain size by altering cell expansion. A 369-bp DNA fragment was found inserted at the first exon, resulting in protein-coding termination. This mutation has not been discovered in previous studies. Complementation tests have confirmed that 369-bp insertion in BRD2 was responsible for the plant height and grain size changing in the zqdm1 mutant. Over-expression of BRD2 driven by different promoters into indica rice variety Jiafuzhan (JFZ) results in slender grains, suggesting its function on regulating grain shape. In summary, the current study has identified a new BRD2 allele, which facilitated the further research on the molecular mechanism of this gene on regulating growth and development.

Epidemiology and Outcomes of Acute Respiratory Distress Syndrome Following Isolated Severe Traumatic Brain Injury.

Patients with traumatic brain injury (TBI) are at risk for extra-cranial complications, such as the acute respiratory distress syndrome (ARDS). We conducted an analysis of risk factors, mortality, and healthcare utilization associated with ARDS following isolated severe TBI. The National Trauma Data Bank (NTDB) dataset files from 2007-2014 were used to identify adult patients who suffered isolated [other body region-specific Abbreviated Injury Scale (AIS) < 3] severe TBI [admission total Glasgow Coma Scale (GCS) from 3 to 8 and head region-specific AIS >3]. In-hospital mortality was compared between patients who developed ARDS and those who did not. Utilization of healthcare resources (ICU length of stay, hospital length of stay, duration of mechanical ventilation, and frequency of tracheostomy and gastrostomy tube placement) was also examined. This retrospective cohort study included 38,213 patients with an overall ARDS occurrence of 7.5%. Younger age, admission tachycardia, pre-existing vascular and respiratory diseases, and pneumonia were associated with the development of ARDS. Compared to patients without ARDS, patients that developed ARDS experienced increased in-hospital mortality (OR 1.13, 95% CI 1.01-1.26), length of stay (p = <0.001), duration of mechanical ventilation (p = < 0.001), and placement of tracheostomy (OR 2.70, 95% CI 2.34-3.13) and gastrostomy (OR 2.42, 95% CI 2.06-2.84). After isolated severe TBI, ARDS is associated with increased mortality and healthcare utilization. Future studies should focus on both prevention and management strategies specific to TBI-associated ARDS.

Hydroxychloroquine might reduce risk of incident endometriosis in patients with systemic lupus erythematosus: A retrospective population-based cohort study.

BACKGROUND: SLE, which is common in women, is commonly treated with HCQ, an anti-inflammation medication. Reproductive-age women with SLE are prone to be impacted by endometriosis. This study analyzes the relationship between HCQ and endometriosis patients with SLE in order to determine whether HCQ is effective for treating the latter. METHODS: This population-based, retrospective cohort study analyzed the SLE risk in a cohort of newly diagnosed SLE patients with endometriosis during 2000 through 2013. Controls were selected at a 1:2 ratio through age-matching using the greedy algorithm. The Cox proportional hazard model was used to analyze the association between HCQ use and endometriosis incidence. Four different Cox regression models were used. Lastly, sensitivity analysis with PSOW and IPW was implemented to evaluate the hazard ratio (HR) of endometriosis after exposure with HCQ. RESULTS: In the cohort where age and sex matched high and low HCQ dosage, the average follow-up time was about 1 year. The cohort's overall incidence rates of endometriosis were 44.54 and 90.03 per 100000 person-month for high and low dosage respectively. The high dose group's conditional hazard ratio (aHR) for incidental endometriosis was 0.482 (CI = 0.191 to 1.213). The incidence rate and Kaplan-Meir curves of endometriosis were consistent with the results for the cohort. CONCLUSION: This study demonstrated that SLE patients continuously treated with HCQ have a lower risk of developing endometriosis. Clinically, HCQ can be beneficial for endometriosis patients with SLE.

Echocardiogram Utilization Patterns and Association With Mortality Following Severe Traumatic Brain Injury.

BACKGROUND: Severe traumatic brain injury (TBI) can result in left ventricular dysfunction, which can lead to hypotension and secondary brain injuries. Although echocardiography is often used to examine cardiovascular function in multiple clinical settings, its use and association with outcomes following severe TBI are not known. To address this gap, we used the National Trauma Data Bank (NTDB) to describe utilization patterns of echocardiography and examine its association with mortality following severe TBI. METHODS: A retrospective cohort study was conducted using a large administrative trauma registry maintained by the NTDB from 2007 to 2014. Patients >18 years with isolated severe TBI, and without concurrent severe polytrauma, were included in the study. We examined echocardiogram utilization patterns (including overall utilization, factors associated with utilization, and variation in utilization) and the association of echocardiography utilization with hospital mortality, using multivariable logistic regression models. RESULTS: Among 47,808 patients, echocardiogram was utilized as part of clinical care in 2548 patients (5.3%). Clinical factors including vascular comorbidities and hemodynamic instability were associated with increased use of echocardiograms. Nearly half (46.0%, 95% confidence interval [CI], 40.3%-51.7%) of the variation in echocardiogram utilization was explained at the individual hospital level, above and beyond patient and injury factors. Exposure to an echocardiogram was associated with decreased odds of in-hospital mortality following severe TBI (adjusted odds ratio [OR] = 0.77; 95% CI, 0.69-0.87; P < .001). CONCLUSIONS: Echocardiogram utilization following severe TBI is relatively low, with wide variation in use at the hospital level. The association with decreased in-hospital mortality suggests that the information derived from echocardiography may be relevant to improving patient outcomes but will require confirmation in further prospective studies.

Kansuinine A Ameliorates Atherosclerosis and Human Aortic Endothelial Cell Apoptosis by Inhibiting Reactive Oxygen Species Production and Suppressing IKKß/IκBα/NF-κB Signaling.

Reactive oxygen species (ROS)-induced vascular endothelial cell apoptosis is strongly associated with atherosclerosis progression. Herein, we aimed to examine whether Kansuinine A (KA), extracted from Euphorbia kansui L., prevents atherosclerosis development in a mouse model and inhibits cell apoptosis through oxidative stress reduction. Atherosclerosis development was analyzed in apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (HFD) using Oil Red O staining and H&E staining. Human aortic endothelial cells (HAECs) were treated with KA, followed by hydrogen peroxide (H2O2), to investigate the KA-mediated inhibition of ROS-induced oxidative stress and cell apoptosis. Oil Red O staining and H&E staining showed that atherosclerotic lesion size was significantly smaller in the aortic arch of ApoE-/- mice in the HFD+KA group than that in the aortic arch of those in the HFD group. Further, KA (0.1-1.0 µM) blocked the H2O2-induced death of HAECs and ROS generation. The H2O2-mediated upregulation of phosphorylated IKKß, phosphorylated IκBα, and phosphorylated NF-κB was suppressed by KA. KA also reduced the Bax/Bcl-2 ratio and cleaved caspase-3 expression, preventing H2O2-induced vascular endothelial cell apoptosis. Our results indicate that KA may protect against ROS-induced endothelial cell apoptosis and has considerable clinical potential in the prevention of atherosclerosis and cardiovascular diseases.

Long noncoding RNA HAS2-AS1 promotes tumor progression in glioblastoma via functioning as a competing endogenous RNA.

Glioblastoma multiforme (GBM) is a refractory tumor with poor prognosis and requires more effective treatment regimens. It has been confirmed that long noncoding RNAs (lncRNAs) substantially regulate various human disease including GBM. However, the biological roles and its underlying molecular mechanisms still need to be further investigated. In this study, the biological function and potential molecular mechanism of lncHAS2-AS1 in GBM were explored. It was discovered that HAS2-AS1 was elevated in glioma tissues and correlated with the prognosis of patients with glioma. Reduction of HAS2-AS1 suppressed the migration and invasion in vitro and in vivo. The transcription factor STAT1 could raise HAS2-AS1 by binding to its promoter region. Besides, HAS2-AS1 could adjust PRPS1 via sponging miR-608 in a direct manner. On the whole, the results of this study evidence that HAS2-AS1 is an oncogene and a potential therapeutic target for GBM.

Associations Between Perioperative Crystalloid Volume and Adverse Outcomes in Five Surgical Populations.

BACKGROUND: Optimal administration of fluids is an important part of enhanced recovery after surgery (ERAS) protocols. We sought to examine the relationship between perioperative crystalloid volume and adverse outcomes in five common types of surgical procedures with ERAS fluid guidelines in place where large randomized controlled trials have not been conducted: breast reconstruction, bariatric, major urologic, gynoncologic, and head and neck oncologic procedures. METHODS: This retrospective cohort study included patients who had undergone any one of the aforementioned procedures within any facility in a large multihospital alliance (Premier, Inc, Charlotte, NC) between 2008 and 2014. We used multivariable generalized additive models to examine relationships between the total crystalloid volume (TCV) on the day of surgery and a composite adverse outcome of prolonged (>75th percentile) hospital or intensive care unit stay or in-hospital mortality. Models were constructed separately within each surgical category and adjusted for demographic, clinical, and hospital characteristics. Informed consent requirements were waived because deidentified data were used. RESULTS: We identified 83,685 patients within 312 US hospitals undergoing breast reconstruction (n = 8738), bariatric surgery (n = 8067), major urologic surgery (n = 28,654), gynoncologic surgery (n = 34,559), and head/neck oncology surgery (n = 3667). There was significant patient-independent variation in TCV. Probabilities of adverse outcomes increased at a TCV below 3 L and above 6 L for all types of surgeries except bariatric surgery, where larger volumes were associated with progressively better outcomes. CONCLUSIONS AND RELEVANCE: Relationships between TCV and adverse outcomes were generally J shaped with higher volumes (>6 L) associated with increased risk. As per current ERAS guidelines, it is important to avoid excessive crystalloid volume in most surgical procedures except for bariatric surgery.

A missense mutation in Large Grain Size 1 increases grain size and enhances cold tolerance in rice.

Grain shape is controlled by quantitative trait loci (QTLs) in rice (Oryza sativa L.). A rice mutant (JF178) with long and large grains has been used in a breeding program for over a decade, but its genetic basis has been unclear. Here, a semi-dominant QTL, designated Large Grain Size 1 (LGS1), was cloned and the potential molecular mechanism of LGS1 function was studied. Near-isogenic lines (NILs) and a map-based approach were employed to clone the LGS1 locus. LGS1 encodes the OsGRF4 transcription factor and contains a 2 bp missense mutation in the coding region that coincides with the putative pairing site of miRNA396. The LGS1 transcript levels in the mutant line were found to be higher than the lgs1 transcript levels in the control plants, suggesting that the mutation might disrupt the pairing of the LGS1 mRNA with miR396. In addition to producing larger grains, LGS1 also enhanced cold tolerance at the seedling stage and increased the survival rate of seedlings after cold stress treatment. These findings indicate that the mutation in LGS1 appears to disturb the GRF4-miR396 stress response network and results in the development of enlarged grains and enhancement of cold tolerance in rice.

Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation.

L5, the most electronegative and atherogenic subfraction of low-density lipoprotein (LDL), induces platelet activation. We hypothesized that plasma L5 levels are increased in acute ischemic stroke patients and examined whether lectin-like oxidized LDL receptor-1 (LOX-1), the receptor for L5 on endothelial cells and platelets, plays a critical role in stroke. Because amyloid ß (Aß) stimulates platelet aggregation, we studied whether L5 and Aß function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum Aß, and platelet LOX-1 expression were significantly higher in acute ischemic stroke patients than in controls without metabolic syndrome (P < .01). In mice subjected to focal cerebral ischemia, L5 treatment resulted in larger infarction volumes than did phosphate-buffered saline treatment. Deficiency or neutralizing of LOX-1 reduced infarct volume up to threefold after focal cerebral ischemia in mice, illustrating the importance of LOX-1 in stroke injury. In human platelets, L5 but not L1 (the least electronegative LDL subfraction) induced Aß release via IκB kinase 2 (IKK2). Furthermore, L5+Aß synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IκBα, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor-κB (NF-κB). Injecting L5+Aß shortened tail-bleeding time by 50% (n = 12; P < .05 vs L1-injected mice), which was prevented by the IKK2 inhibitor. Our findings suggest that, through LOX-1, atherogenic L5 potentiates Aß-mediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-κB signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies.

Sesamol reduces the atherogenicity of electronegative L5 LDL in vivo and in vitro.

Highly electronegative low-density lipoprotein (LDL) L5 induces endothelial cell (EC) apoptosis, which leads to the development of atherosclerosis. We examined the effects of sesamol (1), a natural organic component of sesame oil, on plasma L5 levels and atherosclerosis development in a rodent model and on the L5-induced apoptosis of ECs. Syrian hamsters, which have an LDL profile similar to that of humans, were fed a normal chow diet (control), a high-fat diet (HFD), or a HFD supplemented with the administration of 50 or 100 mg/kg of 1 via oral gavage (HFD+1) for 16 weeks (n = 8 per group). Hamsters in the HFD+1 groups had reduced plasma L5 levels when compared with the HFD group. Oil Red O staining showed that atherosclerotic lesion size was markedly reduced in the aortic arch of hamsters in the HFD+1 groups when compared with that in the HFD group. In human aortic ECs, 0.3-3 µM 1 blocked L5-induced apoptosis in a dose-dependent manner. Further mechanistic studies showed that 1 inhibited the L5-induced lectin-like oxidized LDL receptor-1 (LOX-1)-dependent phosphorylation of p38 MAPK and activation of caspase-3 and increased phosphorylation of eNOS and Akt. Our findings suggest that sesamol (1) protects against atherosclerosis by reducing L5-induced atherogenicity.

The risk factors determined by four machine learning methods for the change of difference of bone mineral density in post-menopausal women after three years follow-up.

The prevalence of osteoporosis has drastically increased recently. It is not only the most frequent but is also a major global public health problem due to its high morbidity. There are many risk factors associated with osteoporosis were identified. However, most studies have used the traditional multiple linear regression (MLR) to explore their relationships. Recently, machine learning (Mach-L) has become a new modality for data analysis because it enables machine to learn from past data or experiences without being explicitly programmed and could capture nonlinear relationships better. These methods have the potential to outperform conventional MLR in disease prediction. In the present study, we enrolled a Chinese post-menopause cohort followed up for 4 years. The difference of T-score (δ-T score) was the dependent variable. Information such as demographic, biochemistry and life styles were the independent variables. Our goals were: (1) Compare the prediction accuracy between Mach-L and traditional MLR for δ-T score. (2) Rank the importance of risk factors (independent variables) for prediction of δ T-score. Totally, there were 1698 postmenopausal women were enrolled from MJ Health Database. Four different Mach-L methods namely, Random forest (RF), eXtreme Gradient Boosting (XGBoost), Naïve Bayes (NB), and stochastic gradient boosting (SGB), to construct predictive models for predicting δ-BMD after four years follow-up. The dataset was then randomly divided into an 80% training dataset for model building and a 20% testing dataset for model testing. A 10-fold cross-validation technique for hyperparameter tuning was used. The model with the lowest root mean square error for the validation dataset was viewed as the best model for each ML method. The averaged metrics of the RF, SGB, NB, and XGBoost models were used to compare the model performance of the benchmark MLR model that used the same training and testing dataset as the Mach-L methods. We defined that the priority demonstrated in each model ranked 1 as the most critical risk factor and 22 as the last selected risk factor. For Pearson correlation, age, education, BMI, HDL-C, and TSH were positively and plasma calcium level, and baseline T-score were negatively correlated with δ-T score. All four Mach-L methods yielded lower prediction errors than the MLR method and were all convincing Mach-L models. From our results, it could be noted that education level is the most important factor for δ-T Score, followed by DBP, smoking, SBP, UA, age, and LDL-C. All four Mach-L outperformed traditional MLR. By using Mach-L, the most important six risk factors were selected which are, from the most important to the least: DBP, SBP, UA, education level, TG and sleeping hour. δ T score was positively related to SBP, education level, UA and TG and negatively related to DBP and sleeping hour in postmenopausal Chinese women.

Fucoidan alleviates high sucrose-induced metabolic disorders and enhances intestinal homeostasis through modulation of Notch signaling.

INTRODUCTION: The therapeutic potential of fucoidan (FUC), a natural polysaccharide, in metabolic disorders is recognized, yet its underlying mechanisms remain unclear. METHODS: We conducted investigations into the therapeutic mechanisms of FUC sourced from Sargassum fulvellum concerning metabolic disorders induced by a high-sucrose diet (HSD), employing Drosophila melanogaster and mice models. Drosophila larvae were subjected to HSD exposure to monitor growth inhibition, reduced pupation, and developmental delays. Additionally, we examined the impact of FUC on growth- and development-related hormones in Drosophila. Furthermore, we assessed the modulation of larval intestinal homeostasis by FUC, focusing on the regulation of Notch signaling. In mice, we evaluated the effects of FUC on HSD-induced impairments in intestinal epithelial barrier integrity and gut hormone secretion. RESULTS: FUC supplementation significantly enhanced pupal weight in Drosophila larvae and effectively countered HSD-induced elevation of glucose and triglyceride levels. It notably influenced the expression of growth- and development-related hormones, particularly augmenting insulin-like peptides production while mitigating larval growth retardation. FUC also modulated larval intestinal homeostasis by negatively regulating Notch signaling, thereby protecting against HSD-induced metabolic stress. In mice, FUC ameliorated HSD-induced impairments in ileum epithelial barrier integrity and gut hormone secretion. CONCLUSIONS: Our findings demonstrate the multifaceted therapeutic effects of FUC in mitigating metabolic disorders and maintaining intestinal health. FUC holds promise as a therapeutic agent, with its effects attributed partly to the sulfate group and its ability to regulate Notch signaling, emphasizing its potential for addressing metabolic disorders.

Targeting the JAK2-STAT3 pathway to inhibit cGAS-STING activation improves neuronal senescence after ischemic stroke.

Neuroinflammation after cerebral ischemia is a key event in progressive brain injury after ischemic stroke. The JAK2/STAT3 pathway is pivotal for neuroinflammation; however, its role in brain senescence after ischemic stroke is unclear. Here, we report that inflammation is increased in the brains of C57BL/6 stroke mice. Treatment of ischemic stroke in adult mice with a JAK kinase inhibitor (AG490) alleviated neurobehavioral defects, reduced brain infarct volume, reduced expression of pro-inflammatory cytokines, and decreased activation of pro-inflammatory microglia. Moreover, AG490 treatment reduced oxidative DNA damage and cellular senescence in the brains of mice following ischemic stroke. Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) were associated with inflammation and senescence. Furthermore, AG490 blocked cGAS/STING/NF-κBp65 expression. Overall, our results indicate that inhibition of JAK2/STAT3 can alleviate the negative neurological consequences of ischemic stroke, likely due to repression of cGAS/STING/NF-κB p65, leading to reduced neuroinflammation and neuronal senescence. Therefore, JAK2/STAT3 may represent a viable therapeutic target for preventing senescence after ischemic stroke.

Changes in insulin resistance, glucose effectiveness, and first and second phases of insulin secretion in women aged 45-60 years old in Taiwan.

BACKGROUND: In women after menopause, the incidence of diabetes mellitus increases. Increased insulin resistance (IR), decreased glucose effectiveness (GE), and the first and second phases of insulin secretion (FPIS and SPIS), are the four most important factors that trigger glucose intolerance and diabetes (diabetogenic factor [DF]). In the cross-sectional study, we enrolled nondiabetic women between the ages of 45 and 60 years to observe the changes in DFs during the perimenopausal period and to elucidate the underlying mechanisms of diabetes in menopausal women. METHODS: We randomly enrolled 4194 women who underwent health checkups. Using demographic and biochemical data, IR, FPIS, SPIS, and GE were calculated using previously published equations. The relationship between the DFs and age was evaluated using a simple correlation. RESULTS: Body mass index, blood pressure, fasting plasma glucose, low-density lipoprotein cholesterol, triglyceride, and SPIS were higher, and GE was lower in older women (≥52 years old). A significant decrease in GE and increased SPIS were observed with age. However, no changes were observed in IR or FPIS. CONCLUSION: The IR and FPIS did not change during perimenopause. Increased SPIS may compensate for the decrease in GE, which is probably one of the reasons for the higher incidence of diabetes in menopausal women.

Using Machine Learning to Predict Abnormal Carotid Intima-Media Thickness in Type 2 Diabetes.

Carotid intima-media thickness (c-IMT) is a reliable risk factor for cardiovascular disease risk in type 2 diabetes (T2D) patients. The present study aimed to compare the effectiveness of different machine learning methods and traditional multiple logistic regression in predicting c-IMT using baseline features and to establish the most significant risk factors in a T2D cohort. We followed up with 924 patients with T2D for four years, with 75% of the participants used for model development. Machine learning methods, including classification and regression tree, random forest, eXtreme gradient boosting, and Naïve Bayes classifier, were used to predict c-IMT. The results showed that all machine learning methods, except for classification and regression tree, were not inferior to multiple logistic regression in predicting c-IMT in terms of higher area under receiver operation curve. The most significant risk factors for c-IMT were age, sex, creatinine, body mass index, diastolic blood pressure, and duration of diabetes, sequentially. Conclusively, machine learning methods could improve the prediction of c-IMT in T2D patients compared to conventional logistic regression models. This could have crucial implications for the early identification and management of cardiovascular disease in T2D patients.