Electroacupuncture alleviates neuropathic pain by regulating hippocampal SP/NK1R/ARRB1 pathway. / 电针调控海马SP/NK1R/ARRB1é€šè·¯ç¼“è§£å¤§é¼ ç¥žç»ç— ç†æ€§ç–¼ç—›çš„ç ”ç©¶.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on pain, anxiety like behavior, and substance P(SP) /neurokinin-1 receptor (NK1R) /ß -arrestin 1(ARRB1) pathway related protein expression in hippocampus of chronic constriction injury (CCI) rats, so as to explore its mechanisms underlying improvement of neuropathic pain. METHODS: Twenty-seven male SD rats were randomly divided into sham operation, model and EA groups, with 9 rats in each group. The CCI model was established by ligature of the left sciatic nerve. On the 8th day following modeling, EA (2 Hz, 0.5-1.5 mA) was applied to the left "Huantiao" (GB34) and "Yanglingquan" (GB34) for 30 min, once every other day for 13 times. Mechanical paw withdrawal threshold (MWT), thermal paw withdrawal threshold (TWL) and difference of the weight distribution of the hind limbs were detected before operation and at the 5th, 9th, 17th, 25th and 33rd days after operation. Open field test was used to evaluate the anxiety-like behavior of rats. The content of SP in hippocampus was determined by ELISA. The protein expression of NK1R and ARRB1 in hippocampus was detected by Western blot. RESULTS: Compared with the sham operation group, the MWT and TWL of the left hind limb at the 5th, 9th, 17th, 25th and 33rd days after operation, the time of entering the central area and the total distance of movement, and the content of SP in the hippocampus were significantly decreased (P<0.001, P<0.01), while the difference of the weight distribution of the hind limbs at the 5th, 9th, 17th, 25th and 33rd days after operation and the protein expression of NK1R and ARRB1 were significantly increased (P<0.001, P<0.05) in the model group. After EA intervention, the MWT and TWL of the left hind limb, the time of entering the central area and the total moving distance, and the expression of SP in the hippocampus were significantly increased (P<0.01, P<0.001, P<0.05), while the difference in the weight distribution of the hind limbs was significantly reduced, and the expression of NK1R and ARRB1 protein in the hippocampus were significantly decreased (P<0.001, P<0.05) in the EA group. CONCLUSIONS: EA can effectively improve the pain and anxiety behaviors in CCI rats, and reverse the abnormal expression of SP, NK1R and ARRB1 proteins in the hippocampus, which may be related to its effects in regulating the SP/NK1R/ARRB1 pathway in the hippocampus.

Cognitive impairment and depression precede increased HDL-C levels in middle-aged and older Chinese adults: cross-lagged panel analyses.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) is widely recognized for its protective effects against cognitive decline. However, recent studies have presented conflicting results, with some suggesting no significant cognitive benefits or even an increased risk of dementia associated with high HDL-C levels. For those who suffer from depression, the cognitive benefits of HDL-C may be diminished or reversed. The purpose of this study is to investigate the associations between HDL-C, cognitive ability, and depressive symptoms in middle-aged and older Chinese adults. METHODS: The datasets utilized were sourced from the China Health and Retirement Longitudinal Study (CHARLS) for the years 2011 and 2015, comprising 4,302 participants. Cross-lagged models were employed to explore the temporal sequence between cognitive performance and HDL-C levels, and to examine the interplay among depression, cognition, and HDL-C. Confounding factors such as sociodemographic characteristics, sleep conditions, and history of chronic diseases were controlled for. RESULTS: The analysis revealed unidirectional effects of baseline impaired cognition and greater severity of depression on increased HDL-C levels at follow-up (ß = - 0.036 and ß = 0.028, respectively, P < 0.05). However, higher baseline HDL-C levels did not significantly predict cognitive performance or depression 4 years later (ß = - 0.008 and ß = 0.023, respectively, P > 0.05). Depressive symptoms and cognition were found to have a significant bidirectional association (ß = - 0.026 and ß = - 0.053, respectively, P < 0.05). CONCLUSIONS: Cognitive impairment and depression are associated with higher HDL-C levels, whereas higher HDL-C levels do not appear to protect against cognitive decline or depressive symptoms. These findings underscore the importance of preserving cognitive and mental health, which may lower the likelihood of cardiovascular disease and dementia. Future studies should validate these findings and develop targeted interventions tailored to specific populations.

Effect of intravenous different drugs on the prevention of restlessness during recovery period of pediatric laparoscopic surgery: a randomized control trial.

PURPOSE: To explored the impact of dexmedetomidine and esketamine in mitigating restlessness during the postoperative recovery phase following laparoscopic surgery in children. METHODS: 102 individuals aged 1 to 7 years experiencing laparoscopic surgery were randomly allocated into three groups, each accepting 1 µg/kg of dexmedetomidine, 0.3 mg/kg of esketamine, or saline immediately at the end of carbon dioxide pneumoperitoneum. Emergence agitation (EA) occurrence was assessed by PAED scale and 5-point agitation scale. Pain was judged using Face, Legs, Activity, Cry, and Consolability (FLACC) scale. The recovery time, extubation time, and post-anesthesia care unit (PACU) stay time were recorded for all three groups. RESULTS: Patients administered 1 µg/kg of dexmedetomidine (8.8%) and individuals given 0.3 mg/kg of esketamine (11.8%) showed lower incidences of emergence agitation compared to those receiving saline (35.5%; P = 0.009). There was no statistically significant difference in the time to discharge from the PACU among the three groups of patients (P > 0.05). The recovery time and extubation time were notably extended in the dexmedetomidine group (40.88 ± 12.95 min, 42.50 ± 13.38 min) when compared to the saline group (32.56 ± 13.05 min, 33.29 ± 11.30 min; P = 0.009, P = 0.010). CONCLUSION: Following CO2 pneumoperitoneum in pediatric laparoscopic surgeries, the intravenous administration of 1 µg/kg dexmedetomidine or 0.3 mg/kg esketamine effectively lowers EA occurrence without extending PACU time.

Dysregulation of Serum Exosomal Lipid Metabolism in Schizophrenia: A Biomarker Perspective.

Exosomes, crucial extracellular vesicles, have emerged as potential biomarkers for neurological conditions, including schizophrenia (SCZ). However, the exploration of exosomal lipids in the context of SCZ remains scarce, necessitating in-depth investigation. Leveraging ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), this study aimed to characterize the lipidomic profile of serum exosomes from SCZ patients, assessing their potential as novel biomarkers for SCZ diagnosis through absolute quantitative lipidomics. Our comprehensive lipidomic analysis unveiled 39 serum exosomal lipids that were differentially expressed between SCZ patients (n = 20) and healthy controls (HC, n = 20). These findings revealed a profound dysregulation in lipid metabolism pathways, notably in sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism. Among these, seven exosomal lipids stood out for their diagnostic potential, exhibiting remarkable ability to differentiate SCZ patients from HCs with an unparalleled classification performance, evidenced by an area under the curve (AUC) of 0.94 (95% CI, 0.82-1.00). These lipids included specific ceramides and phosphoethanolamines, pointing to a distinct lipid metabolic fingerprint associated with SCZ. Furthermore, bioinformatic analyses reinforced the pivotal involvement of these lipids in SCZ-related lipid metabolic processes, suggesting their integral role in the disorder's pathophysiology. This study significantly advances our understanding of SCZ by pinpointing dysregulated exosomal lipid metabolism as a key factor in its pathology. The identified serum exosome-derived lipids emerge as compelling biomarkers for SCZ diagnosis, offering a promising avenue towards the development of objective and reliable diagnostic tools.

Multi-dimensional epidemiology and informatics data on COVID-19 wave at the end of zero COVID policy in China.

Background: China exited strict Zero-COVID policy with a surge in Omicron variant infections in December 2022. Given China's pandemic policy and population immunity, employing Baidu Index (BDI) to analyze the evolving disease landscape and estimate the nationwide pneumonia hospitalizations in the post Zero COVID period, validated by hospital data, holds informative potential for future outbreaks. Methods: Retrospective observational analyses were conducted at the conclusion of the Zero-COVID policy, integrating internet search data alongside offline records. Methodologies employed were multidimensional, encompassing lagged Spearman correlation analysis, growth rate assessments, independent sample T-tests, Granger causality examinations, and Bayesian structural time series (BSTS) models for comprehensive data scrutiny. Results: Various diseases exhibited a notable upsurge in the BDI after the policy change, consistent with the broader trajectory of the COVID-19 pandemic. Robust connections emerged between COVID-19 and diverse health conditions, predominantly impacting the respiratory, circulatory, ophthalmological, and neurological domains. Notably, 34 diseases displayed a relatively high correlation (r > 0.5) with COVID-19. Among these, 12 exhibited a growth rate exceeding 50% post-policy transition, with myocarditis escalating by 1,708% and pneumonia by 1,332%. In these 34 diseases, causal relationships have been confirmed for 23 of them, while 28 garnered validation from hospital-based evidence. Notably, 19 diseases obtained concurrent validation from both Granger causality and hospital-based data. Finally, the BSTS models approximated approximately 4,332,655 inpatients diagnosed with pneumonia nationwide during the 2 months subsequent to the policy relaxation. Conclusion: This investigation elucidated substantial associations between COVID-19 and respiratory, circulatory, ophthalmological, and neurological disorders. The outcomes from comprehensive multi-dimensional cross-over studies notably augmented the robustness of our comprehension of COVID-19's disease spectrum, advocating for the prospective utility of internet-derived data. Our research highlights the potential of Internet behavior in predicting pandemic-related syndromes, emphasizing its importance for public health strategies, resource allocation, and preparedness for future outbreaks.

Indoleamine 2,3-dioxygenase-1 involves in CD8+T cell exhaustion in glioblastoma via regulating tryptophan levels.

Indoleamine 2,3-dioxygenase-1 (IDO-1) is an enzyme that catalyzes the metabolism of tryptophan (Trp). It is expressed in limited amounts in normal tissues but significantly upregulated during inflammation and infection. Various inflammatory factors, especially IFN-γ, can induce the expression of IDO-1. While extensive research has been conducted on the role of IDO-1 in tumors, its specific role in complex central nervous system tumors such as glioblastoma (GBM) remains unclear. This study aims to explore the role of IDO-1 in the development of GBM and analyze its association with tryptophan levels and CD8+T cell exhaustion in the tumor region. To achieve this, we constructed an orthotopic mouse glioblastoma tumor model to investigate the specific mechanisms between IDO-1, GBM, and CD8+T cell exhaustion. Our results showed that IDO-1 can promote CD8+T cell exhaustion by reducing tryptophan levels. When IDO-1 was knocked down in glioblastoma cells, other cells within the tumor microenvironment upregulated IDO-1 expression to compensate for the loss and enhance immunosuppressive effects. Therefore, the data suggest that the GBM microenvironment controls tryptophan levels by regulating IDO-1 expression, which plays a critical role in immune suppression. These findings support the use of immune therapy in combination with IDO-1 inhibitors or tryptophan supplementation as a potential treatment strategy.

Synthesis of quinoxalines and assessment of their inhibitory effects against human non-small-cell lung cancer cells.

Twenty-six quinoxalin derivatives were synthesized to assess their biological activities against human non-small-cell lung cancer cells (A549 cells). Compound 4b (IC50 = 11.98 ± 2.59 µM) and compound 4m (IC50 = 9.32 ± 1.56 µM) possess anticancer activity comparable to 5-fluorouracil (clinical anticancer drug) (IC50 = 4.89 ± 0.20 µM). Western blot tests further confirmed that compound 4m effectively induced apoptosis of A549 cells through mitochondrial- and caspase-3-dependent pathways. The introduction of bromo groups instead of nitro groups into the quinoxaline skeleton has been shown to provide better inhibition against lung cancer cells in this article. This modification in the molecular structure could enhance the biological activity and effectiveness of quinoxaline derivatives in the design and synthesis of anticancer drugs, making bromo-substituted quinoxalines a promising avenue for further research and development in anticancer therapeutics.

A feasibility study on utilizing machine learning technology to reduce the costs of gastric cancer screening in Taizhou, China.

Aim: To optimize gastric cancer screening score and reduce screening costs using machine learning models. Methods: This study included 228,634 patients from the Taizhou Gastric Cancer Screening Program. We used three machine learning models to optimize Li's gastric cancer screening score: Gradient Boosting Machine (GBM), Distributed Random Forest (DRF), and Deep Learning (DL). The performance of the binary classification models was evaluated using the area under the curve (AUC) and area under the precision-recall curve (AUCPR). Results: In the binary classification model used to distinguish low-risk and moderate- to high-risk patients, the AUC in the GBM, DRF, and DL full models were 0.9994, 0.9982, and 0.9974, respectively, and the AUCPR was 0.9982, 0.9949, and 0.9918, respectively. Excluding Helicobacter pylori IgG antibody, pepsinogen I, and pepsinogen II, the AUC in the GBM, DRF, and DL models were 0.9932, 0.9879, and 0.9900, respectively, and the AUCPR was 0.9835, 0.9716, and 0.9752, respectively. Remodel after removing variables IgG, PGI, PGII, and G-17, the AUC in GBM, DRF, and DL was 0.8524, 0.8482, 0.8477, and AUCPR was 0.6068, 0.6008, and 0.5890, respectively. When constructing a tri-classification model, we discovered that none of the three machine learning models could effectively distinguish between patients at intermediate and high risk for gastric cancer (F1 scores in the GBM model for the low, medium and high risk: 0.9750, 0.9193, 0.5334, respectively; F1 scores in the DRF model for low, medium, and high risks: 0.9888, 0.9479, 0.6694, respectively; F1 scores in the DL model for low, medium, and high risks: 0.9812, 0.9216, 0.6394, respectively). Conclusion: We concluded that gastric cancer screening indicators could be optimized when distinguishing low-risk and moderate to high-risk populations, and detecting gastrin-17 alone can achieve a good discriminative effect, thus saving huge expenditures.

Screening of herbal extracts binding with vascular endothelial growth factor by applying HerboChip platform.

BACKGROUND: Traditional Chinese medicine (TCM) has been hailed as a rich source of medicine, but many types of herbs and their functions still need to be rapidly discovered and elucidated. HerboChip, a target-based drug screening platform, is an array of different fractions deriving from herbal extracts. This study was designed to identify effective components from TCM that interact with vascular endothelial growth factor (VEGF) as a target using HerboChip. METHODS: Selected TCMs that are traditionally used as remedies for cancer prevention and wound healing were determined and extracted with 50% ethanol. Biotinylated-VEGF was hybridized with over 500 chips coated with different HPLC-separated fractions from TCM extracts and straptavidin-Cy5 was applied to identify plant extracts containing VEGF-binding fractions. Cytotoxicity of selected herbal extracts and their activities on VEGF-mediated angiogenic functions were evaluated. RESULTS: Over 500 chips were screened within a week, and ten positive hits were identified. The interaction of the identified herbal extracts with VEGF was confirmed in cultured endothelial cells. The identified herbs promoted or inhibited VEGF-mediated cell proliferation, migration and tube formation. Results from western blotting analysis demonstrated the identified herbal extracts significantly affected VEGF-triggered phosphorylations of eNOS, Akt and Erk. Five TCMs demonstrated potentiating activities on the VEGF response and five TCMs revealed suppressive activities. CONCLUSIONS: The current results demonstrated the applicability of the HerboChip platform and systematically elucidated the activity of selected TCMs on angiogenesis and its related signal transduction mechanisms.

Salinomycin, a potent inhibitor of XOD and URAT1, ameliorates hyperuricemic nephropathy by activating NRF2, modulating the gut microbiota, and promoting SCFA production.

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p-NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic.

ß-1,4-Galactosyltransferase 1 protects against cerebral ischemia injury in mice by suppressing ferroptosis via the TAZ/Nrf2/HO-1 signaling pathway.

BACKGROUND: Ischemic stroke leads a primary cause of mortality in human diseases, with a high disability rate worldwide. This study aims to investigate the function of ß-1,4-galactosyltransferase 1 (B4galt1) in mouse brain ischemia/reperfusion (I/R) injury. METHODS: Recombinant human B4galt1 (rh-B4galt1) was intranasally administered to the mice model of middle cerebral artery occlusion (MCAO)/reperfusion. In this study, the impact of rh-B4galt1 on cerebral injury assessed using multiple methods, including the neurological disability status scale, 2,3,5-triphenyltetrazolium chloride (TTC), Nissl and TUNEL staining. This study utilized laser speckle Doppler flowmeter to monitor the cerebral blood flow. Western blotting was performed to assess the protein expression levels, and fluorescence-labeled dihydroethidium method was performed to determine the superoxide anion generation. Assay kits were used for the measurement of iron, malondialdehyde (MDA) and glutathione (GSH) levels. RESULTS: We demonstrated that rh-B4galt1 markedly improved neurological function, reduced cerebral infarct volume and preserved the completeness of blood-brain barrier (BBB) for preventing damage. These findings further illustrated that rh-B4galt1 alleviated oxidative stress, lipid peroxidation, as well as iron deposition induced by I/R. The vital role of ferroptosis was proved in brain injury. Furthermore, the rh-B4galt1 could increase the levels of TAZ, Nrf2 and HO-1 after I/R. And TAZ-siRNA and ML385 reversed the neuroprotective effects of rh-B4galt1. CONCLUSIONS: The results indicated that rh-B4galt1 implements neuroprotective effects by modulating ferroptosis, primarily via upregulating TAZ/Nrf2/HO-1 pathway. Thus, B4galt1 could be seen as a promising novel objective for ischemic stroke therapy.

Association Between Systolic Blood Pressure and in-Hospital Mortality Among Congestive Heart Failure Patients with Chronic Obstructive Pulmonary Disease in the Intensive Care Unit: A Retrospective Cohort Study.

Background: There has been a growing body of research focusing on patients with Congestive Heart Failure (CHF) and chronic obstructive pulmonary disease (COPD) admitted to the intensive care unit (ICU). However, the optimal blood pressure (BP) level for such patients remains insufficiently explored. This study aimed to investigate the associations between systolic blood pressure (SBP) and in-hospital mortality among ICU patients with both CHF and COPD. Methods: This retrospective cohort study enrolled 6309 patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. SBP was examined as both a continuous and categorical variable, with the primary outcome being in-hospital mortality. The investigation involved multivariable logistic regression, restricted cubic spline regression, and subgroup analysis to determine the relationship between SBP and mortality. Results: The cohort consisted of 6309 patients with concurrent CHF and COPD (3246 females and 3063 males), with an average age of 73.0 ± 12.5 years. The multivariate analysis revealed an inverse association between SBP and in-hospital mortality, both as a continuous variable (odds ratio = 0.99 [95% CI, 0.99~1]) and as a categorical variable (divided into quintiles). Restricted cubic spline analysis demonstrated an L-shaped relationship between SBP and mortality risk (P nonlinearity < 0.001), with an inflection point at 99.479 mmHg. Stratified analyses further supported the robustness of this correlation. Conclusion: The relationship between SBP and in-hospital mortality in patients with both CHF and COPD follows an L-shaped pattern, with an inflection point at approximately 99.479 mmHg.

Nanoarchitectonics of Methyl and Aldehyde Group-Decorated SOD-Type Metal-Azolate Framework for SF6 Capture and Recovery.

Sulfur hexafluoride (SF6) is widely used as an insulating gas, being an etchant and contrast agent in the electrical, semiconductor, and medical industries. However, due to its long lifetime and high global warming potential in the atmosphere, SF6 must be carefully handled to prevent leakage during production and usage. Herein, we report a sod-net metal-azolate framework (MAF) named MAF-stu-111, which decorates methyl and aldehyde groups in the porous windows, showing high adsorption affinity for SF6 at low pressure. Stability tests, gas adsorption, and breakthrough experiments demonstrated that MAF-stu-111 possesses excellent water and chemical stability, fully reversible SF6 uptake, high SF6/N2 separation selectivity (10:90, 285.2), good reusability, and high SF6 recovery purity (99.03%). Theoretical calculations revealed that hydrogen atoms of methyl and aldehyde groups can form multiple hydrogen bonds with SF6 molecules, which ensure that SF6 molecules are firmly held within the MAF-stu-111 framework, playing a key role in the selective separation of SF6/N2.

Glymphatic function and its influencing factors in different glucose metabolism states.

BACKGROUND: Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized. AIM: To investigate the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states, the present study employed diffusion tensor imaging along the perivascular space (DTI-ALPS) index. METHODS: Sample size was calculated using the pwr package in R software. This cross-sectional study enrolled 22 patients with normal glucose metabolism (NGM), 20 patients with prediabetes, and 22 patients with type 2 diabetes mellitus (T2DM). A 3.0T magnetic resonance imaging was used to evaluate the function of the glymphatic system. The mini-mental state examination (MMSE) was used to assess general cognitive function. The DTI-ALPS index of bilateral basal ganglia and the mean DTI-ALPS index was calculated. Further, the correlation between DTI-ALPS and clinical features was assessed. RESULTS: The left-side, right-side, and mean DTI-ALPS index in the T2DM group were significantly lower than that in the NGM group. The right-side DTI-ALPS and mean DTI-ALPS index in the T2DM group were significantly lower than those in the prediabetes group. DTI-ALPS index lateralization was not observed. The MMSE score in the T2DM group was significantly lower than that in the NGM and prediabetes group. After controlling for sex, the left-side DTI-ALPS and mean DTI-ALPS index in the prediabetes group were positively correlated with 2-hour postprandial blood glucose level; the left-side DTI-ALPS index was negatively correlated with total cholesterol and low-density lipoprotein level. The right-side DTI-ALPS and mean DTI-ALPS index were negatively correlated with the glycosylated hemoglobin level and waist-to-hip ratio in the prediabetes group. The left-side, right-side, and mean DTI-ALPS index in the T2DM group were positively correlated with height. The left-side and mean DTI-ALPS index in the T2DM group were negatively correlated with high-density lipoprotein levels. CONCLUSION: Cerebral glymphatic system dysfunction may mainly occur in the T2DM stage. Various clinical variables were found to affect the DTI-ALPS index in different glucose metabolism states. This study enhances our understanding of the pathophysiology of diabetic brain damage and provides some potential biological evidence for its early diagnosis.

Association between Red Blood Cell Distribution Width and In-Hospital Mortality among Congestive Heart Failure Patients with Diabetes among Patients in the Intensive Care Unit: A Retrospective Cohort Study.

Background: Elevated red blood cell distribution width (RDW) levels are strongly associated with an increased risk of mortality in patients with congestive heart failure (CHF). Additionally, heart failure has been closely linked to diabetes. Nevertheless, the relationship between RDW and in-hospital mortality in the intensive care unit (ICU) among patients with both congestive heart failure (CHF) and diabetes mellitus (DM) remains uncertain. Methods: This retrospective study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, a comprehensive critical care repository. RDW was assessed as both continuous and categorical variables. The primary outcome of the study was in-hospital mortality at the time of hospital discharge. We examined the association between RDW on ICU admission and in-hospital mortality using multivariable logistic regression models, restricted cubic spline analysis, and subgroup analysis. Results: The cohort consisted of 7,063 patients with both DM and CHF (3,135 females and 3,928 males). After adjusting for potential confounders, we found an association between a 9% increase in mortality rate and a 1 g/L increase in RDW level (OR = 1.09; 95% CI, 1.05∼1.13), which was associated with 11 and 58% increases in mortality rates in Q2 (OR = 1.11, 95% CI: 0.87∼1.43) and Q3 (OR = 1.58, 95% CI: 1.22∼2.04), respectively, compared with that in Q1. Moreover, we observed a significant linear association between RDW and in-hospital mortality, along with strong stratified analyses to support the findings. Conclusions: Our findings establish a positive association between RDW and in-hospital mortality in patients with DM and CHF.

Controlled interconversion of macrocyclic atropisomers via defined intermediates.

Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C2v and C4v symmetry denoted as C2v-OC-4 and C4v-OC-4, respectively. Heating induces the efficient stepwise conversion of C2v- to C4v-OC-4 via a Cs-symmetric intermediate (Cs-OC-4). It differs from the typical transition state-mediated processes of simple C-C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C2v- and Cs-OC-4 from C4v-OC-4. In contrast to C2v-OC-4, C4v-OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations.

Integrating Mendelian randomization and single-cell RNA sequencing to identify therapeutic targets of baicalin for type 2 diabetes mellitus.

Background: Alternative and complementary therapies play an imperative role in the clinical management of Type 2 diabetes mellitus (T2DM), and exploring and utilizing natural products from a genetic perspective may yield novel insights into the mechanisms and interventions of the disorder. Methods: To identify the therapeutic target of baicalin for T2DM, we conducted a Mendelian randomization study. Druggable targets of baicalin were obtained by integrating multiple databases, and target-associated cis-expression quantitative trait loci (cis-eQTL) originated from the eQTLGen consortium. Summary statistics for T2DM were derived from two independent genome-wide association studies available through the DIAGRAM Consortium (74,124 cases vs. 824,006 controls) and the FinnGen R9 repository (9,978 cases vs. 12,348 controls). Network construction and enrichment analysis were applied to the therapeutic targets of baicalin. Colocalization analysis was utilized to assess the potential for the therapeutic targets and T2DM to share causative genetic variations. Molecular docking was performed to validate the potency of baicalin. Single-cell RNA sequencing was employed to seek evidence of therapeutic targets' involvement in islet function. Results: Eight baicalin-related targets proved to be significant in the discovery and validation cohorts. Genetic evidence indicated the expression of ANPEP, BECN1, HNF1A, and ST6GAL1 increased the risk of T2DM, and the expression of PGF, RXRA, SREBF1, and USP7 decreased the risk of T2DM. In particular, SREBF1 has significant interaction properties with other therapeutic targets and is supported by strong colocalization. Baicalin had favorable combination activity with eight therapeutic targets. The expression patterns of the therapeutic targets were characterized in cellular clusters of pancreatic tissues that exhibited a pseudo-temporal dependence on islet cell formation and development. Conclusion: This study identified eight potential targets of baicalin for treating T2DM from a genetic perspective, contributing an innovative analytical framework for the development of natural products. We have offered fresh insights into the connections between therapeutic targets and islet cells. Further, fundamental experiments and clinical research are warranted to delve deeper into the molecular mechanisms of T2DM.

Pediatric massage therapy in infants and children under 5 years: An umbrella review of systematic reviews.

Objective: To systematically evaluate and synthesize quantitative evidence regarding the effects of pediatric massage in infants and children under five years. Review methods: We conducted searches in databases including MEDLINE, Embase, Health Technology Assessment Database, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Allied and Complementary Medicine, Embase, the China National Knowledge Infrastructure, Wanfang Data, SinoMed, and CQVIP up to February 2024. Two reviewers independently screened articles, extracted data, and conducted quality appraisals on the included studies. We focused on systematic reviews with meta-analyses comparing pediatric tuina with a waitlist control, placebo, medication, massage combined with other interventions, and usual care. Outcomes analyzed included physical, psychological, developmental, and safety-related measures for children and their caregivers. Methodological quality was assessed using AMSTAR 2, and evidence quality was evaluated using the GRADE approach. Pooled effect estimates and heterogeneity were extracted for each meta-analyzed outcome. Evidence evaluated as 'high' and 'moderate' quality by GRADEpro with low heterogeneity are presented in the result section. Results: Twenty-two systematic reviews with meta-analysis of 81 outcomes were included. Seven studies (31.8 %) were high quality, and the evidence of 6 (7.4 %) outcomes were evaluated as high quality. The meta-analysis results demonstrate significant benefits of pediatric massage for infants compared to routine care, with increased weight gain (MD 455.07 g; 95 % CI 86.33 to 823.8; I2 = 0 %) based on 2 studies with 157 cases, length growth (MD 1.58 cm; 95 % CI 1.42 to 1.74; I2 = 25 %) from 9 studies with 1294 cases, reduced fussing (MD -0.37 time; 95 % CI -0.53 to -0.21; I2 = 30 %) according to 3 studies with 271 cases, and lower post-intervention bilirubin levels (3 studies/345 cases; MD -31.75 mmol/L; 95 % CI -40.05 to -23.46; I2 = 0 %). Pediatric massage was associated with reduced diarrhea incidence compared to waitlist controls (2 RCTs/310 cases; RR 0.39; 95 % CI 0.2 to 0.76; I2 = 0 %) and improved psychomotor development indices (4 RCTs/466 cases; SMD -0.35; 95 % CI -0.54 to -0.15; I2 = 1.06 %). Additionally, pediatric massage significantly enhanced blood oxygen saturation variation post-procedure for pain management (5 RCTs/355 cases; MD 1.05; 95 % CI 0.51 to 1.58; I2 = 0 %). Conclusions: Pediatric massage significantly enhances mother-child attachment, promotes physical growth, reduces fussing, lowers bilirubin levels, improves motor and psychomotor development, as well as manages digestive conditions and pain in children under 5 years. Future research should improve study quality and comprehensively report adverse events.

Glioblastoma-derived exosomes promote lipid accumulation and induce ferroptosis in dendritic cells via the NRF2/GPX4 pathway.

Glioblastoma-derived exosomes (GDEs), containing nucleic acids, proteins, fatty acids and other substances, perform multiple important functions in glioblastoma microenvironment. Tumor-derived exosomes serve as carriers of fatty acids and induce a shift in metabolism towards oxidative phosphorylation, thus driving immune dysfunction of dendritic cells (DCs). Lipid peroxidation is an important characteristic of ferroptosis. Nevertheless, it remains unclear whether GDEs can induce lipid accumulation and lipid oxidation to trigger ferroptosis in DCs. In our study, we investigate the impact of GDEs on lipid accumulation and oxidation in DCs by inhibiting GDEs secretion through knocking down the expression of Rab27a using a rat orthotopic glioblastoma model. The results show that inhibiting the secretion of GDEs can reduce lipid accumulation in infiltrating DCs in the brain and decrease mature dendritic cells (mDCs) lipid peroxidation levels, thereby suppressing glioblastoma growth. Mechanistically, we employed in vitro treatments of bone marrow-derived dendritic cells (BMDCs) with GDEs. The results indicate that GDEs decrease the viability of mDCs compared to immature dendritic cells (imDCs) and trigger ferroptosis in mDCs via the NRF2/GPX4 pathway. Overall, these findings provide new insights into the development of immune-suppressive glioblastoma microenvironment through the interaction of GDEs with DCs.