Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.

OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS. METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms. RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio. INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024.

Ubiquitination-dependent degradation of nucleolin mediated by porcine circovirus type 3 capsid protein.

IMPORTANCE: Porcine circovirus type 3 (PCV3) is an emerging pathogen that causes multisystem disease in pigs and poses a severe threat to the swine industry. However, the mechanisms of how PCV3 uses host proteins to regulate its own life cycle are not well understood. In this study, we found that PCV3 capsid protein interacts with nucleolin and degrades it. Degradation of nucleolin by the PCV3 capsid protein requires recruitment of the enzyme RNF34, which is transported to the nucleolus from the cytoplasm in the presence of the PCV3 capsid protein. Nucleolin also decreases PCV3 replication by promoting the release of interferon ß. These findings clarify the mechanism by which nucleolin modulates PCV3 replication in cells, thereby facilitating to provide an important strategy for preventing and controlling PCV3 infection.

Insight into neofunctionalization of 2,3-oxidosqualene cyclases in B,C-ring-opened triterpene biosynthesis in quinoa.

Bioactive triterpenes feature complex fused-ring structures, primarily shaped by the first-committed enzyme, 2,3-oxidosqualene cyclases (OSCs) in plant triterpene biosynthesis. Triterpenes with B,C-ring-opened skeletons are extremely rare with unknown formation mechanisms, harbouring unchartered chemistry and biology. Here, through mining the genome of Chenopodium quinoa followed by functional characterization, we identified a stress-responsive and neofunctionalized OSC capable of generating B,C-ring-opened triterpenes, including camelliol A and B and the novel (-)-quinoxide A as wax components of the specialized epidermal bladder cells, namely the quinoxide synthase (CqQS). Protein structure analysis followed by site-directed mutagenesis identified key variable amino acid sites underlying functional interconversion between pentacyclic ß-amyrin synthase (CqbAS1) and B,C-ring-opened triterpene synthase CqQS. Mutation of one key residue (N612K) in even evolutionarily distant Arabidopsis ß-amyrin synthase could generate quinoxides, indicating a conserved mechanism for B,C-ring-opened triterpene formation in plants. Quantum computation combined with docking experiments further suggests that conformations of conserved W613 and F413 of CqQS might be key to selectively stabilizing intermediate carbocations towards B,C-ring-opened triterpene formation. Our findings shed light on quinoa triterpene skeletal diversity and mechanisms underlying B,C-ring-opened triterpene biosynthesis, opening avenues towards accessing their chemistry and biology and paving the way for quinoa trait engineering and quality improvement.

A multi-task learning model using RR intervals and respiratory effort to assess sleep disordered breathing.

BACKGROUND: Sleep-disordered breathing (SDB) affects a significant portion of the population. As such, there is a need for accessible and affordable assessment methods for diagnosis but also case-finding and long-term follow-up. Research has focused on exploiting cardiac and respiratory signals to extract proxy measures for sleep combined with SDB event detection. We introduce a novel multi-task model combining cardiac activity and respiratory effort to perform sleep-wake classification and SDB event detection in order to automatically estimate the apnea-hypopnea index (AHI) as severity indicator. METHODS: The proposed multi-task model utilized both convolutional and recurrent neural networks and was formed by a shared part for common feature extraction, a task-specific part for sleep-wake classification, and a task-specific part for SDB event detection. The model was trained with RR intervals derived from electrocardiogram and respiratory effort signals. To assess performance, overnight polysomnography (PSG) recordings from 198 patients with varying degree of SDB were included, with manually annotated sleep stages and SDB events. RESULTS: We achieved a Cohen's kappa of 0.70 in the sleep-wake classification task, corresponding to a Spearman's correlation coefficient (R) of 0.830 between the estimated total sleep time (TST) and the TST obtained from PSG-based sleep scoring. Combining the sleep-wake classification and SDB detection results of the multi-task model, we obtained an R of 0.891 between the estimated and the reference AHI. For severity classification of SBD groups based on AHI, a Cohen's kappa of 0.58 was achieved. The multi-task model performed better than a single-task model proposed in a previous study for AHI estimation, in particular for patients with a lower sleep efficiency (R of 0.861 with the multi-task model and R of 0.746 with single-task model with subjects having sleep efficiency < 60%). CONCLUSION: Assisted with automatic sleep-wake classification, our multi-task model demonstrated proficiency in estimating AHI and assessing SDB severity based on AHI in a fully automatic manner using RR intervals and respiratory effort. This shows the potential for improving SDB screening with unobtrusive sensors also for subjects with low sleep efficiency without adding additional sensors for sleep-wake detection.

Improving dermal fibroblast-to-epidermis communications and aging wound repair through extracellular vesicle-mediated delivery of Gstm2 mRNA.

Skin aging is characterized by the disruption of skin homeostasis and impaired skin injury repair. Treatment of aging skin has long been limited by the unclear intervention targets and delivery techniques. Engineering extracellular vesicles (EVs) as an upgraded version of natural EVs holds great potential in regenerative medicine. In this study, we found that the expression of the critical antioxidant and detoxification gene Gstm2 was significantly reduced in aging skin. Thus, we constructed the skin primary fibroblasts-derived EVs encapsulating Gstm2 mRNA (EVsGstm2), and found that EVsGstm2 could significantly improve skin homeostasis and accelerate wound healing in aged mice. Mechanistically, we found that EVsGstm2 alleviated oxidative stress damage of aging dermal fibroblasts by modulating mitochondrial oxidative phosphorylation, and promoted dermal fibroblasts to regulate skin epidermal cell function by paracrine secretion of Nascent Polypeptide-Associated Complex Alpha subunit (NACA). Furthermore, we confirmed that NACA is a novel skin epidermal cell protective molecule that regulates skin epidermal cell turnover through the ROS-ERK-ETS-Cyclin D pathway. Our findings demonstrate the feasibility and efficacy of EVs-mediated delivery of Gstm2 for aged skin treatment and unveil novel roles of GSTM2 and NACA for improving aging skin.

A Receptor Integrin ß1 Promotes Infection of Avian Metapneumovirus Subgroup C by Recognizing a Viral Fusion Protein RSD Motif.

Avian metapneumovirus subgroup C (aMPV/C) causes respiratory diseases and egg dropping in chickens and turkeys, resulting in severe economic losses to the poultry industry worldwide. Integrin ß1 (ITGB1), a transmembrane cell adhesion molecule, is present in various cells and mediates numerous viral infections. Herein, we demonstrate that ITGB1 is essential for aMPV/C infection in cultured DF-1 cells, as evidenced by the inhibition of viral binding by EDTA blockade, Arg-Ser-Asp (RSD) peptide, monoclonal antibody against ITGB1, and ITGB1 short interfering (si) RNA knockdown in cultured DF-1 cells. Simulation of the binding process between the aMPV/C fusion (F) protein and avian-derived ITGB1 using molecular dynamics showed that ITGB1 may be a host factor benefiting aMPV/C attachment or internalization. The transient expression of avian ITGB1-rendered porcine and feline non-permissive cells (DQ cells and CRFK cells, respectively) is susceptible to aMPV/C infection. Kinetic replication of aMPV/C in siRNA-knockdown cells revealed that ITGB1 plays an important role in aMPV/C infection at the early stage (attachment and internalization). aMPV/C was also able to efficiently infect human non-small cell lung cancer (A549) cells. This may be a consequence of the similar structures of both metapneumovirus F protein-specific motifs (RSD for aMPV/C and RGD for human metapneumovirus) recognized by ITGB1. Overexpression of avian-derived ITGB1 and human-derived ITGB1 in A549 cells enhanced aMPV/C infectivity. Taken together, this study demonstrated that ITGB1 acts as an essential receptor for aMPV/C attachment and internalization into host cells, facilitating aMPV/C infection.

Health risks and sources of trace elements and black carbon in PM2.5 from 2019 to 2021 in Beijing.

A comprehensive health risk assessment of PM2.5 is meaningful to understand the current status and directions regarding further improving air quality from the perspective of human health. In this study, we evaluated the health risks of PM2.5 as well as highly toxic inorganic components, including heavy metals (HMs) and black carbon (BC) based on long-term observations in Beijing from 2019 to 2021. Our results showed that the relative risks of chronic obstructive pulmonary disease, lung cancer, acute lower respiratory tract infection, ischemic heart disease, and stroke decreased by 4.07%-9.30% in 2020 and 2.12%-6.70% in 2021 compared with 2019. However, they were still at high levels ranging from 1.26 to 1.77, in particular, stroke showed the highest value in 2021. Mn had the highest hazard quotient (HQ, from 2.18 to 2.56) for adults from 2019 to 2021, while Ni, Cr, Pb, As, and BC showed high carcinogenic risks (CR > 1.0×10-6) for adults. The HQ values of Mn and As and the CR values of Pb and As showed constant or slight upwards trends during our observations, which is in contrast to the downward trends of other HMs and PM2.5. Mn, Cr, and BC are crucial toxicants in PM2.5. A significant shrink of southern region sourcesof HMs and BCshrank suggests the increased importance of local sources. Industry, dust, and biomass burning are the major contributors to the non-carcinogenic risks, while traffic emissions and industry are the dominant contributors to the carcinogenic risks in Beijing.

Vitamin D and diabetic peripheral neuropathy: A multi-centre nerve conduction study among Chinese patients with type 2 diabetes.

AIMS: Increasing numbers of reports link vitamin D deficiency to diabetic peripheral neuropathy (DPN), yet evidence regarding neurological deficits and electromyogram is scarce. The present multi-centre study sought to investigate these associations based on objective quantifications. MATERIALS AND METHODS: Information on DPN-related symptoms, signs, all diabetic microvascular complications, and nerve conduction abilities (quantified by nerve conduction amplitude and velocity, F-wave minimum latency (FML) of peripheral nerves) were collected from a derivation cohort of 1192 patients with type 2 diabetes (T2D). Correlation, regression analysis, and restricted cubic splines (RCS) were used to explore linear and non-linear relationships between vitamin D and DPN, which were validated in an external cohort of 223 patients. RESULTS: Patients with DPN showed lower levels of vitamin D than those without DPN; patients with vitamin D deficiency (<30 nmol/L) tended to suffer more DPN-related neurological deficits (paraesthesia, prickling, abnormal temperature, ankle hyporeflexia, and distal pall hypoesthesia correlating with MNSI-exam score (Y = -0.005306X + 2.105, P = 0.048). Worse nerve conduction abilities (decreased motor nerve amplitude, sensory nerve amplitude, motor nerve velocity, and increased FML) were also observed in these patients. Vitamin D had a significant threshold association with DPN (adjusted OR = 4.136, P = 0.003; RCS P for non-linearity = 0.003) and correlates with other microvascular complications (diabetic retinopathy and diabetic nephropathy). CONCLUSIONS: Vitamin D is associated with the conduction ability of peripheral nerves and may have a nerve- and threshold-selective relationship with the prevalence and severity of DPN among patients with T2D.

Virtual screening for potential discoidin domain receptor 1 (DDR1) inhibitors based on structural assessment.

Discoidin domain receptor 1 (DDR1) (EC Number 2.7.10.1) has recently been considered as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF). However, none of the currently discovered DDR1 inhibitors have been included in clinical studies due to low target specificity or druggability limitations, necessitating various approaches to develop novel DDR1 inhibitors. In this study, to assure target specificity, a docking assessment of the DDR1 crystal structures was undertaken to find the well-differentiated crystal structure, and 4CKR was identified among many crystal structures. Then, using the best pharmacophore model and molecular docking, virtual screening of the ChEMBL database was done, and five potential molecules were identified as promising inhibitors of DDR1. Subsequently, all hit compound complex systems were validated using molecular dynamics simulations and MM/PBSA methods to assess the stability of the system after ligand binding to DDR1. Based on molecular dynamics simulations and hydrogen-bonding occupancy analysis, the DDR1-Cpd2, DDR1-Cpd17, and DDR1-Cpd18 complex systems exhibited superior stability compared to the DDR1-Cpd1 and DDR-Cpd33 complex systems. Meanwhile, when targeting DDR1, the descending order of the five hit molecules' binding free energies was Cpd17 (- 145.820 kJ/mol) > Cpd2 (- 131.818 kJ/mol) > Cpd18 (- 130.692 kJ/mol) > Cpd33 (- 129.175 kJ/mol) > Cpd1 (- 126.103 kJ/mol). Among them, Cpd2, Cpd17, and Cpd18 showed improved binding characteristics, indicating that they may be potential DDR1 inhibitors. In this research, we developed a high-hit rate, effective screening method that serves as a theoretical guide for finding DDR1 inhibitors for the development of IPF therapeutics.

Neuron-specific enolase in hypertension patients with acute ischemic stroke and its value forecasting long-term functional outcomes.

BACKGROUND: Neuron Specific Enolase (NSE), a neuro-biochemical protein marker, may correlate with the prognosis of stroke patients. Moreover, hypertension is the most common comorbidities in patients with acute ischemic stroke (AIS), and the relationship between NSE levels and long-term functional outcomes in such an increasingly large population is unclear. The aim of the study was to investigate the relationships mentioned above and optimize the prediction models. METHODS: From 2018 to 2020, 1086 admissions for AIS were grouped as hypertension and non-hypertension, while hypertension group was randomly divided into development and validation cohorts for internal validation. The severity of the stroke was staged by National Institutes of Health Stroke Scale (NIHSS) score. Stroke prognosis after 1 year of follow up was documented by modified Rankin Scale (mRS) score. RESULTS: Analysis revealed the following findings:(i) Serum NSE levels increased greatly in hypertension subjects with poor functional outcomes(p = 0.046). However, there was no association in non-hypertension individuals(p = 0.386). (ii) In addition to the conventional factors (age and NIHSS score), NSE (OR:1.241, 95% CI: 1.025-1.502) and prothrombin time were significantly related to the incidence of unfavorable outcomes. (iii)Based on the above four indicators, a novel nomogram was established to predict the prognosis of stoke in hypertension patients with the c-index values of 0.8851. CONCLUSIONS: Overall, high baseline NSE is associated with poor 1-year AIS outcomes in hypertension patients, suggesting NSE may be a potential prognostic and therapeutic target for stroke in hypertension patients.

[Qualitative and quantitative study of constituents in Lysionoti Herba based on UHPLC-Q-Exactive Orbitrap HRMS and HPLC-UV].

Ultra-high performance liquid chromatography-quadrupole-Exactive Orbitrap high resolution mass spectrometry(UHPLC-Q-Exactive Orbitrap HRMS) was employed to systematically analyze the chemical constituents in Lysionoti Herba, and high perfor-mance liquid chromatography-ultraviolet(HPLC-UV) to determine the content of main compounds. A Synergi~(TM) Hydro-RP 100 Å colu-mn(2 mm×100 mm, 2.5 µm) was used for gradient elution with acetonitrile-0.1% aqueous formic acid as the mobile phase at a flow rate of 0.2 mL·min~(-1) and a column temperature of 40 ℃. MS and MS/MS were conducted with electrospray ionization(ESI) in both positive and negative modes. The chemical components in Lysionoti Herba were identified by comparison with the retention time and mass spectra of reference compounds and the relevant mass spectral data reported in MS databases and relevant literature. Furthermore, the content of five constituents(neochlorogenic acid, chlorogenic acid, forsythoside B, acteoside, and nevadensin) in different Lysiono-ti Herba samples was simultaneously determined by HPLC-UV at the wavelength of 330 nm. A total of 84 compounds were identified in Lysionoti Herba, including 27 flavonoids, 20 phenylethanoid glycosides, 5 amino acids, 18 organic acids, 1 alkaloid, 6 nucleosides, and 7 others. The content of neochlorogenic acid, chlorogenic acid, forsythoside B, acteoside, and nevadensin showed good linear relationship(r>0.999) with the peak area within certain concentration ranges, which were 3.22-102.90, 12.84-410.82, 31.63-1 012.01, 25.00-800.11, and 4.08-130.51 µg·mL~(-1), respectively. The instrument precision, method repeatability, and solution stability all met requirement, and the average recovery rate was 97.31%-100.2%, with RSD ranging from 0.95% to 2.4%. The content of the five components varied among different Lysionoti Herba samples collected from different regions of Guizhou, and the average content of forsythoside B was the highest. The established qualitative method can rapidly and efficiently identify the chemical components of Lysionoti Herba, and the developed HPLC-UV method can simultaneously determine the content of five components in a simple, ra-pid, and accurate manner, providing a scientific basis for the quality evaluation of Lysionoti Herba.

Hypolipidemic effect of ethanol extract from Chimonanthus nitens Oliv. leaves in hyperlipidemia rats via activation of the leptin/JAK2/STAT3 pathway.

BACKGROUND: This study aims to explore the protective role of ethanol extract from Chimonanthus nitens Oliv. leaf (COE) in hyperlipidemia via the leptin/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. METHODS: Male Sprague‒Dawley rats were randomly divided into 6 groups (n = 8): normal-fat diet (NMD), high-fat diet (HFD), HFD treated with simvastatin (SIM, 5 mg/kg/day), and HFD treated with COE (40, 80, 160 mg/kg/day). Lipid parameters, oxidative stress factors, serum leptin, body weight, hepatic wet weight and liver index were measured. Proteins in the leptin/JAK2/STAT3 pathway in liver tissues were determined using western blotting. Additionally, the expression levels of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) were quantified using western blotting and quantitative real-time polymerase chain reaction (qPCR). RESULTS: COE decreased HFD-induced increases in body weight, hepatic wet weight and the liver index. HFD-induced hyperlipidemia and oxidative stress were observed in rat serum and livers. Additionally, COE repressed these two symptoms in rats fed a HFD. Moreover, COE caused CYP7A1 upregulation and HMGCR downregulation in HFD-fed rats. Mechanistically, COE induced the expression of leptin receptor (OB-Rb) and JAK2 and STAT3 phosphorylation in HFD-treated rats. CONCLUSION: COE activates the leptin/JAK2/STAT3 pathway, leading to an improvement in liver function and lipid metabolism and ultimately alleviating hyperlipidemia in rats. Therefore, COE may be a potential hypolipidemic drug for the treatment of hyperlipidemia.

Design of Rational JAK3 Inhibitors Based on the Parent Core Structure of 1,7-Dihydro-Dipyrrolo [2,3-b:3',2'-e] Pyridine.

JAK3 differs from other JAK family members in terms of tissue distribution and functional properties, making it a promising target for autoimmune disease treatment. However, due to the high homology of these family members, targeting JAK3 selectively is difficult. As a result, exploiting small changes or selectively boosting affinity within the ATP binding region to produce new tailored inhibitors of JAK3 is extremely beneficial. PubChem CID 137321159 was used as the lead inhibitor in this study to preserve the characteristic structure and to collocate it with the redesigned new parent core structure, from which a series of 1,7-dihydro-dipyrrolo [2,3-b:3',2'-e] pyridine derivatives were obtained using the backbone growth method. From the proposed compounds, 14 inhibitors of JAK3 were found based on the docking scoring evaluation. The RMSD and MM/PBSA methods of molecular dynamics simulations were also used to confirm the stable nature of this series of complex systems, and the weak protein−ligand interactions during the dynamics were graphically evaluated and further investigated. The results demonstrated that the new parent core structure fully occupied the hydrophobic cavity, enhanced the interactions of residues LEU828, VAL836, LYS855, GLU903, LEU905 and LEU956, and maintained the structural stability. Apart from this, the results of the analysis show that the binding efficiency of the designed inhibitors of JAK3 is mainly achieved by electrostatic and VDW interactions and the order of the binding free energy with JAK3 is: 8 (−70.286 kJ/mol) > 11 (−64.523 kJ/mol) > 6 (−51.225 kJ/mol) > 17 (−42.822 kJ/mol) > 10 (−40.975 kJ/mol) > 19 (−39.754 kJ/mol). This study may provide a valuable reference for the discovery of novel JAK3 inhibitors for those patients with immune diseases.

Early-life gut microbial colonization shapes Th1/Th2 balance in asthma model in BALB/c mice.

BACKGROUND: We aimed to investigate the effect of early-life diverse microbial exposures on gut microbial colonization in an OVA-induced asthma model in BALB/c mice. METHODS: BALB/c mice were divided into 4 groups: A, offsprings were kept in a SPF environment during fetal, lactation, and childhood periods; B, offsprings were kept in the SPF environment during fetal and lactation periods, and kept in the general environment during childhood; C, offsprings were kept in the SPF environment only during fetal period, and then kept in the general environment; and D, offsprings were kept in the general environment during whole periods. The diversity of intestinal flora was analyzed using denaturing gradient gel electrophoresis. Mice were sensitized with OVA to establish an animal model of asthma. Then asthma-related inflammatory cytokines and histological analysis were performed. RESULTS: The diversity of intestinal microflora in group D was significantly higher than groups A, B and C at three days and three weeks after birth, and the diversity of intestinal microflora in groups C and D were significantly higher than groups A and B at five weeks after birth. The pathologic scores of OVA-induced asthmatic mice in group D were significantly lower than group A, and serum IFN-γ levels and the IFN-γ/IL-4 ratio in group D were significantly higher than group A. CONCLUSIONS: Exposure to diverse microbial environments in early life affects gut microbial colonization in BALB/c mice. The diversity of the intestinal flora in early life may prevent airway inflammation in asthma via regulating the Th1/Th2 balance.

[A Review of Methods for Early Evaluation of Alzheimer's Disease].

With the intensified aging problem, the study of age-related diseases is becoming more and more significant. Alzheimer's disease is a kind of dementia, with senile plaques and neurofibrillary tangles as the main pathological features, and has become one of the major diseases that endanger the health of the elderly. This review is concentrated on the research of the early assessment of Alzheimer's disease. The current situation of early diagnosis of the disease is analyzed, and a prospect of the future development of early assessment means of the disease is also made in the paper.

Identification of potentially high drug-like VEGFR2/c-Met dual-target type II kinase inhibitors with symmetric skeletons based on structural screening.

Vascular endothelial growth factor receptor 2 (VEGFR2) and c-Mesenchymal epithelial transition factor (c-Met) are tyrosine kinase receptors associated with the occurrence of malignant tumors. Studies have shown that inhibition of VEGFR2 promotes a feedback increase in c-Met, a mechanism linked to the emergence of resistance to VEGFR2 inhibitors. Therefore, treatment targeting both VEGFR2 and c-Met will have better application prospects. In this study, hierarchical virtual screening was performed on ZINC15, Molport and Mcule-ULTIMATE databases to identify potential VEGFR2/c-Met dual inhibitors. Firstly, the best pharmacophore model for each target was used to cross-screen the three databases, and the compounds that could match the two pharmacophore models were then retained based on the Fit Value of the respective crystal ligands. Compounds ZINC, MOL, and MLB named after their database sources were retained by binding pattern analysis and docking assessment. ADMET predictions indicated that ZINC had significantly higher oral bioavailability compared to the approved drug cabozantinib. This is likely due to ZINC's unique symmetrical backbone with less structure complexity, which may reduce the occurrence of adverse effects. Molecular dynamics simulations and binding free energy analysis showed that all three hit compounds were able to stably bind at the active site, but only ZINC could form high occupancy of hydrogen bonds with both VEGFR2 and c-Met, and also only ZINC had a higher binding free energy than crystal ligands, suggesting that ZINC was the most likely potential VEGFR2/c-Met dual-target inhibitor. This finding provides a promising starting point for the development of VEGFR2/c-Met dual-target inhibitors.Communicated by Ramaswamy H. Sarma.

How inflammation dictates diabetic peripheral neuropathy: An enlightening review.

BACKGROUND: Diabetic peripheral neuropathy (DPN) constitutes a debilitating complication associated with diabetes. Although, the past decade has seen rapid developments in understanding the complex etiology of DPN, there are no approved therapies that can halt the development of DPN, or target the damaged nerve. Therefore, clarifying the pathogenesis of DPN and finding effective treatment are the crucial issues for the clinical management of DPN. AIMS: This review is aiming to summary the current knowledge on the pathogenesis of DPN, especially the mechanism and application of inflammatory response. METHODS: We systematically summarized the latest studies on the pathogenesis and therapeutic strategies of diabetic neuropathy in PubMed. RESULTS: In this seminal review, the underappreciated role of immune activation in the progression of DPN is scrutinized. Novel insights into the inflammatory regulatory mechanisms of DPN have been unearthed, illuminating potential therapeutic strategies of notable clinical significance. Additionally, a nuanced examination of DPN's complex etiology, including aberrations in glycemic control and insulin signaling pathways, is presented. Crucially, an emphasis has been placed on translating these novel understandings into tangible clinical interventions to ameliorate patient outcomes. CONCLUSIONS: This review is distinguished by synthesizing cutting-edge mechanisms linking inflammation to DPN and identifying innovative, inflammation-targeted therapeutic approaches.

Leukocyte indicators and variations predict worse outcomes after intravenous thrombolysis in patients with acute ischemic stroke.

Leukocytes are systematic inflammation indicators related to stroke prognosis and can exhibit large dynamic waves before and after recombinant tissue plasminogen activator (r-tPA) therapy. However, additional evidence is needed to determine the prognostic significance of various leukocytes including both static and dynamic data among patients who underwent r-tPA therapy. A total of 251 patients treated with r-tPA were included; their leukocyte data were collected at two time points, and patients were followed up for three months. Analysis revealed the following findings. (i) Patients with hemorrhagic transformation (HT) and unfavorable outcomes had a higher level of leukocytes after r-tPA therapy (leukocyte count (adjusted OR (aOR) 1.191 for HT and 1.184 for unfavorable outcomes), neutrophil count (aOR 1.215 and 1.214), neutrophil-to-lymphocyte ratio (NLR; aOR 1.084 and 1.091)) and larger dynamic leukocyte changes. (ii)Among all leukocytes, the NLR after r-tPA administration demonstrated the strongest correlation with HT and unfavorable outcomes. (iii) Patients with an NLR ≥ 3.322 had a 3.492-fold increased risk for HT, and those with an NLR ≥ 5.511 had a 3.024-fold increased risk for functional outcomes. Overall, this study shows that leukocytes, especially leukocyte count, neutrophil count and the NLR, are independently associated with HT and functional outcomes in stroke patients.

The Use of Respiratory Effort Improves an ECG-Based Deep Learning Algorithm to Assess Sleep-Disordered Breathing.

BACKGROUND: Sleep apnea is a prevalent sleep-disordered breathing (SDB) condition that affects a large population worldwide. Research has demonstrated the potential of using electrocardiographic (ECG) signals (heart rate and ECG-derived respiration, EDR) to detect SDB. However, EDR may be a suboptimal replacement for respiration signals. METHODS: We evaluated a previously described ECG-based deep learning algorithm in an independent dataset including 198 patients and compared performance for SDB event detection using thoracic respiratory effort versus EDR. We also evaluated the algorithm in terms of apnea-hypopnea index (AHI) estimation performance, and SDB severity classification based on the estimated AHI. RESULTS: Using respiratory effort instead of EDR, we achieved an improved performance in SDB event detection (F1 score = 0.708), AHI estimation (Spearman's correlation = 0.922), and SDB severity classification (Cohen's kappa of 0.62 was obtained based on AHI). CONCLUSION: Respiratory effort is superior to EDR to assess SDB. Using respiratory effort and ECG, the previously described algorithm achieves good performance in a new dataset from an independent laboratory confirming its adequacy for this task.

How vitamins act as novel agents for ameliorating diabetic peripheral neuropathy: A comprehensive overview.

Diabetic peripheral neuropathy (DPN) is a pervasive and incapacitating sequela of diabetes, affecting a significant proportion of those diagnosed with the disease, yet an effective treatment remains elusive. Vitamins have been extensively studied, emerging as a promising target for diagnosing and treating various systemic diseases, but their role in DPN is not known. This review collates and synthesizes knowledge regarding the interplay between vitamins and DPN, drawing on bibliographies from prior studies and relevant articles, and stratifying the therapeutic strategies from prophylactic to interventional. In addition, the clinical evidence supporting the use of vitamins to ameliorate DPN is also evaluated, underscoring the potential of vitamins as putative therapeutic agents. We anticipate that this review will offer novel insights for developing and applying vitamin-based therapies for DPN.