Model informed precision medicine of Chinese herbal medicines formulas-A multi-scale mechanistic intelligent model.

Recent trends suggest that Chinese herbal medicine formulas (CHM formulas) are promising treatments for complex diseases. To characterize the precise syndromes, precise diseases and precise targets of the precise targets between complex diseases and CHM formulas, we developed an artificial intelligence-based quantitative predictive algorithm (DeepTCM). DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling, molecular and theoretical levels of traditional Chinese medicine (TCM). As an example, our model simulated the optimal CHM formulas for the treatment of coronary heart disease (CHD) with depression, and through model sensitivity analysis, we calculated the balanced scoring of the formulas. Furthermore, we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions. Finally, we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice. This novel multiscale model opened up a new avenue to combine "disease syndrome" and "macro micro" system modeling to facilitate translational research in CHM formulas.

Frailty worsens long-term survival in patients with colorectal cancer: a systematic review and meta-analysis.

Background: Colorectal cancer (CRC) is the 3rd most common cancer in men and 2nd most common malignancy in females across the globe leading to high mortality rates. Frailty is an age-related syndrome that has been associated with high morbidity and mortality. This systematic review aimed to examine if frailty can predict long-term (>1 year) outcomes of patients with CRC. Methods: This PROSPERO registered review examined the databases of PubMed, Embase, and Web of Science till 4th September 2023 for cohort studies assessing the association between frailty and long-term outcomes of CRC. Results: 15 studies with 45288 patients were included. 6573 patients (14.5%) were frail. Meta-analysis demonstrated that frailty was associated with statistically significant poor overall survival (OS) (HR: 2.11 95% CI: 1.44, 3.08 I2 = 94%) (14 studies), cancer-specific survival (CSS) (HR: 4.59 95% CI: 2.75, 7.67 I2 = 38%) (2 studies), and disease-free survival (DFS) (HR: 1.46 95% CI: 1.28, 1.66 I2 = 0%) (5 studies) after CRC. Subgroup analysis for OS based on study type, location, sample size, stage of cancer, percentage with frailty, treatment, adjustment for CRC stage and comorbidities, and follow-up did not change the results. These results were not altered in significance on sensitivity analysis. Conclusion: Our results show that frail CRC patients have poor OS and DFS as compared to non-frail patients. Variations in frailty measurement tools and high inter-study heterogeneity are major limitations of the review. Systematic review registration: https://www.crd.york.ac.uk/prospero/, PROSPERO, CRD42023450586.

Cord blood stem cell­derived Angptl7 ameliorates the severity of bronchopulmonary dysplasia via anti­inflammatory and proangiogenic effects.

Perinatal exposure of the neonatal lung to inflammation leads to decreased lung angiogenesis and the development of bronchopulmonary dysplasia (BPD). Notably, autologous cord blood mononuclear cells (ACBMNCs) can substantially prevent severe BPD and decrease the inflammatory response in surviving very preterm neonates. Angiopoietin­like protein 7 (Angptl7) is one of the main paracrine cytokines in cord blood stem cells, and is capable of stimulating human hematopoietic stem and progenitor cell expansion. The present study compared Angptl7 levels between the ACBMNCs infusion and control groups (cohort 1). Subsequently, the association between cord blood Angptl7 levels and BPD incidence in a cohort of very preterm neonates was assessed (cohort 2). The hypothesis was further verified in a lipopolysaccharide (LPS)­induced lung injury mouse model. The mRNA expression levels and protein concentrations of inflammatory cytokines in the lung tissue and mouse serum were measured using reverse transcription­quantitative PCR and ELISA, respectively. The number and diameter of lung vessels and macrophage infiltration were assessed using immunofluorescence staining. Compared with in the control group, Angptl7 levels were significantly higher in the ACBMNCs infusion group in cohort 1. In cohort 2, the cord blood Angptl7 levels were significantly lower in infants who later developed BPD. Multiple linear regression analysis showed that higher Angptl7 level was an independent protective factor for BPD. The concentrations of interleukin­6 and monocyte chemoattractant protein­1 were negatively correlated with cord blood Angptl7 level; whereas, vascular endothelial growth factor­A levels were positively correlated with Angptl7 levels. In the LPS­induced lung injury mouse model, the LPS group presented with a significant loss of pulmonary vessels and smaller vessel diameters, which were ameliorated in the Angptl7 treatment group. Furthermore, LPS­induced lung inflammation and macrophage infiltration were alleviated by Angptl7 treatment (P<0.05). In conclusion, the anti­inflammatory and proangiogenic effects of Angptl7 derived from cord blood stem cells may ameliorate BPD severity. The trial for cohort 1 was registered at ClinicalTrials.gov (trial registration no. NCT02999373; date registered, December 21, 2016).

SIRT1 Activator E1231 Alleviates Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Silencing information regulator 1 (SIRT1) was demonstrated to modulate cholesterol and lipid metabolism in NAFLD. Here, a novel SIRT1 activator, E1231, was studied for its potential improvement effects on NAFLD. C57BL/6J mice were fed a high-fat and high-cholesterol diet (HFHC) for 40 weeks to create a NAFLD mouse model, and E1231 was administered by oral gavage (50 mg/kg body weight, once/day) for 4 weeks. Liver-related plasma biochemistry parameter tests, Oil Red O staining, and hematoxylin-eosin staining results showed that E1231 treatment ameliorated plasma dyslipidemia, plasma marker levels of liver damage (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), liver total cholesterol (TC) and triglycerides (TG) contents, and obviously decreased hepatic steatosis score and NAFLD Activity Score (NAS) in the NAFLD mouse model. Western blot results showed that E1231 treatment significantly regulated lipid-metabolism-related protein expression. In particular, E1231 treatment increased SIRT1, PGC-1α, and p-AMPKα protein expression but decreased ACC and SCD-1 protein expression. Additionally, in vitro studies demonstrated that E1231 inhibited lipid accumulation and improved mitochondrial function in free-fatty-acid-challenged hepatocytes, and required SIRT1 activation. In conclusion, this study illustrated that the SIRT1 activator E1231 alleviated HFHC-induced NAFLD development and improved liver injury by regulating the SIRT1-AMPKα pathway, and might be a promising candidate compound for NAFLD treatment.

PHT427 as an effective New Delhi metallo-ß-lactamase-1 (NDM-1) inhibitor restored the susceptibility of meropenem against Enterobacteriaceae producing NDM-1.

Introduction: With the increasingly serious problem of bacterial drug resistance caused by NDM-1, it is an important strategy to find effective inhibitors to assist ß-lactam antibiotic treatment against NDM-1 resistant bacteria. In this study, PHT427 (4-dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide) was identified as a novel NDM-1 inhibitor and restored the susceptibility of meropenem against Enterobacteriaceae producing NDM-1. Methods: We used a high throughput screening model to find NDM-1 inhibitor in the library of small molecular compounds. The interaction between the hit compound PHT427 and NDM-1 was analyzed by fluorescence quenching, surface plasmon resonance (SPR) assay, and molecular docking analysis. The efficacy of the compound in combination with meropenem was evaluated by determining the FICIs of Escherichia coli BL21(DE3)/pET30a(+)-bla NDM-1 and Klebsiella pneumoniae clinical strain C1928 (producing NDM-1). In addition, the mechanism of the inhibitory effect of PHT427 on NDM-1 was studied by site mutation, SPR, and zinc supplementation assays. Results: PHT427 was identified as an inhibitor of NDM-1. It could significantly inhibit the activity of NDM-1 with an IC50 of 1.42 µmol/L, and restored the susceptibility of meropenem against E. coli BL21(DE3)/pET30a(+)-bla NDM-1 and K. pneumoniae clinical strain C1928 (producing NDM-1) in vitro. The mechanism study indicated that PHT427 could act on the zinc ions at the active site of NDM-1 and the catalytic key amino acid residues simultaneously. The mutation of Asn220 and Gln123 abolished the affinity of NDM-1 by PHT427 via SPR assay. Discussion: This is the first report that PHT427 is a promising lead compound against carbapenem-resistant bacteria and it merits chemical optimization for drug development.

Reduction of antibiotic use and multi-drug resistance bacteria infection in neonates after improvement of antibiotics use strategy in a level 4 neonatal intensive care unit in southern China.

The investigation on antibiotic stewardship in neonatal intensive care unit in China is scarce. This study aimed to analyze the effect of a comprehensive 2-year antibiotic stewardship in a level 4 NICU. During this baseline period from October 1st 2017 to October 1st 2019, continuation of empirical antibiotic therapy for ruled-out sepsis courses was beyond 72 h and for pneumonia was more than 7 days. Meropenem or vancomycin was used even if they were not the only bacterial sensitive antibiotics. The intervention period was from October 2nd 2019 to August 23rd 2021. Three areas for quality improvement were targeted in our center: discontinuation of antibiotic use in ruled-out sepsis within 72 h, treatment duration for culture-negative pneumonia less than 7 days, and vancomycin or meropenem was not used unless the cultured bacteria was only susceptible to them. The total antibiotic consumption decreased from 791.1 to 466.3 days of therapy per 1000 patient days from baseline to intervention period. Antibiotics were stopped within 72 h for 47.48% patients with rule-out sepsis and within 7 days for 75.70% patients with pneumonia compared with 11.56% and 37.69% during the baseline period respectively. The prevalence of multi-drug resistance bacteria decreased from 67.20 to 48.90%. The total use rate of meropenem or vancomycin decreased from 7.6 to 1.8%. Our quality improvement approach on antibiotic strategy significantly reduced antibiotic use and prevalence of multi-drug resistance bacteria in our NICU.

Trichostatin D as a Novel KLF2 Activator Attenuates TNFα-Induced Endothelial Inflammation.

Krüppel-like factor 2 (KLF2) is an atherosclerotic protective transcription factor that maintains endothelial cell homeostasis through its anti-inflammatory, anti-oxidant, and antithrombotic properties. The aim of this study was to discover KLF2 activators from microbial secondary metabolites and explore their potential molecular mechanisms. By using a high-throughput screening model based on a KLF2 promoter luciferase reporter assay, column chromatography, electrospray ionization mass spectrometry (ESI-MS), and nuclear magnetic resonance (NMR) spectra, trichostatin D (TSD) was isolated from the rice fermentation of Streptomyces sp. CPCC203909 and identified as a novel KLF2 activator. Real-time-quantitative polymerase chain reaction (RT-qPCR) results showed that TSD upregulated the mRNA level of KLF2 in endothelial cells. Functional assays showed that TSD attenuated monocyte adhesion to endothelial cells, decreased vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, and exhibited an anti-inflammatory effect in tumor necrosis factor alpha (TNFα)-induced endothelial cells. We further demonstrated through siRNA and western blot assays that the effects of TSD on monocyte adhesion and inflammation in endothelial cells were partly dependent on upregulating KLF2 expression and then inhibiting the NOD-like receptor protein 3 (NLRP3)/Caspase-1/interleukin-1beta (IL-1ß) signaling pathway. Furthermore, histone deacetylase (HDAC) overexpression and molecular docking analysis results showed that TSD upregulated KLF2 expression by inhibiting HDAC 4, 5, and 7 activities. Taken together, TSD was isolated from the fermentation of Streptomyces sp. CPCC203909 and first reported as a potential activator of KLF2 in this study. Furthermore, TSD upregulated KLF2 expression by inhibiting HDAC 4, 5, and 7 and attenuated endothelial inflammation via regulation of the KLF2/NLRP3/Caspase-1/IL-1ß signaling pathway.

LXR agonist inhibits inflammation through regulating MyD88 mRNA alternative splicing.

Liver X receptors (LXRs) are important regulators of cholesterol metabolism and inflammatory responses. LXR agonists exhibit potently anti-inflammatory effects in macrophages, which make them beneficial to anti-atherogenic therapy. In addition to transrepressive regulation by SUMOylation, LXRs can inhibit inflammation by various mechanisms through affecting multiple targets. In this study, we found that the classic LXR agonist T0901317 mediated numerous genes containing alternative splice sites, including myeloid differentiation factor 88 (MyD88), that contribute to inflammatory inhibition in RAW264.7 macrophages. Furthermore, T0901317 increased level of alternative splice short form of MyD88 mRNA by down-regulating expression of splicing factor SF3A1, leading to nuclear factor κB-mediated inhibition of inflammation. In conclusion, our results suggest for the first time that the LXR agonist T0901317 inhibits lipopolysaccharide-induced inflammation through regulating MyD88 mRNA alternative splicing involved in TLR4 signaling pathway.

Synthesis of N-methylpyridine-chlorofuranformamide analogs as novel OPG up-regulators and inhibitors of RANKL-induced osteoclastogenesis.

The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure-activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.

Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-ß-lactamase-1.

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.

Nuclear Factor Erythroid 2 Related Factor 2 Activator JC-5411 Inhibits Atherosclerosis Through Suppression of Inflammation and Regulation of Lipid Metabolism.

Phenethyl isothiocyanate is widely present in cruciferous vegetables with multiple biological effects. Here we reported the antiatherogenic effects and the underlying mechanisms of JC-5411 (Phenethyl isothiocyanate formulation) in vitro and in vivo. Luciferase reporter assay showed that JC-5411 increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). JC-5411 treatment significantly increased the protein expression of Nrf2 and its downstream target gene hemeoxygenase 1 (HO-1) in liver of apolipoprotein E deficient (ApoE-/-) mice. Importantly, JC-5411 treatment significantly reduced atherosclerotic plaque area in both en face aorta and aortic sinus when compared with model group in WD induced ApoE-/- mice. JC-5411 obviously decreased proinflammatory factors' levels in serum of ApoE-/- mice, LPS stimulated macrophages and TNFα induced endothelial cells, respectively. JC-5411 significantly decreased the levels of total cholesterol (TC) and triglyceride (TG) in both serum and liver of ApoE-/- mice and hyperlipidemic golden hamsters. Mechanism studies showed that JC-5411 exerted anti-inflammatory effect through activating Nrf2 signaling and inhibiting NF-κB and NLRP3 inflammasome pathway. JC-5411 exerted regulating lipid metabolism effect through increasing cholesterol transfer proteins (ABCA1 and LDLR) expression, regulating fatty acids synthesis related genes (p-ACC, SCD1 and FAS), and increasing fatty acids ß-oxidation (CPT1A) in vivo. Furthermore, JC-5411 treatment had a favorable antioxidant effect in ApoE-/- mice by increasing the antioxidant related genes expression. Taken together, we conclude that JC-5411 as a Nrf2 activator has anti-inflammatory, rebalancing lipid metabolism, and antioxidant effects, which makes it as a potential therapeutic agent against atherosclerosis.

H2depda: An acyclic adjuvant potentiates meropenem activity in vitro against metallo-ß-lactamase-producing enterobacterales.

Metallo-ß-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containing ligands, H2dedpa and compound 8, were discovered with excellent activities when combined with meropenem (MEM) against MBL (blaNDM and blaIMP)-producing clinical isolates, including Escherichia coli, Citrobacter freundii, Proteus mirabilis, Enterobacter cloacae and Klebsiella pneumoniae. In particular, these two compounds improved the activity of MEM against E. coli harboring the blaNDM-4 gene by nearly 40,960 times. H2dedpa (IC50 = 0.17 ±â€¯0.04 µM) and compound 8 (IC50 = 0.04 ±â€¯0.02 µM) showed higher inhibitory activity against blaNDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC50 = 28.84 ±â€¯0.70 µM). A sterilization kinetics experiment showed that H2dedpain combined with MEM could kill 99.9% of bacteria within 24 h H2dedpa and compound 8 are therefore promising MBL inhibitors.

Lift-off PMN-PT Thick Film for High Frequency Ultrasonic Biomicroscopy.

Piezoelectric 0.65Pb(Mg(1/3)Nb(2/3))O(3)-0.35PbTiO(3) (PMN-35PT) thick film with a thickness of approximately 12 µm has been deposited on the platinum buffered Si substrate via a sol-gel composite method. The separation of the film from the substrate was achieved using a wet chemical method. The lifted-off PMN-35PT thick film exhibited good dielectric and ferroelectric properties. At 1 kHz, the dielectric constant and the dielectric loss were 3,326 and 0.037, respectively, while the remnant polarization was 30.0 µC/cm(2). A high frequency single element acoustic transducer fabricated with this film showed a bandwidth at -6 dB of 63.6% at 110 MHz.