S-Shaped Helical Singlet Diradicaloid and Its Transformation to Circumchrysene via a Two-Stage Cyclization.

Polycyclic hydrocarbons with diradical and polyradical characters usually display unique reactivities in ring-cyclization reactions. However, such reactions are rarely used to construct π-extended polycyclic aromatic hydrocarbons. Here, we describe the synthesis of an S-shaped doubly helical singlet diradicaloid compound and its facile transformation into an unprecedented circumchrysene via a two-stage ring cyclization, which includes: (1) an eletrocylization from diradicaloid precursor and (2) a Scholl reaction. The reaction mechanism was investigated through in situ spectroscopic studies, assisted by theoretical calculations. This reaction sequence yields an optically resolved π-extended [5]helicene derivative with a fluorescence quantum yield up to 85% and a circularly polarized luminescence brightness up to 6.05 M-1 cm-1 in the far-red to near-infrared regions. This sequence also yielded a highly delocalized circumchrysene molecule, exhibiting large electron delocalization, moderate fluorescence quantum yield, and multistage redox properties.

Synthesis, Screening, and Evaluation of Theranostic Molecular CPCR4-Based Probe Targeting CXCR4.

Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.

Design, synthesis, and biological evaluation of first-in-class FABP1 inhibitors for the treatment of NASH.

The fatty acid-binding protein 1 (FABP1) is a fatty acid transporter protein that is considered as an emerging target for metabolic diseases. Despite forceful evidence that the inhibition of FABP1 is essential for ameliorating NASH, pharmacological control and validation of FABP1 are hindered by a lack of relevant inhibitors as pharmacological tool. Therefore, the development of effective FABP1 inhibitors is a current focus of research. Herein, we firstly reported the comprehensive structure-activity relationship (SAR) study of novel FABP1 inhibitors derived from high throughput screening of our in-house library, which resulting in the identification of the optimal compound 44 (IC50 = 4.46 ± 0.54 µM). Molecular docking studies revealed that 44 forms stable hydrogen bonds with amino acids around the active pocket of FABP1. Moreover, 44 alleviated the typical histological features of fatty liver in NASH mice, including steatosis, lobular inflammation, ballooning and fibrosis. Additionally, 44 has been demonstrated to have lipid metabolism regulating, anti-oxidative stress and hepatoprotective properties. This study might be provided a promising insight into the field of NASH and inspiration for the development of FABP1 inhibitors.

A new perspective on structural characterisation and immunomodulatory activity of arabinogalactan in Larix kaempferi from Qinling Mountains.

In this study, crude polysaccharide (LAG-C) and homogeneous arabinogalactan (LAG-W) were isolated from Qinling Larix kaempferi of Shaanxi Province. Bioactivity assays showed that LAG-W and LAG-C enhanced the phagocytic ability, NO secretion, acid phosphatase activity, and cytokine production (IL-6, IL-1ß, and TNF-α) of RAW264.7 macrophages. Notably, LAG-W exhibited a significantly stronger immunomodulatory effect than LAG-C. The primary structure of LAG-W was characterised by chemical methods (monosaccharide composition, methylation analysis, and alkali treatment) and spectroscopic techniques (gas chromatography-mass spectrometry, high-performance liquid chromatography-mass spectrometry, and 1D/2D nuclear magnetic resonance). LAG-W was identified as a 22.08 kilodaltons (kDa) neutral polysaccharide composed of arabinose and galactose at a 1:7.5 molar ratio. Its backbone consisted of repeated →3)-ß-Galp-(1→ residues. Side chains, connected at the O-6 position, were mainly composed of T-ß-Galp-(1→ and T-ß-Galp-(1→6)-ß-Galp-(1→ residues. And it also contained small amounts of T-ß-Arap-(1→, T-α-Araf-(1→6)-ß-Galp-(1→6)-ß-Galp-(1→, and T-α-Araf-(1→3)-α-Araf-(1→6)-ß-Galp-(1→ residues. By structurally and functionally characterising L. kaempferi polysaccharides, this study opens the way for the valorisation of this species.

Rapid quantification of grapeseed oil multiple adulterations using near-infrared spectroscopy coupled with a novel double ensemble modeling method.

As a high-quality edible oil, grapeseed oil is often adulterated with low-price/quality vegetable oils. A novel ensemble modeling method is proposed for quantitative analysis of grapeseed oil adulterations combined with near-infrared (NIR) spectroscopy. The method combines Monte Carlo (MC) sampling and whale optimization algorithm (WOA) to build numerous partial least squares (PLS) sub-models, named MC-WOA-PLS. A total of 80 adulterated grapeseed oil samples were prepared by mixing grapeseed oil with soybean oil, palm oil, cottonseed oil, and corn oil with the designed mass percentages. NIR spectra of the 80 samples were measured in a transmittance mode in the range of 12,000-4000 cm-1. Parameters in MC-WOA-PLS including the number of latent variables (LVs) in PLS, iteration number of WOA, whale number, number of PLS sub-models, and percentage of training subsets were optimized. To validate the prediction performance of the model, root mean square error of calibration (RMSEC), root mean square error of cross-validation (RMSECV), root mean squared error of prediction (RMSEP), correlation coefficient (R), residual predictive deviation (RPD), and standard deviation (S.D.) were used. Compared with PLS, standard normal variate-PLS (SNV-PLS), uninformative variable elimination-PLS (UVE-PLS), Monte Carlo uninformative variable elimination-PLS (MCUVE-PLS), randomization test-PLS (RT-PLS), variable importance in projection-PLS (VIP-PLS), and WOA-PLS, MC-WOA-PLS achieves the best prediction accuracy and stability for quantification of the five pure oils in adulterated grapeseed oil samples.

Microenvironment-differential Imaging of Demethylated Metabolites of Methionine for Identifying Ferroptosis Regional Preferences with Path-independent Equifinal Fluorescence Probes.

We realized the microenvironment-differential Imaging of demethylated metabolites of methionine and the regional regulation of ferroptosis.

Integrated analysis of natural glycans using a versatile pyrazolone-type heterobifunctional tag ANPMP.

Glycans mediate various biological processes through carbohydrate-protein interactions, and glycan microarrays have become indispensable tools for understanding these mechanisms. However, advances in functional glycomics are hindered by the absence of convenient and universal methods for obtaining natural glycan libraries with diverse structures from glycoconjugates. To address this challenge, we have developed an integrative approach that enables one-pot release and simultaneously capture, separation, structural characterization, and functional analysis of N/O-glycans. Using this approach, glycoconjugates are incubated with a pyrazolone-type heterobifunctional tag-ANPMP to obtain glycan-2ANPMP conjugates, which are then converted to glycan-AEPMP conjugates. We prepared a tagged glycan library from porcine gastric mucin, soy protein, human milk oligosaccharides, etc. Following derivatization by N-acetylation and permethylation, glycans were subjected to detailed structural characterization by ESI-MSn analysis, which revealed >83 highly pure glycan-AEPMPs containing various natural glycan epitopes. A shotgun microarray is constructed to study the fine details of glycan-bindings by proteins and antisera.

Comparative Analysis of Free and Glycoconjugates Oligosaccharide Content in Milk from Different Species.

Human milk is important for infant growth, and oligosaccharides are one of its main functional nutrients. To enable a systematic comparison of free oligosaccharide and glycoconjugate content in milk from different species, the phenol-sulfuric acid and resorcinol assays were combined to determine the content. Using real samples, the method revealed that human milk contained the highest amount of total, neutral (9.84 ± 0.31 g/L), and sialylated (3.21 ± 0.11 g/L) free oligosaccharides, followed by goat milk, with neutral (0.135 ± 0.015 g/L) and sialylated (0.192 ± 0.016 g/L) free oligosaccharides and at a distance by bovine and yak milk. The highest total glycoconjugate content was detected in yak milk (0.798 ± 0.011 g/L), followed by human, bovine, and goat milk. These findings suggest that goat milk is the best source of free oligosaccharides in infant formula and functional dairy products and yak milk is the best source of glycoconjugates.

Impact of structurally diverse polysaccharides on colonic mucin O-glycosylation and gut microbiota.

Understanding how dietary polysaccharides affect mucin O-glycosylation and gut microbiota could provide various nutrition-based treatments. Here, the O-glycan profile of the colonic mucosa and gut microbiome were investigated in C57BL/6J mice fed six structurally diverse dietary polysaccharides and a mixture of six fibers. Dietary polysaccharides increased total O-glycans, mainly by stimulating neutral glycans. Highly branched arabinogalactan promoted terminally fucosylated core 1 O-glycans; whereas linear polysaccharides, including pectin, konjac glucomannan, inulin, and the fiber mixture, favored terminally di-fucosylated O-glycans. The last three polysaccharides also lowered the level of sulfated O-glycans and sialylated mono-fucosylated O-glycans. Varied monosaccharide composition in mixed polysaccharides had a synergistic beneficial effect, boosting fucosylated neutral glycans, decreasing acidic glycans, and stimulating microbial richness and diversity. Dietary polysaccharides containing arabinose and sulfate groups enhanced the relative abundances of Akkermansia and Muribaculaceae, respectively. The present comparison reveals the relationship between dietary polysaccharide structure, mucin O-glycan composition, and intestinal microorganisms.

First Report of Cercospora Leaf Spot Caused by Cercospora cf. flagellaris on Lonicera japonica Thunb. in Henan, China.

Honeysuckle flower (Lonicera japonica Thunb.) is a traditional Chinese medicinal plant. It is perennial and widely cultivated in China, Japan and Korea. From late August to October in 2021 and 2022, leaf spots symptoms were observed on L. japonica in different planting fields in Yuzhou, Yuanyang and Fenqiu districts, Henan province, China. The disease incidence was above 85% which reduce photosynthesis. Early disease symptoms appeared as small, circular to elliptical, brown spots on the leaves and later the lesions (1 to 5 mm × 1 to 4 mm) slowly developed yellow haloes. The different brown lesions seldom merge and form larger irregular lesions. Small fragments (3 to 5 mm) of leave tissue were excised from the lesion margins and surface-sterilized in 3% NaClO for 3 min, followed by three washes with sterile distilled water, and then placed on potato dextrose agar (PDA) and incubated at 25°C in the dark for 5 days. A total number of 8 cultures were obtained and purified by single-spore subcultures on PDA for morphological identification. The colonies on PDA were whitish to gray, with cottony aerial mycelium. Conidiophores were fasciculate, olivaceous brown, straight or geniculate, uniform in width, multiseptate, and ranged from 290 to 700 µm (560 µm on average, n = 20). Conidia were hyaline, slightly curved or straight, needle shaped, truncate at the base, and terminal at the tip, 3 to 17-septate, and measuring 150 to 240 µm (180 µm on average, n = 20). The morphological features were consistent with Cercospora cf. flagellaris Ellis & G. Martin (Groenewald et al. 2013). The genomic DNA was extracted using CTAB method. The nuclear ribosomal internal transcribed spacer region (ITS), portions of the actin (ACT), histone H3 (HIS3), and translation elongation factor 1-α (TEF1) genes were amplified using primers ITS1/ITS4 (Groenewald et al. 2013), ACT-512F/ACT-783R (Carbone and Kohn 1999), CYLH3F/CYLH3R (Crous et al. 2006), and EF1-728F/EF1-986R (Carbone and Kohn 1999). The resulting 537-bp ITS, 226-bp ACT, 410-bp HIS3, and 306-bp TEF1 sequences of isolate JDJ002 were deposited in GenBank (accession nos. OR492367, OR548247, OR548248 and OR548248, respectively). Sequence analysis revealed that ITS, ACT, HIS3 and TEF1α sequences exhibited ≥99% of identity with the ITS (KP896013), ACT(KP895965), HIS3(MK991295) and TEF1 (MN180408) sequences of C. cf. flagellaris, respectively. A pathogenicity test was conducted on healthy of L. japonica leaves. The healthy leaves pricked from L. japonica plants, rinsed in autoclaved distilled water three times and dried with distilled filter paper. Then twelve healthy leave were inoculated with a mycelial plug (0.4 cm diameter) harvested from the periphery of two week-old colony. As negative control, leaves inoculated with PDA medium plugs. Inoculated leaves were covered with plastic bags to maintain high relative humidity and incubated at 25°C in growth chamber. After 7 days, the inoculated leaves showed symptoms identical to those observed in the field under natural conditions, whereas negative control remained symptom-free. Re-isolation of the fungus from lesions on inoculated leaves confirmed that the causal agent was C. cf. flagellaris. Pathogenicity tests were repeated three times by the same methods with the same results. To our knowledge, this is the first report of C. cf. flagellaris except Cercospora rhamni Fack., Alternaria alternata, Corynespora cassiicola or Phomopsis sp. causing leave spots on L. japonica in China.

Comprehensive Comparison of Bioactive N-Glycans among Seven Species of Livestock and Poultry Plasma Using a Relative Quantification Strategy.

Glycans have been proven to play special roles in keeping human health as a class of nutritional and bioactive ingredients in many food materials. However, their broad use in the food industry is hindered by the lack of comprehensive analytical methods for high-quality food glycomics studies and large-quantity raw materials for their production. This study focuses on structural identification and quantitative comparison of bioactive N-glycans in seven species of livestock and poultry plasma as potential natural glycan resources by a novel comprehensive relative quantification strategy based on stable isotope labeling with nondeuterated and deuterated 4-methyl-1-(2-hydrazino-2-oxoethyl)-pyridinium bromide (d0/d7-HMP) in combination with linkage-specific derivatization of sialic acid residues. Methodological validation of the method in terms of detection sensitivity, signal resolution, quantification linearity, precision, and accuracy on model neutral and complicated sialylated glycans demonstrated its advantages over the existing methods. Based on this method, a series of bioactive N-glycans were found in seven species of livestock and poultry plasma, and their differences in structure, abundance percentages, and relative contents of N-glycans were revealed, demonstrating their excellent applicability for comprehensive food glycomics analysis and great exploitation potential of these plasma samples as large-quantity raw materials in producing bioactive N-glycans for application in food and pharmaceutical industries.

Structure-activity strategies for mechanically responsive fluorescent materials: a molecular perspective.

Mechanical response luminescence (MRL) describes the photophysical properties triggered by mechanical stimulation. Usually, MRL can be regulated by intermolecular interactions, molecular conformation or molecular packing, to achieve the desirable optical properties. Herein, at the molecular level, this review covers the factors that influence mechanically responsive fluorescent materials, involving the single- or multifactorial modulation of aliphatic chains, donor-receptor switch, substituent adjustment, and position isomerism. According to these factors, the structure-activity strategies can be summarized as: (i) the self-recovery of optical properties, from the final to initial state, can be regulated by introducing long alkyl chains to a fluorophore. (ii) The sensitivity of MRL materials can be controlled by modifying the donor-acceptor structure via the changed ICT (intramolecular charge transfer) and intramolecular interaction. (iii) The electronic and steric effects of substituents can affect ICT and intermolecular interactions, thereby resulting in high quantum yield and high-contrast MRL materials via changing the molecular stacking of crystalline states. (iv) Intermolecular interaction is modulated by the position isomerism of the substituents, which results in switched molecular packing for the extended response toward a wide range of stimuli. It is anticipated that the molecular mechanisms of these structure-activity relationships will serve as a significant reference for developing novel, high contrast, recyclable mechanical response luminous materials.

HP-LSP: A reference of land surface phenology from fused Harmonized Landsat and Sentinel-2 with PhenoCam data.

Land surface phenology (LSP) products are currently of large uncertainties due to cloud contaminations and other impacts in temporal satellite observations and they have been poorly validated because of the lack of spatially comparable ground measurements. This study provided a reference dataset of gap-free time series and phenological dates by fusing the Harmonized Landsat 8 and Sentinel-2 (HLS) observations with near-surface PhenoCam time series for 78 regions of 10 × 10 km2 across ecosystems in North America during 2019 and 2020. The HLS-PhenoCam LSP (HP-LSP) reference dataset at 30 m pixels is composed of: (1) 3-day synthetic gap-free EVI2 (two-band Enhanced Vegetation Index) time series that are physically meaningful to monitor the vegetation development across heterogeneous levels, train models (e.g., machine learning) for land surface mapping, and extract phenometrics from various methods; and (2) four key phenological dates (accuracy ≤5 days) that are spatially continuous and scalable, which are applicable to validate various satellite-based phenology products (e.g., global MODIS/VIIRS LSP), develop phenological models, and analyze climate impacts on terrestrial ecosystems.

Liver-resident CD44hiCD27- γδT Cells Help to Protect Against Listeria monocytogenes Infection.

BACKGROUND & AIMS: Gamma delta (γδ) T cells are heterogeneous and functionally committed to producing interferon (IFN)-γ and interleukin (IL)-17. γδT cells are defined as tissue-resident lymphocytes in barrier tissues. Among them, IL-17-producing γδT cells are relatively abundant in the liver. However, a systematic and comprehensive understanding of the residency characteristics and function of hepatic IL-17A+ γδT cells is lacking. METHODS: We undertook a single-cell analysis of γδT17 cells derived from murine livers. A parabiosis model was used to assess tissue residency. Fluorescence-activated cell sorting and adoptive transfer experiments were used to investigate the response and protective role of liver-resident CD44hiCD27- γδT cells in Listeria monocytogenes infection. Transwell assay was used to assess the role of macrophages in the chemotaxis of liver-resident CD44hiCD27- γδT cells. RESULTS: We identified hepatic IL-17A-producing γδT cells as CD44hiCD27- γδT cells. They had tissue-resident characteristics and resided principally within the liver. Vγ6+ T cells also exhibited liver-resident features. Liver-resident CD44hiCD27- γδT cells had significantly increased proliferation capacity, and their proportion rapidly increased after infection. Some CD44hiCD27- γδT cells could produce IL-17A and IFN-γ simultaneously in response to Lm infection. Adoptive transfer of hepatic CD44hiCD27- γδT cells into Lm-infected TCRδ-/- mice led to markedly lower bacterial numbers in the liver. Hepatic macrophages promoted the migration and accumulation of liver-resident CD44hiCD27- γδT cells into infection sites. CONCLUSIONS: Liver-resident CD44hiCD27- γδT cells protect against Lm infection. Hepatic macrophages coordinate with liver-resident CD44hiCD27- γδT cells and contribute to the clearance of Lm at the early stage of infection corporately.

Discovery of novel carboxylesterase 2 inhibitors for the treatment of delayed diarrhea and ulcerative colitis.

Human carboxylesterase 2 (hCES2) is an enzyme that metabolizes irinotecan to SN-38, a toxic metabolite considered a significant source of side effects (lethal delayed diarrhea). The hCES2 inhibitors could block the hydrolysis of irinotecan in the intestine and thus reduce the exposure of intestinal SN-38, which may alleviate irinotecan-associated diarrhea. However, existing hCES2 inhibitors (except loperamide) are not used in clinical applications due to lack of validity or acceptable safety. Therefore, developing more effective and safer drugs for treating delayed diarrhea is urgently needed. This study identified a lead compound 1 with a novel scaffold by high-throughput screening in our in-house library. After a comprehensive structure-activity relationship study, the optimal compound 24 was discovered as an efficient and highly selective hCES2 inhibitor (hCES2: IC50 = 6.72 µM; hCES1: IC50 > 100 µM). Further enzyme kinetics study indicated that compound 24 is a reversible inhibitor of hCES2 with competitive inhibition mode (Ki = 6.28 µM). The cell experiments showed that compound 24 could reduce the level of hCES2 in living cells (IC50 = 6.54 µM). The modeling study suggested that compound 24 fitted very well with the binding pocket of hCES2 by forming multiple interactions. Notably, compound 24 can effectively treat irinotecan-induced delayed diarrhea and DSS-induced ulcerative colitis, and its safety has also been verified in subtoxic studies. Based on the overall pharmacological and preliminary safety profiles, compound 24 is worthy of further evaluation as a novel agent for irinotecan-induced delayed diarrhea.

Elevated estradiol levels on hCG trigger day adversely effects on the clinical pregnancy rates of blastocyst embryo transfer but not cleavage-stage embryo transfer in fresh cycles: a retrospective cohort study.

Background: Elevated estradiol (E2) levels are an inevitable outcome of the controlled ovulation hyperstimulation. However, the effect of this change on pregnancy is still uncertain. Our study aimed to analyze the impact of increased serum E2 at the day of human chorionic gonadotropin (hCG) administration on the clinical outcomes of women with fresh embryo transfer (ET) cycles. Methods: This study included 3,009 fresh ET cycles from October 2015 to September 2021. Based on the stage of embryos transferred, these cycles were categorized into the cleavage group and blastocyst group. Both groups were then divided into four sets according to E2 levels when hCG was administered: set 1 (E2 ≤ 2,000 pg/ml), set 2 (E2 = 2,001-3,000 pg/ml), set 3 (E2 = 3,001-4,000 pg/ml), and set 4 (E2 > 4,000 pg/ml). The primary outcome was the clinical pregnancy rate (CPR). Binary logistics regression analysis was established to explore the association between CPR and E2 levels. Specifically, the threshold effect of serum E2 on CPR was revealed using the two-piecewise linear regression analyses. Results: The multivariate regression model in the cleavage group showed that patients' CPR in set 4 was 1.59 times higher than those in reference set 1, but the statistical difference was insignificant (P = 0.294). As for the blastocyst group, patients in set 4 had a lower CPR with adjusted ORs of 0.43 (P = 0.039) compared to patients in set 1. The inflection point for the blastocyst group was 39.7 pg/dl according to the results of the two-piecewise linear regression model. When E2 levels were over the point, the CPR decreased by 17% with every 1 pg/dl increases in serum E2 (adjusted OR = 0.83, 95% CI [0.72-0.96], P = 0.012). Conclusions: Elevated E2 levels (>39.7 pg/dl) on hCG trigger day were associated with decreased CPR in patients with fresh blastocyst ET. However, it had no similar effect on the CPR of patients with fresh cleavage-stage ET.

Design, synthesis, and biological studies of novel sulfonamide derivatives as farnesoid X receptor agonists.

Farnesoid X receptor (FXR) is considered as a promising target for the treatment of NASH. Although many non-steroidal FXR agonists have been reported, the structure types are quite scarce and mainly limited to the isoxazole scaffold derived from GW4064. Therefore, it is crucial to expand the structure types of FXR agonist to explore wider chemical space. In this study, the structure-based scaffold hopping strategy was performed by hybrid FXR agonist 1 and T0901317, which resulted in the discovery of sulfonamide FXR agonist 19. Molecular docking study reasonably explained the SAR in this series, and compound 19 fitted well with the binding pocket in a similar mode to the co-crystal ligand. In addition, compound 19 exhibited considerable selectivity against other nuclear receptors. In NASH model, compound 19 alleviated the typical histological features of fatty liver, including steatosis, lobular inflammation, ballooning, and fibrosis. Moreover, compound 19 exhibited acceptable safety profiles with no acute toxicity to major organ. These results suggested that the novel sulfonamide FXR agonist 19 might be a promising agent for the treatment of NASH.

Design, synthesis, and biological evaluation studies of novel carboxylesterase 2 inhibitors for the treatment of irinotecan-induced delayed diarrhea.

Human carboxylesterase 2 (hCES2A), one of the most important serine hydrolases distributed in the small intestine and colon, plays a crucial role in the hydrolysis of various prodrugs and esters. Accumulating evidence has demonstrated that the inhibition of hCES2A effectively alleviate the side effects induced by some hCES2A-substrate drugs, including delayed diarrhea caused by the anticancer drug irinotecan. Nonetheless, there is a scarcity of selective and effective inhibitors that are suitable for irinotecan-induced delayed diarrhea. Following screening of the in-house library, the lead compound 01 was identified with potent inhibition on hCES2A, which was further optimized to obtain LK-44 with potent inhibitory activity (IC50 = 5.02 ± 0.67 µM) and high selectivity on hCES2A. Molecular docking and molecular dynamics simulations indicated that LK-44 can formed stable hydrogen bonds with amino acids surrounding the active cavity of hCES2A. The results of inhibition kinetics studies unveiled that LK-44 inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a Ki value of 5.28 µM. Notably, LK-44 exhibited low toxicity towards HepG2 cells according to the MTT assay. Importantly, in vivo studies showed that LK-44 significantly reduced the side effects of irinotecan-induced diarrhea. These findings suggested that LK-44 is a potent inhibitor of hCES2A with high selectivity against hCES1A, which has potential as a lead compound for the development of more effective hCES2A inhibitors to mitigate irinotecan-induced delayed diarrhea.

Huangqi Guizhi Wuwu decoction improves hemorheology and inhibits inflammatory response after PCI for acute myocardial infarction.

OBJECTIVE: To determine the impact of Huangqi Guizhi decoction of five ingredients on hemorheology and inflammatory factors in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). METHODS: A total of 111 cases of AMI treated in Tongchuan Hospital of Traditional Chinese Medicine from February 2019 to February 2022 were analyzed retrospectively. Among them, 47 patients who received routine treatment were assigned to the control group, while those who received Huangqi Guizhi decoction of five ingredients in addition to the treatment of the control group were assigned to the study group. The clinical efficacy in the two groups was evaluated after therapy. The two groups were compared as to changes in serum inflammatory factors [tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6)] before and after therapy. The two groups were also compared as to differences in fibrinogen, plasma viscosity, whole blood low-shear viscosity (WBLSV), and whole blood high-shear viscosity (WBHSV) before and after therapy. Left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) in the two groups were evaluated. In addition, the two groups were compared as to incidence of major adverse cardiovascular events (MACE) in 6 months. Logistic regression analysis was conducted to analyze the risk factors for MACE. RESULTS: The study group showed a significantly higher treatment efficacy than the control group (P < 0.05). After therapy, the study group had significantly lower levels of TNF-α, hs-CRP, IL-6, fibrinogen, plasma viscosity, WBLSV, and WBHSV than the control group (all P < 0.05), and showed lower LVEDD and LVESD levels and a higher LVEF level than the control group. According to logistic regression analysis, age, history of diabetes mellitus (TM), New York Heart Association (NYHA) classification, hsCPR, and LVEF were independent risk factors for MACE (all P < 0.05). CONCLUSION: Huangqi Guizhi decoction of five ingredients contributes to higher efficacy in AMI and has the effects of inhibiting the inflammation and hemorheology of patients. In addition, age, history of TM, NYHA classification, hsCPR, and LVEF were independent risk factors for MACE.

Exogenous Electroactive Microbes Regulate Soil Geochemical Properties and Microbial Communities by Enhancing the Reduction and Transformation of Fe(III) Minerals.

Electroactive microbes can conduct extracellular electron transfer and have the potential to be applied as a bioresource to regulate soil geochemical properties and microbial communities. In this study, we incubated Fe-limited and Fe-enriched farmland soil together with electroactive microbes for 30 days; both soils were incubated with electroactive microbes and a common iron mineral, ferrihydrite. Our results indicated that the exogenous electroactive microbes decreased soil pH, total organic carbon (TOC), and total nitrogen (TN) but increased soil conductivity and promoted Fe(III) reduction. The addition of electroactive microbes also changed the soil microbial community from Firmicutes-dominated to Proteobacteria-dominated. Moreover, the total number of detected microbial species in the soil decreased from over 700 to less than 500. Importantly, the coexistence of N-transforming bacteria, Fe(III)-reducing bacteria and methanogens was also observed with the addition of electroactive microbes in Fe-rich soil, indicating the accelerated interspecies electron transfer of functional microflora.