Single-cell RNA sequencing and immune repertoire analysis revealed dynamic immune characteristics associated with peripheral blood during sepsis.

Sepsis is a potentially fatal condition arising from an abnormal immune response to an infection, which can result in organ failure and even death. To explore the mechanism underlying the dysregulated immune response during sepsis and identify potential therapeutic targets, single-cell RNA sequencing (scRNA-seq) and immune repertoire analysis were conducted to depict the cellular landscape of peripheral blood cells in septic mice. We observed significant alterations in the number and proportion of peripheral blood cell populations driven by sepsis. By combining single-cell gene expression profiles and B cell receptor (BCR) repertoire analysis, we discerned that infection inflicted serious damage on the antigen presentation ability of B cells and the diversity of BCR in a short time. In addition, we found that the cecal ligation and puncture procedure in mice inhibited the communication signals of CD4+ and CD8+ T cells and decreased the interactions between B cells and other cells. Our study provides detailed insights into the dynamic changes in the biological characteristics of peripheral blood cells driven by sepsis and provides important advances in our understanding of immune disorders during sepsis.

Further structural optimization and SAR study of sungsanpin derivatives as cell-invasion inhibitors.

Metastasis is one of the major causes of death in patients with cancer, and cell invasion plays a fundamental part in this process. Because of the absence of efficacious treatments, caring for these patients is challenging. Recently, we optimized the structure of the naturally occurring lasso peptide sungsanpin. We identified two peptides, octapeptide S3 and cyclic peptide S4, which inhibited invasion into A549 cells effectively. We undertook an alanine scan of S3 to explore the structure-activity relationship. The linear octapeptide S3-4 and cyclic peptide S4-1 exhibited improved inhibition of invasion into A549 cells. We modified S3-4 to obtain S3-4K, which displayed much higher inhibitory activity against invasion into A549 cells than S3-4. Of all peptides tested, S4-1 upregulated significantly mRNA of tissue inhibitor matrix metalloproteinase TIMP-1 and TIMP-2.

Design, synthesis, evaluation and optimization of novel azole analogues as potent antifungal agents.

In order to develop antifungal drugs, a series of novel azole analogues were designed and synthesized based on our previous work. Most of the target compounds had broad-spectrum antifungal activity, which showed excellent to moderate inhibitory activity against the tested strains, except A. fum 0504656. Among these, compounds B3, B7, B8, B11, B12 and E9 showed excellent activity against C. alb Y0109 and C. alb SC5314 (with the MIC80: 0.0156 ug/mL). In addition, compound B3 showed the best inhibitory activity against fluconazole-resistant strains C. alb 901 and C. alb 904, and had low toxicity against NIH/3T3 cells at the effective MIC range against fungi. Structure-activity relationship and docking studies of the derivatives suggest that the presence of the 2-fluoro-4-hydroxyphenyl and 1,2,3-triazole group enhance the antifungal activity of the compounds, which may be related to the interaction of the key groups with the amino acids surrounding the target enzyme.

Energy gap of conformational transition related with temperature for the NACore of α-synuclein.

Pathological aggregation of α-synuclein (α-syn) into amyloid fibrils is a major feature of Parkinson's disease (PD). The self-assembly of α-syn is mainly governed by a non-amyloid-ß component core (NACore). However, the effects of concentrations and temperatures on their conformational transition remain unclear. To answer this question, we investigated the aggregation kinetics of NACore oligomers in silico by performing several independent all-atom molecular dynamics simulations. The simulation results show that tetramers are more prone to form ß-sheets at 300 K than dimers and octamers. We also found that the NACore oligomers had higher ß-sheet and ß-barrel contents at 310 K. The inter-chain hydrophobic interactions, the backbone hydrogen bonding, the residue-residue interactions between V70-V77 as well as V77-V77 play important roles in the aggregation tendency of NACore octamers at 310 K. Interestingly, the energy gap analysis revealed that the conformational transition of NACore oligomers from intermediate states (ß-barrel conformation) to stable structures (ß-sheet layers) was dependent on the temperatures. In short, our study provides insight into the kinetic and thermodynamic mechanisms of the conformational transition of NACore at different concentrations and temperatures, contributing to a better understanding of the aggregation process of α-syn in Parkinson's disease.

Phosphorus-loaded coconut biochar: A novel strategy for cadmium remediation and soil fertility enhancement.

The management of cadmium (Cd) contamination in soils poses a significant environmental challenge. This study investigates the effectiveness of phosphorus (P)-loaded coconut biochar, synthesized at various pyrolysis temperatures (450°C, 500°C, 550°C, and 600°C), in immobilizing Cd and enhancing P availability in soil environments. The biochar underwent a series of treatments including activation and P enrichment, followed by incubation trials to evaluate its performance in Cd immobilization and P bioavailability enhancement across varying soil concentrations (0.5 %, 1.0 %, and 2.0 %) over time periods of 15, 30, and 45 days. Remediation progress was monitored using phytotoxicity assessments with radish (Raphanus sativus) root length as a bioindicator, supplemented by urease activity analyses. Notably, the activation process increased the P loading capacity of biochar produced at 450°C, 500°C, and 550°C by 54.6 %, 72.4 %, and 51.8 %, respectively, while reducing the P retention capacity of biochar prepared at 600°C by 31.0 %. The biochar activated at 550°C presented the highest efficiency in remediating Cd-contaminated soils. Key findings indicate that the enhanced specific surface area and oxygenated functional group content of the activated biochar facilitated Cd adsorption and P uptake. The P-loaded biochar exhibited a substantial adsorption capacity for Cd, particularly effective at lower concentrations, rendering it highly suitable for soil remediation purposes. Additionally, the study revealed that the application of biochar led to an increase in soil pH, resulting in precipitation of Cd as hydroxide species and formation of insoluble complexes with phosphate ions, thereby reducing its bioavailability. In summary, incorporating P-loaded biochar into soil significantly improved soil quality and enhanced Cd passivation in contaminated soils. The utilization of biochar produced at 550°C, which exhibited optimal performance, suggests a practical and sustainable approach for soil remediation. Future research endeavors should prioritize the refinement of the biochar production process to enhance cost-effectiveness while maintaining high P loading efficiency.

Antinociceptive iridoid glycosides from the aerial parts of Paederia foetida.

Two previously undescribed iridoid glycosides, 6'-O-trans-feruloyl-(4S,6R)-3,4-dihydro-3ß-ethoxypaederoside (1) and 6'-O-trans-caffeoyl-(4S,6R)-3,4-dihydro-2'-O-3α-paederoside (2), were isolated from the 90% EtOH extract of the air dried aerial parts of Paederia Foetida. Structural elucidation of all the compounds was performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. The two isolated iridoid glycosides were tested in vivo for their antinociceptive properties. As a result, 2 showed potent antinociceptive effect and its ID50 value (53.4 µmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.

Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain.

Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B-BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B-BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology.

SOS1-inspired hydrocarbon-stapled peptide as a pan-Ras inhibitor.

Blocking the interaction between Ras and Son of Sevenless homolog 1 (SOS1) has been an attractive therapeutic strategy for treating cancers involving oncogenic Ras mutations. K-Ras mutation is the most common in Ras-driven cancers, accounting for 86%, with N-Ras mutation and H-Ras mutation accounting for 11% and 3%, respectively. Here, we report the design and synthesis of a series of hydrocarbon-stapled peptides to mimic the alpha-helix of SOS1 as pan-Ras inhibitors. Among these stapled peptides, SSOSH-5 was identified to maintain a well-constrained alpha-helical structure and bind to H-Ras with high affinity. SSOSH-5 was furthermore validated to bind with Ras similarly to the parent linear peptide through structural modeling analysis. This optimized stapled peptide was proven to be capable of effectively inhibiting the proliferation of pan-Ras-mutated cancer cells and inducing apoptosis in a dose-dependent manner by modulating downstream kinase signaling. Of note, SSOSH-5 exhibited a high capability of crossing cell membranes and strong proteolytic resistance. We demonstrated that the peptide stapling strategy is a feasible approach for developing peptide-based pan-Ras inhibitors. Furthermore, we expect that SSOSH-5 can be further characterized and optimized for the treatment of Ras-driven cancers.

Rational Optimizations of the Marine-Derived Peptide Sungsanpin as Novel Inhibitors of Cell Invasion.

Cancer metastasis, including cell invasion, is a major cause of poor clinical outcomes and death in numerous cancer patients. In recent years, many efforts have been made to develop potent therapeutic molecules from naturally derived peptides. Sungsanpin is a naturally derived lasso peptide that inhibits A549 cell invasion. We aimed to evaluate the potential of sungsanpin derivatives as candidates for anti-invasion drugs. We synthesized an analog of sungsanpin (Sun A) using a solid-phase peptide synthesis strategy (SPPS) and further modified its structure to improve its anti-invasion activity. All peptides were tested for their proliferative inhibition and anti-invasion activities in the A549 cell lines. Octapeptide S3 and cyclooctapeptide S4 upregulated the expression of TIMP-1 and TIMP-2 mRNA effectively and thus improved the inhibitory effect on the invasion of A549 cells. The two peptides can inhibit the invasion of A549 cells by up to 60 %, suggesting that they have potential as lead molecules for the development of peptide inhibitors.

Design, Synthesis, and Antitumor Activities of Isomers of Artemisinin Dimer Derivatives.

In recent years, numerous studies have reported on the anti-tumor properties of artemisinin and its derivatives. However, the relationship between their artemisinin chirality and activity remains unknown. In this study, we synthesized a series of artemisinin dimer derivatives with three different chiral structures and tested their antiproliferative activity in MCF-7 and HepG2 cells using the CCK-8 assay. Interestingly, we discovered that artemisinin dimer derivatives with ß, ß and α, ß conformations at C-10 exhibited stronger anti-tumor activity than those with an α, α configuration in MCF-7 and HepG2 cells. Notably, compound 4 showed an activity of 0.06 µM in MCF-7 cells. This study demonstrates the relationship between the conformation and activity of artemisinin dimer derivatives, and these derivatives have the potential to be developed into anti-cancer drugs.

Synthesis and preliminary immunologic properties of di-/trisaccharide-conjugates related to Bacillus anthracis.

Herein, the di- and trisaccharide mimics of the hexasaccharide antigen related to Bacillus anthracis were synthesized and covalently coupled with carrier proteins, such as keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA), to form the corresponding glycoconjugates 1-6. 2,3,4,6-Tetra-O-benzyl thioglycoside and 2-deoxyl-2-phthalylamino-3,4,6-tri-O-benzyl thioglycoside were applied as glycosyl donors to guarantee α or ß-configuration of the newly formed glycosidic bonds. Glutaraldehyde was used as a homobifunctional cross-linker for high-efficiency coupling. The synthetic KLH-glycoconjugates 2, 4 and 6 were also used to vaccinate female Balb/c mice and the preliminary results of ELISA uncovered that all three KLH-conjugates could induce immune responses and generate oligosaccharide-specific total IgG antibodies. The trisaccharide 8, the glycosyl part of glycoconjugate 4, is of great immunogenicity.

Reproducing the invention of a named reaction: zero-shot prediction of unseen chemical reactions.

While state-of-art models can predict reactions through the transfer learning of thousands of samples with the same reaction types as those of the reactions to predict, how to prepare such models to predict "unseen" reactions remains an unanswered question. We aimed to study the Transformer model's ability to predict "unseen" reactions through "zero-shot reaction prediction (ZSRP)", a concept derived from zero-shot learning and zero-shot translation. We reproduced the human invention of the Chan-Lam coupling reaction where the inventor was inspired by the Suzuki reaction when improving Barton's bismuth arylation reaction. After being fine-tuned with samples from these two "existing" reactions, the USPTO-trained Transformer could predict "unseen" Chan-Lam coupling reactions with 55.7% top-1 accuracy. Our model could also mimic the later stage of the history of this reaction, where the initial case of this reaction was generalized to more reactants and reagents via "one-shot/few-shot reaction prediction (OSRP/FSRP)" approaches.

ARG1 as a promising biomarker for sepsis diagnosis and prognosis: evidence from WGCNA and PPI network.

BACKGROUND: Sepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication. METHODS: Preliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results. RESULTS: Four hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally. CONCLUSIONS: We identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

Interactions between lead(II) ions and dissolved organic matter derived from organic fertilizers incubated in the field.

This work was to study composition characteristics and the subsequent effect on the lead (Pb) binding properties of dissolved organic matter (DOM) derived from seaweed-based (SWOF) and chicken manure organic fertilizers (CMOF) during a one-year field incubation experiment using the excitation-emission matrix-parallel factor (EEM-PARAFAC) and two-dimensional correlation spectroscopy (2DCOS) analysis. Results showed that high aromatic and hydrophobic fluorescent substances were enriched in CMOF-derived DOM and SWOF-derived DOM and enhanced over time. And phenolic groups in the fulvic-like substances for SWOF-derived DOM and carboxyl groups in the humic-like substances for CMOF-derived DOM had the fastest responses over time, respectively. Moreover, both non-fluorescent polysaccharides and fluorescent humic-like substances or fulvic-like substances with aromatic (C=C) groups first participated in the binding process of Pb to SWOF-derived DOM on day 0 and 180 during the lead binding process. In contrast, humic-like substances associated with aromatic (C=C) and phenolic groups gave a faster response to Pb binding on day 360. Regarding CMOF-derived DOM, the fulvic-like substances associated with aromatic (C=C) and carboxylic groups displayed a faster response to Pb ions on day 0. Nonetheless, polysaccharides and humic-like associated with phenolic groups had a faster response on days 180 and 360. It is noteworthy that the polysaccharides, which participated in Pb binding to CMOF-derived DOM, posed a higher risk of Pb in the environment after 360 days. Therefore, these findings gave new insights into the long-term applications of commercial organic fertilizers for the amendment of soil.

Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6.

Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase with a significant role in 20% of all cancers, such as colon cancers and rectal adenocarcinoma. However, there is currently no effective drug for cancers related to SIRT6. To explore potential inhibitors of SIRT6, it is essential to reveal details of the interaction mechanisms between inhibitors and SIRT6 at the atomic level. The nature of small molecules from herbs have many advantages as inhibitors. Based on the conformational characteristics of the inhibitor Compound 9 (Asinex ID: BAS13555470), we explored the natural molecule Scutellarin, one compound of Huang Qin, which is an effective herb for curing cancer that has been described in the Traditional Chinese Medicine (TCMS) library. We investigated the interactions between SIRT6 and the inhibitors using molecular dynamics (MD) simulations. We illustrated that the structurally similar inhibitors have a similar binding mode to SIRT6 with residues-Leu9, Phe64, Val115, His133 and Trp188. Hydrophobic and π-stacking interactions play important roles in the interactions between SIRT6 and inhibitors. In summary, our results reveal the interactive mechanism of SIRT6 and the inhibitors and we also provide Scutellarin as a new potential inhibitor of SIRT6. Our study provides a new potential way to explore potential inhibitors from TCMS.

Clinical and molecular spectrum of CHOPS syndrome.

CHOPS syndrome is a multisystem disorder caused by missense mutations in AFF4. Previously, we reported three individuals whose primary phenotype included cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, and short stature. This syndrome overlaps phenotypically with Cornelia de Lange syndrome, but presents distinct differences including facial features, pulmonary involvement, and obesity. Here, we provide clinical descriptions of an additional eight individuals with CHOPS syndrome, as well as neurocognitive analysis of three individuals. All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes. All 11 individuals had short stature and obesity. Congenital heart disease and pulmonary involvement were common, and those were seen in about 70% of individuals with CHOPS syndrome. Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density. Our observation indicates that obesity, pulmonary involvement, skeletal findings are the most notable features distinguishing CHOPS syndrome from Cornelia de Lange syndrome. In fact, two out of eight of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing. These phenotypic findings establish CHOPS syndrome as a distinct, clinically recognizable disorder. Additionally, we report three novel missense mutations causative for CHOPS syndrome that lie within the highly conserved, 14 amino acid sequence of the ALF homology domain of the AFF4 gene, emphasizing the critical functional role of this region in human development.

Continuation of structure-activity relationship study of novel benzamide derivatives as potential antipsychotics.

A series of benzamide derivatives possessing potent dopamine D2 , serotonin 5-HT1A , and 5-HT2A receptor properties were synthesized and evaluated as potential antipsychotics. Among them, 5-(4-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy)-N-cyclopropyl-2-fluorobenzamide (4k) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D2 , 5-HT1A , and 5-HT2A receptors, but was also endowed with low to moderate activities for the 5-HT2C , H1 , and M3 receptors, suggesting a low propensity for inducing weight gain or diabetes. In animal models, compound 4k reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy or muscle relaxation induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, 4k was selected as a candidate for further development.

A novel matrine derivative WM622 inhibits hepatocellular carcinoma by inhibiting PI3K/AKT signaling pathways.

Hepatocellular carcinoma (HCC) is among the most common lethal cancers of the digestive system with poor prognosis rates and ineffective therapeutic options. Matrine, a traditional Chinese medicine found in the roots of sophora species, has been used in the clinical treatment of liver fibrosis, chronic hepatitis B and other diseases. We have synthesized a matrine derivatives named WM622 (C26H35ON3S2) with a significant inhibitory effect on transplanted tumors in vivo. The half inhibitory concentration (IC50) of WM622 is 34 µM, which is much lower than matrine. WM622 inhibited the proliferation and promoted apoptosis of hepatocellular carcinoma cells significantly, and the cell cycle was blocked in G0/G1 phase. The protein phosphorylation levels of EGFR, AKT, PI3K and GSK3ß (p-EGFR, p-AKT, p-PI3K, and p-GSK3ß) were also decreased by WM622 treatment dose dependently. In tumor-bearing mice, WM622 could reduce the tumor volumes. In conclusion, the study demonstrated that WM622 could inhibit the proliferation of the hepatocellular carcinoma both in vivo and in vitro by inducing apoptosis, blocking cell cycle in G0/G1 phase and inhibiting the PI3K/AKT signal pathways.

The mimics of Nε-acyl-lysine derived from cysteine as sirtuin inhibitors.

Sirtuin inhibitors as physiological research tools and therapeutic potentials have caught many attentions in last decades. The mimics of acyl lysine have been approved to be a very efficient strategy for development of mechanism-based sirtuin inhibitors. In current study, a novel scaffold of l-S-(3-carboxamidopropyl) cysteine (l-CAPC) has been exploited for design and synthesis of sirtuin inhibitors. As a result, the mimics of Nε-acyl-lysine derived from cysteine including small molecules (5a-m) and peptides (9a-m) have been synthesized. Among these, the peptides 9g and 9h were found to be the most inhibitory potency and selectivity against SIRT2.

Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs.

In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D2, serotonin 5-HT1A and 5-HT2A receptors, but also exhibited low potency for α1A, H1 and 5-HT2C receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain. Furthermore, 7h exhibited more potent antipsychotic-like effect than aripiprazole in behavioral studies. The preliminary results were promising enough for further research around this scaffold.