Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a multifactorial chronic inflammation of the intestine and has become a global public health concern. A farnesoid X receptor (FXR) was recently reported to play a key role in hepatic-intestinal circulation, intestinal metabolism, immunity, and microbial regulation, and thus, it becomes a promising therapeutic target for IBD. In this study, we identified a series of nonbile acid FXR agonists, in which 33 novel compounds were designed and synthesized by the structure-based drug design strategy from our previously identified hit compound. Compound 33 exhibited a potent FXR agonistic activity, high intestinal distribution, good anti-inflammatory activity, and the ability to repair the colon epithelium in a DSS-induced acute enteritis model. Based on the results of RNA-seq analysis, we further investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment.

Stability analysis of a SAIR epidemic model on scale-free community networks.

The presence of asymptomatic carriers, often unrecognized as infectious disease vectors, complicates epidemic management, particularly when inter-community migrations are involved. We introduced a SAIR (susceptible-asymptomatic-infected-recovered) infectious disease model within a network framework to explore the dynamics of disease transmission amid asymptomatic carriers. This model facilitated an in-depth analysis of outbreak control strategies in scenarios with active community migrations. Key contributions included determining the basic reproduction number, $ R_0 $, and analyzing two equilibrium states. Local asymptotic stability of the disease-free equilibrium is confirmed through characteristic equation analysis, while its global asymptotic stability is investigated using the decomposition theorem. Additionally, the global stability of the endemic equilibrium is established using the Lyapunov functional theory.

Depression- and anxiety-associated disrupted brain structural networks revealed by probabilistic tractography in thyroid associated ophthalmopathy.

BACKGROUND: Patients with thyroid-associated opthalmopathy (TAO) have widespread white matter (WM) abnormalities in the emotional and cognitive functional regions. However, the topological representation of these WM abnormalities and the network-level structural aberrations underlying TAO and concomitant affective disorders are still unclear. METHODS: We used probabilistic diffusion tractography and graph theory to investigate brain network topology in 37 active, 35 inactive TAO patients and 23 healthy controls. Then, we evaluated the partial correlations between network topological metrics and clinical parameters. RESULTS: For global topology, only active TAO patients exhibited significantly decreased global (Eglob) and local (Eloc) efficiency compared with controls, while no significant difference was observed between active and inactive TAO patients. For regional topology, we found a significantly decreased nodal efficiency in the left orbital superior frontal gyrus (ORBsup), medial orbital superior frontal gyrus (ORBsupmed), hippocampus and amygdala in active TAO patients compared with inactive ones. Intriguingly, Eglob, Eloc, and nodal efficiency of left ORBsup, ORBsupmed, olfactory cortex, gyrus rectus, hippocampus, right parahippocampal gyrus and amygdala had significantly positive correlations with anxiety/depression scores, bilateral exophthalmos and intraocular pressure in active TAO patients, while no significant correlation was observed in inactive TAO patients. LIMITATIONS: No longitudinal follow-up. CONCLUSIONS: WM networks of TAO are characterized by decreased local specialization and global integration in the active phase, and decreased nodal efficiency highly related to anxiety and depression in the emotional and cognitive regions. Our findings provide new insight regarding the neurobiological mechanisms of TAO and contribute to the treatment of concomitant affective disorders.

Novel imidazo[1,2,4] triazole derivatives: Synthesis, fluorescence, bioactivity for SHP1.

The Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) is a convergent node for oncogenic cell-signaling cascades. Consequently, SHP1 represents a potential target for drug development in cancer treatment. The development of efficient methods for rapidly tracing and modulating the SHP1 activity in complex biological systems is of considerable significance for advancing the integration of diagnosis and treatment of the related disease. Thus, we designed and synthesized a series of imidazo[1,2,4] triazole derivatives containing salicylic acid to explore novel scaffolds with inhibitory activities and good fluorescence properties for SHP1. The photophysical properties and inhibitory activities of these imidazo[1,2,4] triazole derivatives (5a-5y) against SHP1PTP were thoroughly studied from the theoretical simulation and experimental application aspects. The representative compound 5p exhibited remarkable fluorescence response (P: 0.002) with fluorescence quantum yield (QY) of 0.37 and inhibitory rate of 85.21 ± 5.17% against SHP1PTP at the concentration of 100 µM. Furthermore, compound 5p showed obvious aggregation caused quenching (ACQ) effect and had high selectivity for Fe3+ ions, good anti-interference and relatively low detection limit (5.55 µM). Finally, the cellular imaging test of compound 5p also exhibited good biocompatibility and certain potential biological imaging application. This study provides a potential way to develop molecules with fluorescent properties and bioactivities for SHP1.

Early-season and refined mapping of winter wheat based on phenology algorithms - a case of Shandong, China.

Winter wheat is one of the major food crops in China, and timely and effective early-season identification of winter wheat is crucial for crop yield estimation and food security. However, traditional winter wheat mapping is based on post-season identification, which has a lag and relies heavily on sample data. Early-season identification of winter wheat faces the main difficulties of weak remote sensing response of the vegetation signal at the early growth stage, difficulty of acquiring sample data on winter wheat in the current season in real time, interference of crops in the same period, and limited image resolution. In this study, an early-season refined mapping method with winter wheat phenology information as priori knowledge is developed based on the Google Earth Engine cloud platform by using Sentinel-2 time series data as the main data source; these data are automated and highly interpretable. The normalized differential phenology index (NDPI) is adopted to enhance the weak vegetation signal at the early growth stage of winter wheat, and two winter wheat phenology feature enhancement indices based on NDPI, namely, wheat phenology differential index (WPDI) and normalized differential wheat phenology index (NDWPI) are developed. To address the issue of " different objects with the same spectra characteristics" between winter wheat and garlic, a plastic mulched index (PMI) is established through quantitative spectral analysis based on the differences in early planting patterns between winter wheat and garlic. The identification accuracy of the method is 82.64% and 88.76% in the early overwintering and regreening periods, respectively, These results were consistent with official statistics (R2 = 0.96 and 0.98, respectively). Generalization analysis demonstrated the spatiotemporal transferability of the method across different years and regions. In conclusion, the proposed methodology can obtain highly precise spatial distribution and planting area information of winter wheat 4_6 months before harvest. It provides theoretical and methodological guidance for early crop identification and has good scientific research and application value.

Exploring the mechanism of the PTP1B inhibitors by molecular dynamics and experimental study.

Protein tyrosine phosphatase 1B (PTP1B) has proven to be an attractive target for the treatment of cancer, diabetes and other diseases. Although many PTP1B inhibitors with various scaffolds have been developed, there is still a lack of PTP1B inhibitor with high specificity and acceptable pharmacological properties. Therefore, it is urgent to develop more methods to explore complex action mode of PTP1B and ligands for designing ideal PTP1B modulators. In this work, we developed a potential molecular dynamics (MD) analytic mode to analyze the mechanism of active compounds 6a and 6e against PTP1B from different perspectives, including the stable ability, interactions and binding site of ligand and protein, the binding energy, relative movement between residues and changes in protein internal interactions. The simulated results demonstrated that compound 6a bound more stably to the active pocket of PTP1B than 6e due to its smaller molecular volume (326 Å3), matched electronegativity, and enhanced the positive correlation motion of residues, especially for WPD loop and P loop. Lastly, compound 6a as a competitive inhibitor for PTP1B was verified by enzyme kinetic assay. This work successfully studied the mechanism of compound 6a against PTP1B from various aspects, enriched the analysis of interaction mode between PTP1B and inhibitors. In summary, we hope that this work could provide more theoretical information for designing and developing more novel and ideal PTP1B inhibitors in the future.

Exploration of novel four-membered-heterocycle constructed peptidyl proteasome inhibitors with improved metabolic stability for cancer treatment.

Peptides have limitations as active pharmaceutical agents due to rapid hydrolysis by proteases and poor cell permeability. To overcome these limitations, a series of peptidyl proteasome inhibitors embedded with four-membered heterocycles were designed to enhance their metabolic stabilities. All synthesized compounds were screened for their inhibitory activities against human 20S proteasome, and 12 target compounds displayed potent efficacy with IC50 values lower than 20 nM. Additionally, these compounds exhibited strong anti-proliferative activities against multiple myeloma (MM) cell lines (MM1S: 72, IC50 = 4.86 ± 1.34 nM; RPMI-8226: 67, IC50 = 12.32 ± 1.44). Metabolic stability assessments of SGF, SIF, plasma and blood were conducted, and the representative compound 73 revealed long half-lives (Plasma: T1/2 = 533 min; Blood: T1/2 > 1000 min) and good proteasome inhibitory activity in vivo. These results suggest that compound 73 serve as a lead compound for the development of more novel proteasome inhibitors.

Design, Synthesis and Evaluation of Fluorescent Properties of Benzothiazole Derivatives.

Fluorescence imaging is conducive to establish a bridge between molecular biology and clinical medicine, and provides new tools for disease process research, early diagnosis, and efficacy evaluation, because of the advantages of rapid imaging and nondestructive detection. Herein, a series of fluorescent molecules with thiadiazole, or thiazole, or benzothiazole cores were designed and synthesized to develop more excellent fluorescent molecules in bio-imaging. According to theoretical and experimental methods, we found that benzothiazole derivative 14 B with conjugate expansion by (4-aminophenyl) ethynyl group was the most excellent fluorescent molecule among all the investigated compounds and exhibited low cytotoxicity and strong blue and green fluorescence by confocal cell imaging.

Stack-VTP: prediction of vesicle transport proteins based on stacked ensemble classifier and evolutionary information.

Vesicle transport proteins not only play an important role in the transmembrane transport of molecules, but also have a place in the field of biomedicine, so the identification of vesicle transport proteins is particularly important. We propose a method based on ensemble learning and evolutionary information to identify vesicle transport proteins. Firstly, we preprocess the imbalanced dataset by random undersampling. Secondly, we extract position-specific scoring matrix (PSSM) from protein sequences, and then further extract AADP-PSSM and RPSSM features from PSSM, and use the Max-Relevance-Max-Distance (MRMD) algorithm to select the optimal feature subset. Finally, the optimal feature subset is fed into the stacked classifier for vesicle transport proteins identification. The experimental results show that the of accuracy (ACC), sensitivity (SN) and specificity (SP) of our method on the independent testing set are 82.53%, 0.774 and 0.836, respectively. The SN, SP and ACC of our proposed method are 0.013, 0.007 and 0.76% higher than the current state-of-the-art methods.

Synthesis and Biological Evaluation of 3-Amino-4,4-Dimethyl Lithocholic Acid Derivatives as Novel, Selective, and Cellularly Active Allosteric SHP1 Activators.

Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), a non-receptor member of the protein tyrosine phosphatase (PTP) family, negatively regulates several signaling pathways that are responsible for pathological cell processes in cancers. In this study, we report a series of 3-amino-4,4-dimethyl lithocholic acid derivatives as SHP1 activators. The most potent compounds, 5az-ba, showed low micromolar activating effects (EC50: 1.54-2.10 µM) for SHP1, with 7.63-8.79-fold maximum activation and significant selectivity over the closest homologue Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) (>32-fold). 5az-ba showed potent anti-tumor effects with IC50 values of 1.65-5.51 µM against leukemia and lung cancer cells. A new allosteric mechanism of SHP1 activation, whereby small molecules bind to a central allosteric pocket and stabilize the active conformation of SHP1, was proposed. The activation mechanism was consistent with the structure-activity relationship (SAR) data. This study demonstrates that 3-amino-4,4-dimethyl lithocholic acid derivatives can be selective SHP1 activators with potent cellular efficacy.

High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound 3 with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors' potency and selectivity. The representative compound B2 potently inhibited CDK7 with an IC50 value of 4 nM and showed high selectivity over CDKs. Compound B2 showed high potency to inhibit cyst growth and exhibited lower cytotoxicity than THZ1 in an in vitro Madin-Darby canine kidney cyst model. In addition, compound B2 was also highly efficacious in suppressing renal cyst development in an ex vivo embryonic kidney cyst model and in vivo ADPKD mouse model. These results indicate that compound B2 represents a promising lead compound that deserves further investigation to discover novel therapeutic agents for ADPKD.

Morphological brain changes between active and inactive phases of thyroid-associated ophthalmopathy: A voxel-based morphometry study.

AIM: To explore the morphological brain changes among active thyroid-associated ophthalmopathy (TAO) patients, inactive TAO patients and healthy controls and to investigate the neuropathological relationship of TAO using magnetic resonance imaging (MRI) data. METHODS: In this observational case-control study, we included 35 inactive TAO patients, 37 active TAO patients and 23 healthy controls. Voxel-based morphometry (VBM) analysis was conducted to evaluate the gray matter volume (GMV) changes among groups, and the correlations between GMV alterations and clinical parameters in active and inactive TAO groups were investigated. RESULTS: Active TAO patients showed significantly increased GMV in the right inferior frontal gyrus, left superior frontal gyrus (SFG), orbital superior frontal gyrus, orbital middle frontal gyrus, precuneus and postcentral gyrus compared with controls and significantly increased GMV in the right middle temporal gyrus, left SFG and precuneus compared with the inactive TAO group. No significant differences were observed between the inactive TAO group and healthy controls. Notably, the receiver operating characteristic (ROC) curve analysis demonstrated altered GMV among groups and significantly (p < 0.001) differentiated active TAO from inactive TAO and healthy controls. In addition, the mean GMV in precuneus and postcentral gyrus were significantly associated with clinical parameters in active TAO. CONCLUSION: Our findings suggested the localized GMV alterations among groups were associated with the pathophysiology of TAO and served as a potential discriminative pattern to detect clinical phases of TAO at the individual level. The altered brain morphometry may suggest a corresponding process of self-repair and remodeling of the brain structure as the disease progresses in TAO.

Synthesis and Biochemical Evaluation of 8H-Indeno[1,2-d]thiazole Derivatives as Novel SARS-CoV-2 3CL Protease Inhibitors.

The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CLpro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H-indeno[1,2-d]thiazole derivatives and evaluated their biochemical activities against SARS-CoV-2 3CLpro. Among them, the representative compound 7a displayed inhibitory activity with an IC50 of 1.28 ± 0.17 µM against SARS-CoV-2 3CLpro. Molecular docking of 7a against 3CLpro was performed and the binding mode was rationalized. These preliminary results provide a unique prototype for the development of novel inhibitors against SARS-CoV-2 3CLpro.

Metabolism guided optimization of peptidomimetics as non-covalent proteasome inhibitors for cancer treatment.

A series of novel non-covalent peptidomimetic proteasome inhibitors possessing bulky group at the C-terminus and N-alkylation at the N-terminus were designed with the aim to increase metabolic stabilities in vivo. All the target compounds were screened for their inhibitory activities against human 20S proteasome, and most analogs exhibited notable potency compared with the positive control bortezomib with IC50 values lower than 10 nM, which also displayed potent cytotoxic activities against multiple myeloma (MM) cell lines and human acute myeloid leukemia (AML) cells. Furthermore, whole blood stability and in vivo proteasome inhibitory activity experiments of selected compounds were conducted for further evaluation, and the representative compound 43 (IC50 = 8.39 ± 2.32 nM, RPMI-8226: IC50 = 15.290 ± 2.281 nM, MM-1S: IC50 = 9.067 ± 3.103 nM, MV-4-11: IC50 = 2.464 ± 0.713 nM) revealed a half-life extension of greater than 9-fold (329.21 min VS 36.79 min) and potent proteasome inhibitory activity in vivo. The positive results confirmed the reliability of the metabolism guided optimization strategy, and the analogs discovered are potential leads for exploring new anti-MM drugs.

Retinal nerve fiber layer and ganglion cell complex thickness as a diagnostic tool in early stage dysthyroid optic neuropathy.

PURPOSE: To compare the diagnostic accuracy of peripapillary retinal nerve fiber layer with macular ganglion cell complex thickness as an auxiliary tool for the early diagnosis of dysthyroid optic neuropathy and help assess the effectiveness of the treatment. METHODS: In this retrospective case-control study, a total of 58 thyroid-associated opthalmopathy patients and 58 healthy participants were enrolled in the study. Thyroid-associated opthalmopathy patients were divided according to the European Group Graves' Orbitopathy severity classification. The thicknesses of peripapillary nerve fiber layer and macular ganglion cell complex were measured using optical coherence tomography and their correlation with the severity of the disease as well as the effect of the treatment was investigated. RESULTS: No statistically significant differences were found between the mild thyroid-associated opthalmopathy group and the control group in both peripapillary nerve fiber layer and macular ganglion cell complex thickness. In the moderate-to-severe thyroid-associated opthalmopathy group, however, Temporal and Nasal peripapillary nerve fiber layer thicknesses were lower compared to the control group (p = 0.041, p = 0.012), whereas in the sight-threatening thyroid-associated opthalmopathy group Temporal Inferior, Nasal Superior, and mean (G) peripapillary nerve fiber layer thicknesses were larger (p = 0.000, p = 0.004, p = 0.000). No significant differences were observed in the macular ganglion cell complex thickness among the different severity groups and the control groups (p > 0.05). After treatment, the mean peripapillary nerve fiber layer thickness decreased whereas mean macular ganglion cell complex thickness showed no significant change in the sight-threatening group. A correlation was established between exophthalmos, best corrected visual acuity, clinical activity score, disease course, and the mean peripapillary nerve fiber layer thickness. The area under curve analysis indicated that mean peripapillary nerve fiber layer thickness can be used as a powerful diagnostic tool in early stage dysthyroid optic neuropathy in thyroid-associated opthalmopathy patients. CONCLUSION: Our study indicates that peripapillary nerve fiber layer act as an auxiliary tool for the early diagnosis of dysthyroid optic neuropathy and helps assess the effectiveness of the treatment.

Theoretical study and application of 2-phenyl-1,3,4-thiadiazole derivatives with optical and inhibitory activity against SHP1.

Src homology-2 domain-containing protein tyrosine phosphatase 1 (SHP1) is mainly restricted to hematopoietic and epithelial cells and widely accepted as a convergent node for oncogenic cell-signaling cascades. The development of efficient methods for rapidly tracing and inhibiting the SHP1 activity in complex biological systems is of considerable significance for advancing the integration of diagnosis and treatment of the related disease. With this aim, we designed and synthesized five 2-phenyl-1,3,4-thiadiazole derivatives (PT2, PT5, PT8, PT9 and PT10) here based on the reported SHP1 inhibitors (PT1, PT3, PT4, PT6 and PT7). The photophysical properties and inhibitory activities of these 2-phenyl-1,3,4-thiadiazole derivatives (PT1-PT10) against SHP1 were thoroughly studied from the theoretical simulation and experimental application aspects. The representative compound PT10 exhibited a larger quantum yield than the other molecules because of the smaller geometric relaxation and reorganization energy of the excited state, which was consistent with the results from the fluorescence experiments in organic solvents. In addition, PT10 showed a selective fluorescence response for SHP1 activity and low cytotoxicity in HeLa cells. Lastly, it indicated the potential application in two-photon cell fluorescence imaging in the future according to the calculated excellent two-photon absorption properties. In this contribution, firstly, we offered the fluorescent and activated molecule PT10 against SHP1, which achieved the integration of visualization and inhibitory activity of SHP1 preliminarily at the enzyme molecular level.

Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors.

The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 ± 0.20 µM, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.

Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia.

CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression with a T/C value of 27.80%. Compound 37 represents a promising lead compound for the development of a novel class of CDK9 inhibitors for the treatment of acute myeloid leukemia.

Synthesis of 2-ethoxycarbonylthieno[2,3-b]quinolines in biomass-derived solvent γ-valerolactone and their biological evaluation against protein tyrosine phosphatase 1B.

A series of 2-ethoxycarbonylthieno[2,3-b]quinolines were synthesized in the bio-derived "green" solvent γ-valerolactone (GVL) and evaluated for their inhibitory activities against PTP1B, the representative compound 6a displayed an IC50 value of 8.04 ± 0.71 µM with 4.34-fold preference over TCPTP. These results provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.