Crystallographic fragment screening delivers diverse chemical scaffolds for Zika virus NS2B-NS3 protease inhibitor development.

Zika virus (ZIKV) infections cause microcephaly in new-borns and Guillain-Barre syndrome in adults raising a significant global public health concern, yet no vaccines or antiviral drugs have been developed to prevent or treat ZIKV infections. The viral protease NS3 and its co-factor NS2B are essential for the cleavage of the Zika polyprotein precursor into individual structural and non-structural proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 48 binders with diverse chemical scaffolds were identified in the active site of the protease, with another 6 fragment hits observed in a potential allosteric binding site. Our work provides potential starting points for the development of potent NS2B-NS3 protease inhibitors. Furthermore, we have structurally characterized a potential allosteric binding pocket, identifying opportunities for allosteric inhibitor development.

A comprehensive review of the botany, phytochemistry, pharmacology, and toxicology of Murrayae Folium et Cacumen.

Ethnopharmacological relevance: Murrayae Folium et Cacumen (MFC) is a plant considered to be a traditional Chinese medicine with culinary value as well. The dry leaves and twigs of Murraya paniculata and M. exotica are used to treat stomach aches, rheumatism, toothaches, swelling, and insect and snake bites. They are also used to prepare spicy chicken dishes. Aim of the review: This review comprehensively summarizes the available information on the botanical characterization, phytochemistry, pharmacological activities, pharmacodynamics, pharmacokinetics, and toxicity of MFC. Methods: Relevant scientific literature up to August 2023 was included in the study. Chinese and English studies on MFC were collected from databases, including PubMed, Elsevier, Web of Science, Springer, Science Direct, Wiley, ACS, and CNKI (Chinese). Doctoral and Master's dissertations were also included. Results: In total, 720 compounds have been identified and reported in the literature, including flavonoids, coumarins, alkaloids, sterols, phenylpropenols, organic acids, spirocyclopentenones, and volatile oils. Flavonoids and coumarins are the two most important bioactive compounds responsible for these pharmacological activities. MFC has anti-inflammatory, anti-bacterial, anti-microbial, anti-diabetic, anti-tumor, anti-oxidant, anti-depressant, potential anti-Alzheimer's disease, chondroprotective, and analgesic properties. The pharmacological effects include interrupting the STAT3/NF-κB/COX-2 and EGFR signaling pathways, downregulating EpCAM expression, inhibiting NF-κB and ERK signals, inhibiting the EP/cAMP/PKA signaling pathway and miR-29a/Wnt/ß-catenin signaling activity, and upregulating Foxo3a expression. Conclusion: This review demonstrates that the chemical constituents, pharmacological activities, pharmacodynamics, pharmacokinetics, and toxicity of MFC support its use in traditional Chinese botanical medicines. MFC contains a wide range of chemical compounds. Flavonoids and coumarins promote strong pharmacological activity and, are low-toxicity natural phytomedicines that are widely used in medicine, food, ornamentation, and cosmetics, making MFC a promising compound for development and use in the treatment of several medical conditions.

Bufei Huoxue capsule attenuates COPD-related inflammation and regulates intestinal microflora, metabolites.

Background: Bufei Huoxue capsule (BFHX) is widely used for the clinical treatment of chronic obstructive pulmonary disease (COPD) in China. Objectives: The aim of this study is to explore the effects on COPD and the underlying mechanism of BFHX. The process and methods: In this study, we established a COPD mouse model through cigarette smoke (CS) exposure in combination with lipopolysaccharide (LPS) intratracheal instillation. Subsequently, BFHX was orally administrated to COPD mice, and their pulmonary function, lung pathology, and lung inflammation, including bronchoalveolar lavage fluid (BALF) cell count and classification and cytokines, were analyzed. In addition, the anti-oxidative stress ability of BFHX was detected by Western blotting, and the bacterial diversity, abundance, and fecal microbiome were examined using 16S rRNA sequencing technology. Outcome: BFHX was shown to improve pulmonary function, suppress lung inflammation, decrease emphysema, and increase anti-oxidative stress, whereas 16S rRNA sequencing indicated that BFHX can dynamically regulate the diversity, composition, and distribution of the intestinal flora microbiome and regulate the lysine degradation and phenylalanine metabolism of COPD mice. These results highlight another treatment option for COPD and provide insights into the mechanism of BFHX.

Assessment of the correlation between supracrestal gingival tissue dimensions and other periodontal phenotypes components via the digital registration method: a cross­sectional study in a Chinese population.

BACKGROUND: Supracrestal gingival tissue dimensions (SGTDs) has been considered to be an essential element of periodontal phenotype (PP) components. This study aimed to explore the relationship between SGTDs and other PP components by digital superposition method that integrated cone beam computed tomography (CBCT) with intraoral scanning. METHODS: This cross-sectional study was conducted at the Stomatology Hospital of Fujian Medical University. Participants were recruited based on the inclusion and exclusion criteria. The data obtained from the digital scanner (TRIOS 3, 3Shape, Denmark) and CBCT images were imported into the TRIOS software (Implant Studio, 3Shape, Denmark) for computing relevant parameters. The significant level was set at 0.05. RESULTS: A total of 83 participants with 498 maxillary anterior teeth were finally included. The mean values of supracrestal gingival height (SGH) and the distance from the cementoenamel junction (CEJ) to the crest of the alveolar ridge (CEJ-ABC) on the buccal site were significantly higher than palatal SGH (SGH-p) and palatal CEJ-ABC (CEJ-ABC-p). Men exhibited taller CEJ-ABC and SGH-p than women. Additionally, tooth type was significantly associated with the SGH, SGH-p and CEJ-ABC-p. Taller SGH was associated with wider crown, smaller papilla height (PH), flatter gingival margin, thicker bone thickness (BT) and gingival thickness (GT) at CEJ, the alveolar bone crest (ABC), and 2 mm apical to the ABC. Smaller SGH-p displayed thicker BT and GT at CEJ, the ABC, and 2 and 4 mm apical to the ABC. Higher CEJ-ABC showed lower interproximal bone height, smaller PH, flatter gingival margin, thinner GT and BT at CEJ, and 2 mm apical to the ABC. Smaller CEJ-ABC-p displayed thicker BT at CEJ and 2 and 4 mm apical to the ABC. On the buccal, thicker GT was correlated with thicker BT at 2 and 4 mm below the ABC. CONCLUSION: SGTDs exhibited a correlation with other PP components, especially crown shape, gingival margin and interdental PH. The relationship between SGTDs and gingival and bone phenotypes depended on the apico-coronal level evaluated. TRIAL REGISTRATION: This study was approved by the Biomedical Research Ethics Committee of Stomatology Hospital of Fujian Medical University (approval no. 2023-24).

Regulation of VEGF gene expression by bisacridine derivative through promoter i-motif for cancer treatment.

BACKGROUND: Vascular endothelial growth factor (VEGF) is overexpressed in most malignant tumors, which has important impact on tumor angiogenesis and development. Its gene promoter i-motif structure formed by C-rich sequence can regulate gene expression, which is a promising new target for anti-tumor therapy. METHODS: We screened various compounds and studied their effects on VEGF through extensive experiments, including SPR, MST, TO displacement, FRET, CD, ESI-MS, NMR, MTT, clone formation, qPCR, Western blot, dual-luciferase reporter assay, immunofluorescence, cell scrape, apoptosis, transwell assay, and animal model. RESULTS: After extensive screening, bisacridine derivative B09 was found to have selective binding and stabilization to VEGF promoter i-motif, which could down-regulate VEGF gene expression. B09 showed potent inhibition on MCF-7 and HGC-27 cell proliferation and metastasis. B09 significantly inhibited tumor growth in xenograft mice model with HGC-27 cells, showing decreased VEGF expression analyzed through immunohistochemistry. CONCLUSION: B09 could specifically regulate VEGF gene expression, possibly through interacting with promoter i-motif structure. As a lead compound, B09 could be further developed for innovative anti-cancer agent targeting VEGF.

Polyacetylenes from Saposhnikovia divaricata and their anticancer activity.

Nine polyacetylenes, including five new compounds named sadivaethynes E-I (1-5), were isolated from the roots of Saposhnikovia divaricata. Structural elucidation of compounds 1-5 was established by extensive spectroscopic analysis, quantum chemical calculations and DP4+ probability analysis. Among them, the absolute configuration of compound 1-2, 4-5 was unambiguous determined by ECD. Also, all compounds were evaluated for cytotoxicity against two human cancer cell lines (A549, HEPG2) in vitro, compound 9 showed moderate inhibitory effect with an IC50 value of 11.66 µM against HEPG2.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Five new sesquiterpenoids isolated from Dictamnus dasycarpus Turcz.

Five new sesquiterpenoids, dictamtrinorguaianols E and F (1-2), and dictameudesmnosides F, G, and H (3-5), along with seven known sesquiterpenoids (6-12) were isolated from Dictamnus dasycarpus Turcz. The structures of all new compounds were characterized by spectroscopic methods, including UV, IR, HR-ESI-MS, and 1D and 2D NMR. The In-vitro anti-proliferative activities of all the compounds against two human cancer cell lines (SW982 and A549) were evaluated by CCK-8 assay. Compounds 1 and 4 showed medium anti-proliferative activity against SW982 cells, with IC50 values of 3.49 ± 0.10 and 6.42 ± 1.23 µM, respectively. Additionally, compounds 2, 7, and 8 exhibited medium anti-proliferative activity against A549 cells, with IC50 values ranging from 0.80 ± 0.05 to 6.60 ± 0.46 µM.

Determination of free fatty acids in edible oil based on hollow mesoporous silica nanoparticles.

In our study, ammoniated hollow mesoporous silica nanoparticles (NH2-HMSN) with uniform diameter and stable structure were successively prepared via SiO2 core hard template method. Fourier transformed infrared spectroscopy revealed that amino group was effectively modified. Adsorption experiments showed that adsorption capacity of NH2-HMSN towards free fatty acids (FFAs) was superior to aminated mesopores or silica microspheres. Following through optimization of extraction conditions, FFAs from edible oil samples were successfully gathered by NH2-HMSN and showed favorable linearities (0.2-90 µg g-1), remarkably low limit of detections (0.03-0.15 nmol g-1), acceptable recoveries (85.08-96.82 %) and relatively accurate precisions (1.64-4.99 %). In comparison to existing adsorbent, NH2-HMSN could be successfully prepared via the chemical reaction of common raw materials under normal pressure and temperature. Furthermore, NH2-HMSN with hollow and mesoporous structure was more effective than the current adsorbents aimed at FFAs analysis in aspect of surface area and adsorption capacity.

Association between atherogenic index of plasma control level and incident cardiovascular disease in middle-aged and elderly Chinese individuals with abnormal glucose metabolism.

BACKGROUND: The atherogenic index of plasma (AIP) and cardiovascular disease (CVD) in participants with abnormal glucose metabolism have been linked in previous studies. However, it was unclear whether AIP control level affects the further CVD incidence among with diabetes and pre-diabetes. Therefore, our study aimed to investigate the association between AIP control level with risk of CVD in individuals with abnormal glucose metabolism. METHODS: Participants with abnormal glucose metabolism were included from the China Health and Retirement Longitudinal Study. CVD was defined as self-reporting heart disease and/or stroke. Using k-means clustering analysis, AIP control level, which was the log-transformed ratio of triglyceride to high-density lipoprotein cholesterol in molar concentration, was divided into five classes. The association between AIP control level and incident CVD among individuals with abnormal glucose metabolism was investigated multivariable logistic regression analysis and application of restricted cubic spline analysis. RESULTS: 398 (14.97%) of 2,659 participants eventually progressed to CVD within 3 years. After adjusting for various confounding factors, comparing to class 1 with the best control of the AIP, the OR for class 2 with good control was 1.31 (95% CI, 0.90-1.90), the OR for class 3 with moderate control was 1.38 (95% CI, 0.99-1.93), the OR for class 4 with worse control was 1.46 (95% CI, 1.01-2.10), and the OR for class 5 with consistently high levels was 1.56 (95% CI, 1.03-2.37). In restricted cubic spline regression, the relationship between cumulative AIP index and CVD is linear. Further subgroup analysis demonstrated that the similar results were observed in the individuals with agricultural Hukou, history of smoking, diastolic blood pressure ≥ 80mmHg, and normal body mass index. In addition, there was no interaction between the AIP control level and the subgroup variables. CONCLUSIONS: In middle-aged and elderly participants with abnormal glucose metabolism, constant higher AIP with worst control may have a higher incidence of CVD. Monitoring long-term AIP change will contribute to early identification of high risk of CVD among individuals with abnormal glucose metabolism.

Two new alkaloids isolated from Dictamnus dasycarpus Turcz.

Two new quinoline alkaloids (1-2) together with twenty-two known alkaloids (3-24) were isolated and identified from Dictamnus dasycarpus Turcz. Compounds 6-7, 9, 11, 15-16, 19 and 24 were isolated from D. dasycarpus for the first time. The structures of all compounds were characterised by spectroscopic methods (1D, 2D NMR and HRESIMS). The anti-proliferative activity was mediated by the arrest of three human cancer cell lines (SW982, HepG2 and A549) of all the compounds that were evaluated by CCK-8 assay.

Cytotoxic withanolides from the leaves of Datura stramonium L.

Six novel withanolides, along with nine known related compounds were isolated from the leaves of Datura stramonium L. The structures and absolute configurations of the new withanolides were elucidated by employing various spectral techniques and comparing them with those previously reported in the literature. In addition, four withanlides demonstrated interesting cytotoxic activity on LN229 cells with IC50 <20 µM.

A pH-Responsive DNA Tetrahedron/Methotrexate Drug Delivery System Used for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that leads to progressive and aggressive joint inflammation. The disease process is characterized by the activation of macrophages, which then release tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), accelerating tissue damage. Tackling tissue damage is a crucial target in the treatment of RA. In this study, a macrophage-targeted and pH-response DNA tetrahedron/methotrexate drug delivery system was constructed by loading methotrexate (MTX) onto a DNA duplex. MTX was used as a drug model, and a pH-response DNA tetrahedron (TET) was used as the drug carrier, which was modified with hyaluronic acid (HA) to target macrophages. The aim of this study was to evaluate the potential of TET as an effective drug carrier for the treatment of RA. On this basis, we successfully prepared TETs loaded with MTX, and in vitro assays showed that the MTX-TET treatment could successfully target macrophages and induce macrophages to polarize to M1 phenotype. At the same time, we also injected MTX-TET intravenously into collagen-induced arthritis (CIA) model mice, and the redness and swelling of the paws of mice were significantly alleviated, proving that the MTX-TET could successfully target inflamed joints and release MTX to treat joint swelling. In addition, the histochemical results showed that the MTX-TET could reduce synovitis and joint swelling in CIA mice, reduce the level of inflammatory factors in vivo, and improve the disease status while maintaining a good biosafety profile. This study showed that the MTX-TET treatment has beneficial therapeutic effects on RA, providing a new strategy for the clinical treatment of RA.

Data Mining Suggests That CXCL14 Gene Silencing in Colon Cancer Is Due to Promoter Methylation.

CXCL14 is one of the most evolutionarily conserved members of the chemokine family and is constitutionally expressed in multiple organs, suggesting that it is involved in the homeostasis maintenance of the system. CXCL14 is highly expressed in colon epithelial cells and shows obvious gene silencing in clinical colon cancer samples, suggesting that its silencing is related to the immune escape of cancer cells. In this paper, we analyzed the expression profiles of multiple human clinical colon cancer datasets and mouse colon cancer models to reveal the variation trend of CXCL14 expression during colitis, colon polyps, primary colon cancer, and liver metastases. The relationship between CXCL14 gene silencing and promoter hypermethylation was revealed through the colorectal carcinoma methylation database. The results suggest that CXCL14 is a tumor suppressor gene in colorectal carcinoma which is activated first and then silenced during the process of tumor occurrence and deterioration. Promoter hypermethylation is the main cause of CXCL14 silencing. The methylation level of CXCL14 is correlated with the anatomic site of tumor occurrence, positively correlated with patient age, and associated with prognosis. Reversing the hypermethylation of CXCL14 may be an epigenetic therapy for colon cancer.

Mechanical Signaling in Dental Pulp Stem Cells.

Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells derived from dental pulp that serves as an important model for investigating biological regeneration. DPSCs have a multipotent differentiation capacity and can promote different biological processes, including osteogenesis, odontogenesis, chondrogenesis, and angiogenesis. These biological processes are regulated by an extensive range of intra- and extra-cellular factors. Further, biomechanical cues, such as substrate stiffness, physical stress, and cell spreading, have been highlighted as particularly important modulators of DPSC function. This review sought to discuss various related signaling components involved in biomechanical cues and their respective roles in cellular and tissue responses in DPSCs, summarize current findings, and provide an outlook on the potential applications of biomechanics in regenerative medicine and tissue engineering.

Natural epidithiodiketopiperazine alkaloids as potential anticancer agents: Recent mechanisms of action, structural modification, and synthetic strategies.

Cancer has become a grave health crisis that threatens the lives of millions of people worldwide. Because of the drawbacks of the available anticancer drugs, the development of novel and efficient anticancer agents should be encouraged. Epidithiodiketopiperazine (ETP) alkaloids with a 2,5-diketopiperazine (DKP) ring equipped with transannular disulfide or polysulfide bridges or S-methyl moieties constitute a special subclass of fungal natural products. Owing to their privileged sulfur units and intriguing architectural structures, ETP alkaloids exhibit excellent anticancer activities by regulating multiple cancer proteins/signaling pathways, including HIF-1, NF-κB, NOTCH, Wnt, and PI3K/AKT/mTOR, or by inducing cell-cycle arrest, apoptosis, and autophagy. Furthermore, a series of ETP alkaloid derivatives obtained via structural modification showed more potent anticancer activity than natural ETP alkaloids. To solve supply difficulties from natural resources, the total synthetic routes for several ETP alkaloids have been designed. In this review, we summarized several ETP alkaloids with anticancer properties with particular emphasis on their underlying mechanisms of action, structural modifications, and synthetic strategies, which will offer guidance to design and innovate potential anticancer drugs.

Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer.

DNA damage-repair machinery participates in maintaining genomic integrity and affects tumorigenesis. Molecular signatures based on DNA damage-repair-related genes (DRGs) capable of comprehensively indicating the prognosis, tumor immunometabolic profile and therapeutic responsiveness of breast cancer (BRCA) patients are still lacking. Integrating public datasets and bioinformatics algorithms, we developed a robust prognostic signature based on 27 DRGs. Multiple patient cohorts identified significant differences in various types of survival between high- and low-risk patients stratified by the signature. The signature correlated well with clinicopathological factors and could serve as an independent prognostic indicator for BRCA patients. Furthermore, low-risk tumors were characterized by more infiltrated CD8+ T cells, follicular helper T cells, M1 macrophages, activated NK cells and resting dendritic cells, and fewer M0 and M2 macrophages. The favorable immune infiltration patterns of low-risk tumors were also accompanied by specific metabolic profiles, decreased DNA replication, and enhanced antitumor immunity. Low-risk patients may respond better to immunotherapy, and experience improved outcomes with conventional chemotherapy or targeted medicine. Real-world immunotherapy and chemotherapy cohorts verified the predictive results. Additionally, four small molecule compounds promising to target high-risk tumors were predicted. In vitro experiments confirmed the high expression of GNPNAT1 and MORF4L2 in BRCA tissues and their association with immune cells, and the knockdown of these two DRGs suppressed the proliferation of human BRCA cells. In summary, this DNA damage-repair-related signature performed well in predicting patient prognosis, immunometabolic profiles and therapeutic sensitivity, hopefully contributing to precision medicine and new target discovery of BRCA.

Altered neuromagnetic activity in default mode network in childhood absence epilepsy.

Purpose: The electrophysiological characterization of resting state oscillatory functional connectivity within the default mode network (DMN) during interictal periods in childhood absence epilepsy (CAE) remains unclear. Using magnetoencephalographic (MEG) recordings, this study investigated how the connectivity within the DMN was altered in CAE. Methods: Using a cross-sectional design, we analyzed MEG data from 33 children newly diagnosed with CAE and 26 controls matched for age and sex. The spectral power and functional connectivity of the DMN were estimated using minimum norm estimation combined with the Welch technique and corrected amplitude envelope correlation. Results: Default mode network showed stronger activation in the delta band during the ictal period, however, the relative spectral power in other bands was significantly lower than that in the interictal period (p corrected < 0.05 for DMN regions, except bilateral medial frontal cortex, left medial temporal lobe, left posterior cingulate cortex in the theta band, and the bilateral precuneus in the alpha band). It should be noted that the significant power peak in the alpha band was lost compared with the interictal data. Compared with controls, the interictal relative spectral power of DMN regions (except bilateral precuneus) in CAE patients was significantly increased in the delta band (p corrected < 0.01), whereas the values of all DMN regions in the beta-gamma 2 band were significantly decreased (p corrected < 0.01). In the higher frequency band (alpha-gamma1), especially in the beta and gamma1 band, the ictal node strength of DMN regions except the left precuneus was significantly higher than that in the interictal periods (p corrected < 0.01), and the node strength of the right inferior parietal lobe increased most significantly in the beta band (Ictal: 3.8712 vs. Interictal: 0.7503, p corrected < 0.01). Compared with the controls, the interictal node strength of DMN increased in all frequency bands, especially the right medial frontal cortex in the beta band (Controls: 0.1510 vs. Interictal: 3.527, p corrected < 0.01). Comparing relative node strength between groups, the right precuneus in CAE children decreased significantly (ß: Controls: 0.1009 vs. Interictal: 0.0475; γ 1: Controls:0.1149 vs. Interictal:0.0587, p corrected < 0.01) such that it was no longer the central hub. Conclusion: These findings indicated DMN abnormalities in CAE patients, even in interictal periods without interictal epileptic discharges. Abnormal functional connectivity in CAE may reflect abnormal anatomo-functional architectural integration in DMN, as a result of cognitive mental impairment and unconsciousness during absence seizure. Future studies are needed to examine if the altered functional connectivity can be used as a biomarker for treatment responses, cognitive dysfunction, and prognosis in CAE patients.

Syntheses and evaluation of acridone derivatives as anticancer agents targeting Kras promoter i-motif structure.

Two series of novel acridone derivatives were designed and synthesized, with their anticancer activity evaluated. Most of these compounds showed potent antiproliferative activity against cancer cell lines. Among them, compound C4 with dual 1,2,3-triazol moieties exhibited the most potent activity against Hep-G2 cells with IC50 value determined to be 6.29 ± 0.93 µM. Subsequent experiments showed that C4 could bind to and destabilize Kras gene promoter i-motif structure without significant interaction with its corresponding G-quadruplex. C4 could down-regulate Kras expression in Hep-G2 cells, possibly due to its interaction with the Kras i-motif. Further cellular studies indicated that C4 could induce apoptosis of Hep-G2 cells, possibly related to its effect on mitochondrial dysfunction. These results indicated that C4 could be further developed as a promising anticancer agent.