Emission characteristics, environmental impacts and health risk assessment of volatile organic compounds from the typical chemical industry in China.

To study the volatile organic compounds (VOCs) emission characteristics of industrial enterprises in China, 6 typical chemical industries in Yuncheng City were selected as research objects, including the modern coal chemical industry (MCC), pharmaceutical industry (PM), pesticide industry (PE), coking industry (CO) and organic chemical industry (OC). The chemical composition of 91 VOCs was quantitatively analyzed. The results showed that the emission concentration of VOCs in the chemical industry ranged from 1.16 to 155.59 mg/m3. Alkanes were the main emission components of MCC (62.0%), PE (55.1%), and OC (58.5%). Alkenes (46.5%) were important components of PM, followed by alkanes (23.8%) and oxygenated volatile organic compounds (OVOCs) (21.2%). Halocarbons (8.6%-71.1%), OVOCs (9.7%-37.6%) and alkanes (11.2%-27.0%) were characteristic components of CO. The largest contributor to OFP was alkenes (0.6%-81.7%), followed by alkanes (9.3%-45.9%), and the lowest one was alkyne (0%-0.5%). Aromatics (66.9%-85.4%) were the largest contributing components to SOA generation, followed by alkanes (2.6%-28.5%), and the lowest one was alkenes (0%-4.1%). Ethylene and BTEX were the key active species in various chemical industries. The human health risk assessment showed workers long-term exposed to the air in the chemical industrial zone had a high cancer and non-cancer risk during work, and BTEX and dichloromethane were the largest contributors.

Discovery of Potent Selective HDAC6 Inhibitors with 5-Phenyl-1H-indole Fragment: Virtual Screening, Rational Design, and Biological Evaluation.

Among the HDACs family, histone deacetylase 6 (HDAC6) has attracted extensive attention due to its unique structure and biological functions. Numerous studies have shown that compared with broad-spectrum HDACs inhibitors, selective HDAC6 inhibitors exert ideal efficacy in tumor treatment with insignificant toxic and side effects, demonstrating promising clinical application prospect. Herein, we carried out rational drug design by integrating a deep learning model, molecular docking, and molecular dynamics simulation technology to construct a virtual screening process. The designed derivatives with 5-phenyl-1H-indole fragment as Cap showed desirable cytotoxicity to the various tumor cell lines, all of which were within 15 µM (ranging from 0.35 to 14.87 µM), among which compound 5i had the best antiproliferative activities against HL-60 (IC50 = 0.35 ± 0.07 µM) and arrested HL-60 cells in the G0/G1 phase. In addition, 5i exhibited better isotype selective inhibitory activities due to the potent potency against HDAC6 (IC50 = 5.16 ± 0.25 nM) and the reduced inhibitory activities against HDAC1 (selective index ≈ 124), which was further verified by immunoblotting results. Moreover, the representative binding conformation of 5i on HDAC6 was revealed and the key residues contributing 5i's binding were also identified via decomposition free-energy analysis. The discovery of lead compound 5i also indicates that virtual screening is still a beneficial tool in drug discovery and can provide more molecular skeletons with research potential for drug design, which is worthy of widespread application.

Living Artificial Skin: Photosensitizer and Cell Sandwiched Bacterial Cellulose for Chronic Wound Healing.

Chronic wounds pose a significant global public health challenge due to their suboptimal treatment efficacy caused by bacterial infections and microcirculatory disturbances. Inspired by the biofunctionality of natural skin, an artificial skin (HV@BC@TBG) is bioengineered with bacterial cellulose (BC) sandwiched between photosensitizers (PS) and functionalized living cells. Glucose-modified PS (TBG) and vascular endothelial growth factor (VEGF)-functionalized living cells (HV) are successively modified on each side of BC through biological metabolism and bio-orthogonal reaction. As the outermost layer, the TBG layer can generate reactive oxygen species (ROS) upon light illumination to efficiently combat bacterial infections. The HV layer is the inner layer near the diabetic wound, which servs as a living factory to continuously secrete VEGF to accelerate wound repair by promoting fibroblast proliferation and angiogenesis. The sandwiched structural artificial skin HV@BC@TBG is nontoxic, biocompatible, and demonstrated its ability to significantly accelerate the healing process of infected diabetic wounds, rendering it a promising next-generation medical therapy for chronic wound management.

Effectiveness and safety of auricular acupuncture on adjuvant analgesia in patients with total knee arthroplasty: a randomized sham-controlled trial.

Objective: This study aimed to evaluate the effectiveness and safety of auricular acupuncture (AA) on postoperative analgesia, the degree of postoperative nausea, and the effect of inflammation after total knee arthroplasty (TKA). Methods: This was a single-center, placebo-controlled, randomized clinical trial. In total, 96 patients were randomly divided into an AA group with an indwelling intradermal needle (n = 48) and a sham auricular acupuncture (SAA) group with a non-penetrating placebo needle (n = 48). Intra-spinal anesthesia was adopted in both groups during surgery, and an epidural analgesic pump was implanted after surgery for 48 h. The primary outcome was the post-surgery visual analog score (VAS) of resting and movement states (at 6, 12 h and 1, 2, 3, 5, and 7 days). The secondary outcomes included additional doses of analgesic injection during the treatment, C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and white blood cell (WBC) count on the 1st, 3rd, and 7th day after the operation, nausea on the 1st, 2nd, and 3rd day after the operation, the Hospital for Special Surgery Knee Score (HSS) on the 2nd and 12th week after the operation, and adverse events. Results: The VAS in the AA group at 6 h, 12 h, 2, 3, and 5 days after surgery were lower than those of the SAA group (p < 0.05). Among the secondary outcomes, the total dose of additional analgesic injection after surgery in the AA group was lower than that in the SAA group (p < 0.05). The serum CRP on the 1st day after operation in the AA group was lower than that in the SAA group (p < 0.05). The degree of nausea on 2nd day after surgery in the AA group was lower than that in the SAA group (p < 0.05). There was no significant difference in other outcomes (p > 0.05). Conclusion: In this study, AA was shown to be an effective and safe complementary and alternative therapy for pain relief after TKA, which was able to reduce the total postoperative dose of additional painkillers, decrease serum CRP 1 day after surgery, and improve the degree of postoperative nausea. Clinical trial registration: www.chictr.org.cn, ChiCTR2100054403.

Highly-Selective Analytical Strategy for 90 Pesticides and Metabolites Residues in Fish and Shrimp Samples.

The analysis of pesticide residues in aquatic products is challenging due to low residue levels and the complex matrix interference. In this study, we developed a simple, fast method for the trace analysis of 90 pesticides and metabolites in aquatic products. The analytes covered a wide polarity range with log Kow (log octanol-water partition coefficient) ranging from -1.2 to 6.37. Grass carp (Ctenopharyngodon idellus) and prawn (Penaeus chinensis) samples were chosen to validate the quantification method. The samples were extracted by 0.2% formic-acetonitrile, cleaned by solid-phase extraction (PRiME HLB), and analyzed by high performance liquid chromatography-tandem mass spectrometry. The results showed good linearities for the analytes and were observed in the range of 0.05-50 µg/L. The recoveries of the method were within 50.4-118.6%, with the relative standard deviations being lower than 20%. The limits of quantifications (LOQs) of the method were in the range of 0.05-5.0 µg/kg, which were superior to values compared with other research. The developed method was applied to detect pesticide residues in prawn samples from eastern coastal areas of China. Three herbicide residues of diuron, prometryn, and atrazine were detected in prawn samples. The method was sensitive and efficient, which is of significance in expanding the screening scope and improving the quantitative analysis efficiency in aquatic products.

Delineation of clinical target volume and organs at risk in cervical cancer radiotherapy by deep learning networks.

PURPOSE: Delineation of the clinical target volume (CTV) and organs-at-risk (OARs) is important in cervical cancer radiotherapy. But it is generally labor-intensive, time-consuming, and subjective. This paper proposes a parallel-path attention fusion network (PPAF-net) to overcome these disadvantages in the delineation task. METHODS: The PPAF-net utilizes both the texture and structure information of CTV and OARs by employing a U-Net network to capture the high-level texture information, and an up-sampling and down-sampling (USDS) network to capture the low-level structure information to accentuate the boundaries of CTV and OARs. Multi-level features extracted from both networks are then fused together through an attention module to generate the delineation result. RESULTS: The dataset contains 276 computed tomography (CT) scans of patients with cervical cancer of staging IB-IIA. The images are provided by the West China Hospital of Sichuan University. Simulation results demonstrate that PPAF-net performs favorably on the delineation of the CTV and OARs (e.g., rectum, bladder and etc.) and achieves the state-of-the-art delineation accuracy, respectively, for the CTV and OARs. In terms of the Dice Similarity Coefficient (DSC) and the Hausdorff Distance (HD), 88.61% and 2.25 cm for the CTV, 92.27% and 0.73 cm for the rectum, 96.74% and 0.68 cm for the bladder, 96.38% and 0.65 cm for the left kidney, 96.79% and 0.63 cm for the right kidney, 93.42% and 0.52 cm for the left femoral head, 93.69% and 0.51 cm for the right femoral head, 87.53% and 1.07 cm for the small intestine, and 91.50% and 0.84 cm for the spinal cord. CONCLUSIONS: The proposed automatic delineation network PPAF-net performs well on CTV and OARs segmentation tasks, which has great potential for reducing the burden of radiation oncologists and increasing the accuracy of delineation. In future, radiation oncologists from the West China Hospital of Sichuan University will further evaluate the results of network delineation, making this method helpful in clinical practice.

Discovery of selective HDAC6 inhibitors based on a multi-layer virtual screening strategy.

The abnormal enhancement of histone deacetylase 6 (HDAC6) has been demonstrated to be closely related to the occurrence and development of various malignant tumors, attracting extensive attention as a promising target for cancer therapy. Currently, only limited selective HDAC6 inhibitors have entered clinical trials, making the rapid discovery of selective HDAC6 inhibitors with safety profiles particularly urgent. In this study, a multi-layer virtual screening workflow was established, and the representative compounds screened were biologically evaluated in combination with enzyme inhibitory and anti-tumor cell proliferation experiments. The experimental results showed that the screened compounds L-25, L-32, L-45 and L-81 exhibited nanomolar inhibitory activity against HDAC6, and exerted a certain degree of anti-proliferative activities against tumor cells, especially the cytotoxicity of L-45 to A375 (IC50 = 11.23 ± 1.27 µM) and the cytotoxicity of L-81 against HCT-116 (IC50 = 12.25 ± 1.13 µM). Additionally, the molecular mechanisms underlying the subtype selective inhibitory activities of the selected compounds were further elucidated using computational approaches, and the hotspot residues on HDAC6 contributing to the ligands' binding were identified. In summary, this study established a multi-layer screening scheme to quickly and effectively screen out hit compounds with enzyme inhibitory activity and anti-tumor cell proliferation, providing novel scaffolds for the subsequent anti-tumor drug design based on HDAC6 target.

Attention-guided multi-scale context aggregation network for multi-modal brain glioma segmentation.

BACKGROUND: Accurate segmentation of brain glioma is a critical prerequisite for clinical diagnosis, surgical planning and treatment evaluation. In current clinical workflow, physicians typically perform delineation of brain tumor subregions slice-by-slice, which is more susceptible to variabilities in raters and also time-consuming. Besides, even though convolutional neural networks (CNNs) are driving progress, the performance of standard models still have some room for further improvement. PURPOSE: To deal with these issues, this paper proposes an attention-guided multi-scale context aggregation network (AMCA-Net) for the accurate segmentation of brain glioma in the magnetic resonance imaging (MRI) images with multi-modalities. METHODS: AMCA-Net extracts the multi-scale features from the MRI images and fuses the extracted discriminative features via a self-attention mechanism for brain glioma segmentation. The extraction is performed via a series of down-sampling, convolution layers, and the global context information guidance (GCIG) modules are developed to fuse the features extracted for contextual features. At the end of the down-sampling, a multi-scale fusion (MSF) module is designed to exploit and combine all the extracted multi-scale features. Each of the GCIG and MSF modules contain a channel attention (CA) module that can adaptively calibrate feature responses and emphasize the most relevant features. Finally, multiple predictions with different resolutions are fused through different weightings given by a multi-resolution adaptation (MRA) module instead of the use of averaging or max-pooling to improve the final segmentation results. RESULTS: Datasets used in this paper are publicly accessible, that is, the Multimodal Brain Tumor Segmentation Challenges 2018 (BraTS2018) and 2019 (BraTS2019). BraTS2018 contains 285 patient cases and BraTS2019 contains 335 cases. Simulations show that the AMCA-Net has better or comparable performance against that of the other state-of-the-art models. In terms of the Dice score and Hausdorff 95 for the BraTS2018 dataset, 90.4% and 10.2 mm for the whole tumor region (WT), 83.9% and 7.4 mm for the tumor core region (TC), 80.2% and 4.3 mm for the enhancing tumor region (ET), whereas the Dice score and Hausdorff 95 for the BraTS2019 dataset, 91.0% and 10.7 mm for the WT, 84.2% and 8.4 mm for the TC, 80.1% and 4.8 mm for the ET. CONCLUSIONS: The proposed AMCA-Net performs comparably well in comparison to several state-of-the-art neural net models in identifying the areas involving the peritumoral edema, enhancing tumor, and necrotic and non-enhancing tumor core of brain glioma, which has great potential for clinical practice. In future research, we will further explore the feasibility of applying AMCA-Net to other similar segmentation tasks.

New Set of Isobaric Labeling Reagents for Quantitative 16Plex Proteomics.

Peptide labeling by isobaric tags is a powerful approach for the relative quantitative analysis of proteomes in multiple groups. There has been a revolution in the innovation of new isobaric reagents; however, great effort is being made to expand simultaneous labeling groups to identify more labeled peptides and reduce reporter ion signal suppression. We redesigned the original chemical structure of the deuterium isobaric amine-reactive tag developed in our laboratory. We optimized the synthetic pathway to create a new set of 16-plex isobaric tags (IBT-16plex). The novel reagent enabled almost complete labeling of peptides within 90 min, with all labeling reporter ions exhibiting comparable MS/MS signals. Compared to a typical 16plex reagent, TMTpro-16plex, the peptides and proteins identified by IBT-16plex in trypsinized HeLa cells were significantly increased by 14.8 and 8.6%, respectively. Moreover, differences in peptide abundance within 10-fold among multiple groups were barely suppressed in IBT-16plex, whereas the dynamic range in TMTpro-16plex-labeled groups was smaller. After quantitative examination of MCF7 cell proteins, IBT-16plex was confirmed as feasible and useful for evaluating protein responses of glucose-starved MCF7 cells to a glucose-rich medium.

Organic Small Molecule Contrast Agent for Targeted Photoacoustic Imaging of Patient-Derived Brain Tumors.

Traditional glioblastoma (GBM) cell lines do not maintain the heterogeneity of the original tumor, cell interactions, and therapy response, thus limiting their investigation in GBM theranostics. Herein, a kind of GBM tumor-targeting nanoparticles (NPs) TCFNP@iRGD are designed and constructed, which are generated by photoacoustic (PA) contrast agent 2-(3-cyano-4,5,5-trimethylfuran-2(5H)-ylidene) malononitrile (TCF)-OH through facile nanoprecipitation and decorated with an active targeting ligand iRGD. Their potential in GBM detection via PA imaging on glioma patient-derived cells intracranial xenograft models is evaluated for the first time. Excellent tumor-specific PA mapping performance of GBM is realized by TCFNP@iRGD, demonstrating its promising potential in the clinical diagnosis of GBM.

Application of insecticides by soil drenching before seedling transplanting combined with anti-insect nets to control tobacco whitefly in tomato greenhouses.

Application of chemical pesticides is currently the main effective method to control tobacco whitefly (Bemisa tabaci) in tomato in China. The B. tabaci control efficacy of three systemic insecticides (thiamethoxam, sulfoxaflor and cyantraniliprole) by pre-transplant soil drenching with anti-insect nets throughout the tomato growth period was evaluated in two tomato greenhouses in the suburbs of Beijing, China, in 2018 and 2019. In two greenhouse trials, thiamethoxam 25% water dispersible granules (WDG) at a field rate of 21 g a.i./hm2, sulfoxaflor 22% aqueous suspension (AS) at 18 g a.i./hm2 or cyantraniliprole 10% oil-based suspension concentrate (OD) at 18 g a.i./hm2 applied via soil drenching before seedling transplanting in combination with white anti-insect nets (50 mesh) all effectively controlled the damage to B. tabaci and resulted in a low density of adults and eggs during the entire growing season, which was significantly lower than application of thiamethoxam, sulfoxaflor or cyantraniliprole via soil drenching before seedling transplanting without anti-insect net treatments or anti-insect nets alone (P < 0.05). All of the above treatments provided significantly better results than the untreated control (P < 0.05). All chemically treated tomato fruits had acceptable insecticide residuals that were lower than the corresponding maximum residue limits. The results suggest that application of thiamethoxam 25% WDG at a field rate of 21 g a.i./hm2, sulfoxaflor 22% AS at 18 g a.i./hm2 or cyantraniliprole 10% OD at 18 g a.i./hm2 by pre-transplant soil drenching combined with anti-insect nets could be recommended to control B. tabaci throughout the tomato growth period as part of integrated pest management programs in China.

Gas-PM2.5 partitioning, health risks, and sources of atmospheric PAHs in a northern China city: Impact of domestic heating.

The diurnal variation, gas-particle partitioning, health risks, and sources of polycyclic aromatic hydrocarbons (PAHs) were investigated in a northern basin city of China in winter, 2020. The mean concentrations of particulate and gaseous PAHs were 87.90 ng m-3 and 69.65 ng m-3, respectively, and their concentrations were considerably enhanced during the domestic heating period. The relationship between the gas-particle partitioning coefficient of PAHs (KP) and subcooled liquid vapor pressure of PAHs (PL0) indicated organic absorption as the mechanism for this partitioning. However, the dual sorption model confirmed adsorption onto elemental carbon (EC). The health risks indicated by several equivalent parameters showed an important health effect of PAHs, especially of particulate PAHs bound onto PM2.5 during the heating period. Environmentally persistent free radicals (EPFRs) were also studied as an auxiliary parameter to evaluate the health impact of PAHs. According to the diagnostic ratios of PAHs and PMF model results, petroleum volatilization and coal combustion were the dominant sources of particulate PAHs during the non-heating and heating periods, respectively. The source apportionment results can help efficiently control PAHs and their health risks.

Do biological activities of selective histone deacetylase 6 (HDAC6) inhibitors rely on the modification of cap group?

Nowadays, significant progress has been made in the development of selective histone deacetylase 6 (HDAC6) inhibitors, exerting great potential in the treatment of various malignant tumors and neurodegenerative diseases. Previously, selective inhibitory activities of HDAC inhibitors were generally considered sensitive to the interactions between the Cap group and the binding site of HDAC6, and a large number of selective HDAC6 inhibitors have been designed and synthesized based on the strategy. However, some inhibitors without Cap group could also exhibit excellent potency and selective inhibition towards HDAC6, and in this study, BRD9757 and compound 8, as capless selective HDAC6 inhibitors, were selected as molecular probes to explore the difference of their binding interactions in HDAC1&6. Through the analysis of binding-free energies and conformational rearrangements after 1 µs molecular dynamics simulation, it could be learned that although the residues in the binding site remained highly consistent, the binding mechanisms of BRD9757 and compound 8 in HDAC1&6 were different, which will provide valuable hints for the discovery of novel selective HDAC6 inhibitors.

Pyroptosis Remodeling Tumor Microenvironment to Enhance Pancreatic Cancer Immunotherapy Driven by Membrane Anchoring Photosensitizer.

Immunotherapy, the most promising strategy of cancer treatment, has achieved promising outcomes, but its clinical efficacy in pancreatic cancer is limited mainly due to the complicated tumor immunosuppressive microenvironment. As a highly inflammatory form of immunogenic cell death (ICD), pyroptosis provides a great opportunity to alleviate immunosuppression and promote systemic immune responses in solid tumors. Herein, membrane-targeted photosensitizer TBD-3C with aggregation-induced emission (AIE) feature to trigger pyroptosis-aroused cancer immunotherapy via photodynamic therapy (PDT) is applied. The results reveal that pyroptotic cells induced by TBD-3C could stimulate M1-polarization of macrophages, cause maturation of dendritic cells (DCs), and activation of CD8+ cytotoxic T-lymphocytes (CTLs). Pyroptosis-aroused immunological responses could convert immunosuppressive "cold" tumor microenvironment (TME) to immunogenic "hot" TME, which not only inhibits primary pancreatic cancer growth but also attacks the distant tumor. This work establishes a platform with high biocompatibility for light-controlled antitumor immunity and solid tumor immunotherapy aroused by cell pyroptosis.

Sublethal toxicity, transgenerational effects, and transcriptome expression of the neonicotinoid pesticide cycloxaprid on demographic fitness of Coccinella septempunctata.

Evaluating side effects of new neonicotinoids in terms of sublethal doses and transcriptome expression is a crucial but challenging part of integrated pest management (IPM) approaches. To this end, a study of lethal and sublethal effects on Coccinella septempunctata larvae was conducted, and an age-stage, two-sex life table procedure was performed to investigate life-table parameters. Cycloxaprid (CYC) was shown to have adverse effects on survival, development, total longevity, reproductive capacity, and predation ability in C. septempunctata. In addition, demographic growth parameters of the F1 generation such as net reproductive rate, and the intrinsic and finite rates of increase were significantly decreased under sublethal dosage LR30 (1.91 g ai/hm2). These results demonstrated that the population growth of C. septempunctata was impacted by a sublethal dosage of CYC. For transcriptome expression, 544 up- and 338 down-regulated significantly differentially expressed genes (DEGs), were observed between LR30 treatment and control groups. Moreover, pathways related to metabolism of retinol, carcinogenesis, biosynthesis of steroid hormone, P450 metabolism, and metabolism of xenobiotics were identified in KEGG pathway analysis. Ten DEGs were chosen and confirmed with quantitative real-time PCR analysis. Based on these findings, CYC should be considered as a component of IPM strategies in the field.

Assessment of the Therapeutic Potential of Melatonin for the Treatment of Osteoporosis Through a Narrative Review of Its Signaling and Preclinical and Clinical Studies.

Melatonin is a bioamine produced primarily in the pineal gland, although peripheral sites, including the gut, may also be its minor source. Melatonin regulates various functions, including circadian rhythm, reproduction, temperature regulation, immune system, cardiovascular system, energy metabolism, and bone metabolism. Studies on cultured bone cells, preclinical disease models of bone loss, and clinical trials suggest favorable modulation of bone metabolism by melatonin. This narrative review gives a comprehensive account of the current understanding of melatonin at the cell/molecular to the systems levels. Melatonin predominantly acts through its cognate receptors, of which melatonin receptor 2 (MT2R) is expressed in mesenchymal stem cells (MSCs), osteoblasts (bone-forming), and osteoclasts (bone-resorbing). Melatonin favors the osteoblastic fate of MSCs, stimulates osteoblast survival and differentiation, and inhibits osteoclastogenic differentiation of hematopoietic stem cells. Produced from osteoblastic cells, osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) critically regulate osteoclastogenesis and melatonin by suppressing the osteoclastogenic RANKL, and upregulating the anti-osteoclastogenic OPG exerts a strong anti-resorptive effect. Although the anti-inflammatory role of melatonin favors osteogenic function and antagonizes the osteoclastogenic function with the participation of SIRT signaling, various miRNAs also mediate the effects of the hormone on bone cells. In rodent models of osteoporosis, melatonin has been unequivocally shown to have an anti-osteoporotic effect. Several clinical trials indicate the bone mass conserving effect of melatonin in aging/postmenopausal osteoporosis. This review aims to determine the possibility of melatonin as a novel class of anti-osteoporosis therapy through the critical assessment of the available literature.

Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy.

The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level. The enzyme inhibition assay showed that compound 12c exerted broad-spectrum enzyme inhibitory activities and compounds 9m and 9q were more inclined to inhibit HDAC6, exhibiting certain selective inhibitory activities among the representative subtypes. Moreover, the binding modes of compounds 9q and 12c in HDAC1&6 were further explored via computational approaches to elucidate the molecular mechanisms underlying selective inhibitory activities, providing valuable hints for the discovery of novel HDAC6 inhibitors.

Enzyme-Mediated Intracellular Polymerization of AIEgens for Light-Up Tumor Localization and Theranostics.

Improving the enrichment of drugs or theranostic agents within tumors is vital to achieve effective cancer diagnosis and therapy with reduced dosage and damage to normal tissues. In this work, an enzyme-mediated aggregation-induced emission fluorogen (AIEgen) intracellular polymerization strategy that can simultaneously promote the accumulation and retention of the AIEgen in the tumor for prolonged imaging and enhanced tumor growth inhibition is described. An AIEgen-peptide conjugate (D2P1) and cyanobenzothiazole-cysteine (3CBT) that can undergo rapid condensation reaction to form nanoaggregates in tumor cells are rationally designed. Upon tumor-specific cathepsin protease reaction, the cleavage of peptides induces condensate polymerization between the exposed cysteine and 2-cyanobenzothiazole on 3CBT, triggering accumulation of D2P1 into the tumor site, leading to fluorescence light-up. Such enzyme-mediated polymerization of D2P1 and 3CBT alters cellular motility via disrupting actin organization and in turn inhibiting cell proliferation. In addition, due to the built-in intrinsic photosensitization property of the AIEgen, the accumulation of D2P1 can remarkably promote the tumor photodynamic therapy effect in vivo under light irradiation. This study thus represents the enzyme-mediated intracellular polymerization system with high potential to improve the diagnostic and therapeutic outcomes of tumors in vivo.

Metabolically engineered bacteria as light-controlled living therapeutics for anti-angiogenesis tumor therapy.

A living therapeutic system based on attenuated Salmonella was developed via metabolic engineering using an aggregation-induced emission (AIE) photosensitizer MA. The engineered bacteria could localize in the tumor tissues and continue to colonize and express exogenous genes. Under light irradiation, the encoded VEGFR2 gene was released and expressed in tumor tissues, which can suppress angiogenesis induced by a T cell-mediated autoimmune response and inhibit tumor growth.

Discovery of Potent EGFR Inhibitors With 6-Arylureido-4-anilinoquinazoline Derivatives.

According to the classical pharmacophore fusion strategy, a series of 6-arylureido-4-anilinoquinazoline derivatives ( Compounds 7a - t ) were designed, synthesized, and biologically evaluated by the standard CCK-8 method and enzyme inhibition assay. Among the title compounds, Compounds 7a , 7c , 7d , 7f , 7i , 7o , 7p , and 7q exhibited promising anti-proliferative bioactivities, especially Compound 7i , which had excellent antitumor activity against the A549, HT-29, and MCF-7 cell lines (IC50 = 2.25, 1.72, and 2.81 µM, respectively) compared with gefitinib, erlotinib, and sorafenib. In addition, the enzyme activity inhibition assay indicated that the synthesized compounds had sub-micromolar inhibitory levels (IC50, 11.66-867.1 nM), which was consistent with the results of the tumor cell line growth inhibition tests. By comparing the binding mechanisms of Compound 7i (17.32 nM), gefitinib (25.42 nM), and erlotinib (33.25 nM) to the EGFR, it was found that Compound 7i could extend into the effective region with a similar action conformation to that of gefitinib and interact with residues L85, D86, and R127, increasing the binding affinity of Compound 7i to the EGFR. Based on the molecular hybridization strategy, 14 compounds with EGFR inhibitory activity were designed and synthesized, and the action mechanism was explored through computational approaches, providing valuable clues for the research of antitumor agents based on EGFR inhibitors.