Recent Progress in Cyclic Aryliodonium Chemistry: Syntheses and Applications.

Hypervalent aryliodoumiums are intensively investigated as arylating agents. They are excellent surrogates to aryl halides, and moreover they exhibit better reactivity, which allows the corresponding arylation reactions to be performed under mild conditions. In the past decades, acyclic aryliodoniums are widely explored as arylation agents. However, the unmet need for acyclic aryliodoniums is the improvement of their notoriously low reaction economy because the coproduced aryl iodides during the arylation are often wasted. Cyclic aryliodoniums have their intrinsic advantage in terms of reaction economy, and they have started to receive considerable attention due to their valuable synthetic applications to initiate cascade reactions, which can enable the construction of complex structures, including polycycles with potential pharmaceutical and functional properties. Here, we are summarizing the recent advances made in the research field of cyclic aryliodoniums, including the nascent design of aryliodonium species and their synthetic applications. First, the general preparation of typical diphenyl iodoniums is described, followed by the construction of heterocyclic iodoniums and monoaryl iodoniums. Then, the initiated arylations coupled with subsequent domino reactions are summarized to construct polycycles. Meanwhile, the advances in cyclic aryliodoniums for building biaryls including axial atropisomers are discussed in a systematic manner. Finally, a very recent advance of cyclic aryliodoniums employed as halogen-bonding organocatalysts is described.

Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets.

Metastasis remains the principal cause of cancer-related lethality despite advancements in cancer treatment. Dysfunctional epigenetic alterations are crucial in the metastatic cascade. Among these, super-enhancers (SEs), emerging as new epigenetic regulators, consist of large clusters of regulatory elements that drive the high-level expression of genes essential for the oncogenic process, upon which cancer cells develop a profound dependency. These SE-driven oncogenes play an important role in regulating various facets of metastasis, including the promotion of tumor proliferation in primary and distal metastatic organs, facilitating cellular migration and invasion into the vasculature, triggering epithelial-mesenchymal transition, enhancing cancer stem cell-like properties, circumventing immune detection, and adapting to the heterogeneity of metastatic niches. This heavy reliance on SE-mediated transcription delineates a vulnerable target for therapeutic intervention in cancer cells. In this article, we review current insights into the characteristics, identification methodologies, formation, and activation mechanisms of SEs. We also elaborate the oncogenic roles and regulatory functions of SEs in the context of cancer metastasis. Ultimately, we discuss the potential of SEs as novel therapeutic targets and their implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.

Enhancement of hydrogenotrophic methanogenesis for methane production by nano zero-valent iron in soils.

Nanoscale zero-valent iron (nZVI) is attracting increasing attention as the most commonly used environmental remediation material. However, given the high surface area and strong reducing capabilities of nZVI, there is a lack of understanding regarding its effects on the complex anaerobic methane production process in flooded soils. To elucidate the mechanism of CH4 production in soil exposed to nZVI, paddy soil was collected and subjected to anaerobic culture under continuous flooding conditions, with various dosages of nZVI applied. The results showed that the introduction of nZVI into anaerobic flooded rice paddy systems promoted microbial utilization of acetate and carbon dioxide as carbon sources for methane production, ultimately leading to increased methane production. Following the introduction of nZVI into the soil, there was a rapid increase in hydrogen levels in the headspace, surpassing that of the control group. The hydrogen levels in both the experimental and control groups were depleted by the 29th day of culture. These findings suggest that nZVI exposure facilitates the enrichment of hydrogenotrophic methanogens, providing them with a favorable environment for growth. Additionally, it affected soil physicochemical properties by increasing pH and electrical conductivity. The metagenomic analysis further indicates that under exposure to nZVI, hydrogenotrophic methanogens, particularly Methanobacteriaceae and Methanocellaceae, were enriched. The relative abundance of genes such as mcrA and mcrB associated with methane production was increased. This study provides important theoretical insights into the response of key microbes, functional genes, and methane production pathways to nZVI during anaerobic methane production in rice paddy soils, offering fundamental insights into the long-term fate and risks associated with the introduction of nZVI into soils.

Tripartite motif-containing protein 11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome-mediated degradation of pleckstrin homology domain leucine-rich repeats protein phosphatase 1.

BACKGROUND AND AIMS: HCC is one of the main types of primary liver cancer, with high morbidity and mortality and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC remain open for study. APPROACH AND RESULTS: Through clinical analysis, we found that the expression of TRIM11 was up-regulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade, and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with pleckstrin homology domain leucine-rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1 and thus promoted activation of the protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. CONCLUSIONS: Our study confirmed that TRIM11 plays an oncogenic role in HCC through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of HCC.

The Efficacy and Safety of Telerehabilitation for Fibromyalgia: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Fibromyalgia is a chronic pain syndrome characterized by persistent and widespread musculoskeletal pain. Telerehabilitation is a promising treatment for patients with fibromyalgia through long-term monitoring, intervention, supervision, consultation, and education. OBJECTIVE: This study aimed to perform a comprehensive systematic review and meta-analysis of the efficacy and safety of telerehabilitation in patients with fibromyalgia. METHODS: Randomized controlled trials (RCTs) related to fibromyalgia and telerehabilitation were systematically searched in the PubMed, PEDro, Cochrane Library, ScienceDirect, Ovid MEDLINE, Embase, and Web of Science databases from inception to November 13, 2022. Two independent researchers screened the literatures and evaluated the methodological quality using the Cochrane Risk of Bias Tool. The outcome measures included the Fibromyalgia Impact Questionnaire scale, pain intensity, depression, pain catastrophizing, quality of life (QoL), and adverse events. Pooled effect sizes were calculated by Stata SE 15.1; a fixed effects model was used when I2<50%, whereas a random effects model was used when I2≥50%. RESULTS: A total of 14 RCTs with 1242 participants were included in this meta-analysis. The pooled results indicated that the telerehabilitation improved the Fibromyalgia Impact Questionnaire score (weighted mean difference -8.32, 95% CI -11.72 to -4.91; P<.001), pain intensity (standardized mean difference [SMD] -0.62, 95% CI -0.76 to -0.47; P<.001), depression levels (SMD -0.42, 95% CI -0.62 to -0.22; P<.001), pain catastrophizing (weighted mean difference -5.81, 95% CI -9.40 to -2.23; P=.001), and QoL (SMD 0.32, 95% CI 0.18 to 0.47; P<.001) in patients with fibromyalgia compared to control interventions. Only 1 RCT reported a mild adverse event of telerehabilitation; the other 13 RCTs did not mention this. CONCLUSIONS: Telerehabilitation can improve the symptoms and QoL of fibromyalgia. However, the safety of telerehabilitation remains uncertain due to the lack of sufficient evidence for the management of fibromyalgia. More rigorously designed trials are needed in the future to verify the safety and efficacy of telerehabilitation in fibromyalgia. TRIAL REGISTRATION: PROSPERO CRD42022338200; https://tinyurl.com/322keukv.

Selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors for cancer therapy.

Poly ADP-ribose polymerase (PARP) plays a critical role in many cellular processes such as DNA damage repair, gene transcription and cell apoptosis. Therefore, targeting PARP represents a promising strategy for cancer therapy. To date, numerous small molecule PARP1 inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, PARP1 inhibitor-based combination therapies, and other PARP1 modulators (e.g. PROTAC degraders, dual acting agents) have attracted great attention with significant advancements achieved in the past few years. In this review, we overviewed the recent progress on PARP1-based drug discovery with a focus on PARP1 inhibitor-based drug combination therapy and other PARP1-targeting strategies (e.g. selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors). In addition, we also summarized the reported co-crystal structures of PARP1 inhibitors in complex with their target proteins as well as the binding interactions. Finally, the challenges and future directions for PARP-based drug discovery in cancer therapy are also discussed in detail.

Rutaecarpine Prevents High Glucose-Induced Endothelial Cell Senescence Through Transient Receptor Potential Vanilloid Subtype 1/ SIRT1 Pathway.

ABSTRACT: SIRT1 functions as a longevity factor to counteract vascular aging induced by high glucose. Our previous study revealed that rutaecarpine, the natural agonist of transient receptor potential vanilloid subtype 1 (TRPV1), prevented high glucose-induced endothelial dysfunction. The present study aims to evaluate the effects of rutaecarpine on endothelial cell senescence induced by high glucose, and focus on the regulatory effect on SIRT1 expression. In cultured human umbilical vein endothelial cell (HUVEC), exposure to 33 mM high glucose for 72 hours induced cellular senescence, demonstrated as cell cycle arrest at G0/G1 phase, decreased cell viability, and increased number of senescence-associated ß-galactosidase positive senescence cells and ROS production, which were effectively attenuated by treatment with rutaecarpine (0.3, 1, and 3 µM). Furthermore, rutaecarpine upregulated longevity protein SIRT1 expression in HUVECs, accompanied by decreased level of senescence marker p21. In addition, rutaecarpine increased intracellular calcium level in HUVECs, and pretreatment with TRPV1 antagonist capsazepine, intracellular Ca2+ chelator BAPTA-AM or CaM antagonist W-7 abolished the effects of rutaecarpine on SIRT1 expression. In summary, this study shows that rutaecarpine upregulates SIRT1 expression and prevents high glucose-induced endothelial cell senescence, which is related to activation of TRPV1/[Ca2+]i/CaM signal pathway. Our findings provide evidence that rutaecarpine may be a promising candidate with a novel mechanism in prevention vascular aging in diabetes.

Recent Advances in Understanding the Role of Cartilage Lubrication in Osteoarthritis.

The remarkable lubrication properties of normal articular cartilage play an essential role in daily life, providing almost frictionless movements of joints. Alterations of cartilage surface or degradation of biomacromolecules within synovial fluid increase the wear and tear of the cartilage and hence determining the onset of the most common joint disease, osteoarthritis (OA). The irreversible and progressive degradation of articular cartilage is the hallmark of OA. Considering the absence of effective options to treat OA, the mechanosensitivity of chondrocytes has captured attention. As the only embedded cells in cartilage, the metabolism of chondrocytes is essential in maintaining homeostasis of cartilage, which triggers motivations to understand what is behind the low friction of cartilage and develop biolubrication-based strategies to postpone or even possibly heal OA. This review firstly focuses on the mechanism of cartilage lubrication, particularly on boundary lubrication. Then the mechanotransduction (especially shear stress) of chondrocytes is discussed. The following summarizes the recent development of cartilage-inspired biolubricants to highlight the correlation between cartilage lubrication and OA. One might expect that the restoration of cartilage lubrication at the early stage of OA could potentially promote the regeneration of cartilage and reverse its pathology to cure OA.

Challenges in Bio-fabrication of Organoid Cultures.

Three-dimensional (3D) organoids have shown advantages in cell culture over traditional two-dimensional (2D) culture, and have great potential in various applications of tissue engineering. However, there are limitations in current organoid fabrication technologies, such as uncontrolled size, poor reproductively, and inadequate complexity of organoids. In this chapter, we present the existing techniques and discuss the major challenges for 3D organoid biofabrication. Future perspectives on organoid bioprinting are also discussed, where bioprinting technologies are expected to make a major contribution in organoid fabrication, such as realizing mass production and constructing complex heterotypic tissues, and thus further advance the translational application of organoids in tissue engineering and regenerative medicine as well drug testing and pharmaceutics.

Rutaecarpine Reverses the Altered Connexin Expression Pattern Induced by Oxidized Low-density Lipoprotein in Monocytes.

Adhesion of monocytes to the vascular endothelium is crucial in atherosclerosis development. Connexins (Cxs) which form hemichannels or gap junctions, modulate monocyte-endothelium interaction. We previously found that rutaecarpine, an active ingredient of the Chinese herbal medicine Evodia, reversed the altered Cx expression induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells, and consequently decreases the adhesive properties of endothelial cells to monocytes. This study further investigated the effect of rutaecarpine on Cx expression in monocytes exposed to ox-LDL. In cultured human monocytic cell line THP-1, ox-LDL rapidly reduced the level of atheroprotective Cx37 but enhanced that of atherogenic Cx43, thereby inhibiting adenosine triphosphate release through hemichannels. Pretreatment with rutaecarpine recovered the expression of Cx37 but inhibited the upregulation of Cx43 induced by ox-LDL, thereby improving adenosine triphosphate-dependent hemichannel activity and preventing monocyte adhesion. These effects of rutaecarpine were attenuated by capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. The antiadhesive effects of rutaecarpine were also attenuated by hemichannel blocker 18α-GA. This study provides additional evidence that rutaecarpine can modulate Cx expression through transient receptor potential vanilloid subtype 1 activation in monocytes, which contributes to the antiadhesive properties of rutaecarpine.

Bisphenol A regulates the estrogen receptor alpha signaling in developing hippocampus of male rats through estrogen receptor.

Bisphenol A (BPA), one of the most common environmental endocrine disruptors, has been recognized to have wide adverse effects on the brain development and behavior. These adversities are related to its ability to bind estrogen receptor (ER) with subsequent alteration of its expression in the target areas. However, very little is known about whether BPA exposure also affects ER phosphorylation and its translocation to nucleus during postnatal development, two critical steps for its function. Here, we found that during development from postnatal day 7 (P7) to P21, the alpha subtype of ER (ERα) in the hippocampus of male rats experienced remarkable alterations in terms of its expression, phosphorylation and translocation to nucleus. Exposure to low level of BPA had bidirectional, development-dependent effects on the expression of ERα mRNA and protein, but decreased ERα phosphorylation and impaired its translocation to nucleus throughout the period investigated. Treatment with low dose of ICI 182,780 (ICI), an ER antagonist to block the binding of ER with BPA, reversed the altered ERα following BPA exposure, highlighting critical involvement of ER. Moreover, ICI treatment rescued the hippocampus-dependent behavioral deficits in the adult rats experiencing early-life BPA exposure. Overall, our results indicate that BPA interferes with the ERα signaling in the developing hippocampus in an ER-dependent manner, which may underlie its adverse behavioral and cognitive outcomes in adult animals.

Harpagide inhibits the TNF-α-induced inflammatory response in rat articular chondrocytes by the glycolytic pathways for alleviating osteoarthritis.

Osteoarthritis (OA) causes severe and functional dysfunction due to abnormal inflammation. The objective of this study was to evaluate the effect of Harpagide (HPG) on TNF-α-induced inflammation in vitro and in vivo. The effect of HPG on the proliferation of rat chondrocytes was studied. The anti-inflammatory effect of HPG and its molecular mechanisms were elucidated by qPCR, Western blotting, flow cytometry, metabolome analysis in vitro. In addition, the OA rat model was established, and the effect of HPG on OA was verified in vivo. We revealed 10 µM HPG demonstrated biocompatibility. The results demonstrated that HPG restored the upregulation of MMP-13, COX2, IL-1ß and IL-6 induced by TNF-α. Moreover, HPG reversed TNF-α induced degradation of the extracellular matrix of chondrocytes. TNF-α treatment induced down-regulation of the mRNA/protein levels of proliferative markers Bcl2, CDK1 and Cyclin D1 were also recovered. HPG can inhibit TNF-α-induced inflammatory response through glycolytic metabolic pathways. HPG can restore TNF-α-induced upregulation of GRP78/IRE1α, and downregulation of AMPK proteins. In vivo experiments demonstrated that after HPG treatment, the appearance and physiological structure of articular cartilage were more integrated with highly organized chondrocytes and rich cartilage matrix compared with OA group. Finally, the molecular docking of HPG and selected key factors in glycolysis results showed that HPG had good binding potential with PFKM, PFKP, PFKFB3, PKM, HK2, and PFKL. In conclusion, the results shown HPG protects and activates chondrocytes, inhibits TNF-α-induced inflammatory response by glycolysis pathway in rat articular chondrocytes, and plays a role in the treatment of OA.

Responses of methane production and methanogenic pathways to polystyrene nanoplastics exposure in paddy soil.

Nanoplastics (NPs) have attracted increasing attention within terrestrial ecosystems. However, our understanding of their impacts on the intricate anaerobic methanogenesis processes occurring in paddy soils microbial communities remains limited with respect to nanoplastics shape, function, and metabolic effects. Herein, we explored the effects of polystyrene nanoplastics (PS-NPs) and microplastics (PS-MPs) on anaerobic methanogenesis in a typical paddy soil. The results show that PS-NPs delayed methane production and the time to reach peak acetate content in incubation process of paddy soils, and the methanogenic rate increased rapidly after 13 days, with a maximum increase of 87.97%. However, PS-MPs had no marked effect on CH4, CO2 and acetate production. In addition, PS-NPs affected soil physicochemical properties by reducing pH and increasing electrical conductivity. Acetoclastic methanogens were enriched and the relative abundance of the genes ackA, pta, ACSS, cdhC, cdhD and cdhE in the acetoclastic pathways were significantly increased under PS-NPs exposure. In addition, PS-MPs had significant effect on the microbial community structure but no effect on methanogenic pathways of the paddy soils. This study provides important insights into the response of key microorganisms, functional genes and methanogenesis pathways to NPs during anaerobic methanogenesis in paddy soils.

3D Spheroids Facilitate Differentiation of Human Adipose-Derived Mesenchymal Stem Cells into Hepatocyte-Like Cells via p300-Mediated H3K56 Acetylation.

Hepatocyte-like cells (HLCs) that are differentiated from mesenchymal stem cells (MSCs) provide a valuable resource for drug screening and cell-based regeneration therapy. Differentiating HLCs into 3D spheroids enhances their phenotypes and functions. However, the molecular mechanisms underlying MSCs hepatogenic differentiation are not fully understood. In this study, we generated HLCs from human adipose-derived mesenchymal stem cells (hADMSCs) in both 2D and 3D cultures. We performed an acetyl-proteomics assay on the HLCs derived from both 2D and 3D differentiation and identified a differential change in H3K56 acetylation between the 2 differentiated cells. Our findings revealed that 3D differentiation activated ALB gene transcription by increasing the acetylation level of H3K56, thereby enhancing the phenotypes and functions of HLCs and further promoting their maturation. Notably, inhibiting p300 reduced the acetylation level of H3K56 during hepatogenic differentiation, leading to decreased phenotypes and functions of HLCs, whereas activation of p300 promoted hepatogenic differentiation, suggesting that p300 plays a critical role in this process. In summary, our study demonstrates a potential mechanism through which 3D spheroids differentiation facilitates hADMSCs differentiation into HLCs by promoting p300-mediated H3K56 acetylation, which could have significant clinical applications in liver regeneration and disease modeling.

A comprehensive review on 3D tissue models: Biofabrication technologies and preclinical applications.

The limitations of traditional two-dimensional (2D) cultures and animal testing, when it comes to precisely foreseeing the toxicity and clinical effectiveness of potential drug candidates, have resulted in a notable increase in the rate of failure during the process of drug discovery and development. Three-dimensional (3D) in-vitro models have arisen as substitute platforms with the capacity to accurately depict in-vivo conditions and increasing the predictivity of clinical effects and toxicity of drug candidates. It has been found that 3D models can accurately represent complex tissue structure of human body and can be used for a wide range of disease modeling purposes. Recently, substantial progress in biomedicine, materials and engineering have been made to fabricate various 3D in-vitro models, which have been exhibited better disease progression predictivity and drug effects than convention models, suggesting a promising direction in pharmaceutics. This comprehensive review highlights the recent developments in 3D in-vitro tissue models for preclinical applications including drug screening and disease modeling targeting multiple organs and tissues, like liver, bone, gastrointestinal tract, kidney, heart, brain, and cartilage. We discuss current strategies for fabricating 3D models for specific organs with their strengths and pitfalls. We expand future considerations for establishing a physiologically-relevant microenvironment for growing 3D models and also provide readers with a perspective on intellectual property, industry, and regulatory landscape.

3'-Daidzein Sulfonate Sodium Protects against Glutamate-induced Neuronal Injuries by Regulating NMDA Receptors.

BACKGROUND: It was previously found that 3'-Daidzein Sulfonate Sodium (DSS) exhibits protective effects on Cerebral Ischemia-Reperfusion Injury (CI/RI). AIM: This study aimed to explore the underlying molecular mechanisms involved in the neuroprotective effects of DSS against ischemic stroke. METHODS: In this study, rats with transient middle cerebral artery occlusion (tMCAO) were used as an in vivo model, whereas PC12 cells treated with glutamate alone and rat primary cortical neurons treated with the combination of glutamate and glycine were used as in vitro models. Cell viability and lactate dehydrogenase (LDH) release were used to evaluate cell injury. Cell apoptosis was determined by flow cytometry. Quantitative polymerase chain reaction (qPCR), Western blotting, and immunofluorescent staining methods were used to determine the mRNA expressions and protein levels and location. RESULTS: It was found that DSS significantly suppressed the impaired viability of PC12 cells induced by glutamate. DSS also increased cell viability while reducing the LDH release and apoptosis in primary cortical neurons injured by glutamate and glycine. In addition, DSS decreased GluN2B subunit expression while enhancing the expressions of GluN2A subunit and PSD95 in tMCAO rats' brains. CONCLUSION: This study demonstrated that DSS protects against excitotoxic damage in neurons by regulating the expression of NMDA receptors and PSD95 in the brain with cerebral ischemia-reperfusion injury. Our findings provide experimental evidence for the potential clinical administration of DSS in ischemic stroke.

Hyaluronic acid modified nanocarriers for aerosolized delivery of verteporfin in the treatment of acute lung injury.

Verteporfin (VER), a photosensitizer used in macular degeneration therapy, has shown promise in controlling macrophage polarization and alleviating inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, its hydrophobicity, limited bioavailability, and side effects hinder its therapeutic potential. In this study, we aimed to enhance the therapeutic potential of VER through pulmonary nebulized drug delivery for ALI/ARDS treatment. We combined hydrophilic hyaluronic acid (HA) with an oil-in-water system containing a poly(lactic acid-co-glycolic acid) (PLGA) copolymer of VER to synthesize HA@PLGA-VER (PHV) nanoparticles with favorable surface characteristics to improve the bioavailability and targeting ability of VER. PHV possesses suitable electrical properties, a narrow size distribution (approximately 200 nm), and favorable stability. In vitro and in vivo studies demonstrated the excellent biocompatibility, safety, and anti-inflammatory responses of the PHV by suppressing M1 macrophage polarization while inducing M2 polarization. The in vivo experiments indicated that the treatment with aerosolized nano-VER (PHV) allowed more drugs to accumulate and penetrate into the lungs, improved the pulmonary function and attenuated lung injury, and mortality of ALI mice, achieving improved therapeutic outcomes. These findings highlight the potential of PHV as a promising delivery system via nebulization for enhancing the therapeutic effects of VER in ALI/ARDS.

Potentials of ribosomopathy gene as pharmaceutical targets for cancer treatment.

Ribosomopathies encompass a spectrum of disorders arising from impaired ribosome biogenesis and reduced functionality. Mutation or dysexpression of the genes that disturb any finely regulated steps of ribosome biogenesis can result in different types of ribosomopathies in clinic, collectively known as ribosomopathy genes. Emerging data suggest that ribosomopathy patients exhibit a significantly heightened susceptibility to cancer. Abnormal ribosome biogenesis and dysregulation of some ribosomopathy genes have also been found to be intimately associated with cancer development. The correlation between ribosome biogenesis or ribosomopathy and the development of malignancies has been well established. This work aims to review the recent advances in the research of ribosomopathy genes among human cancers and meanwhile, to excavate the potential role of these genes, which have not or rarely been reported in cancer, in the disease development across cancers. We plan to establish a theoretical framework between the ribosomopathy gene and cancer development, to further facilitate the potential of these genes as diagnostic biomarker as well as pharmaceutical targets for cancer treatment.

Anti-colorectal cancer of Ardisia gigantifolia Stapf. and targets prediction via network pharmacology and molecular docking study.

BACKGROUND: Ardisia gigantifolia Stapf. (AGS), a Chinese folk medicine widely grows in the south of China and several studies reported that AGS could inhibit the proliferation of breast cancer, liver cancer, and bladder cancer cell lines. However, little is known about its anti-colorectal cancer (CRC) efficiency. METHODS: In the present study, a combination of MTT assay, network pharmacological analysis, bioinformatics, molecular docking, and molecular dynamics simulation study was used to investigate the active ingredients, and targets of AGS against CRC, as well as the potential mechanism. RESULTS: MTT assay showed that three kinds of fractions from AGS, including the n-butanol extract (NBAGS), ethyl acetate fraction (EAAGS), and petroleum ether fraction (PEAGS) significantly inhibited the proliferation of CRC cells, with the IC50 values of 197.24, 264.85, 15.45 µg/mL on HCT116 cells, and 523.6, 323.59, 150.31 µg/mL on SW620 cells, respectively. Eleven active ingredients, including, 11-O-galloylbergenin, 11-O-protocatechuoylbergenin, 11-O-syringylbergenin, ardisiacrispin B, bergenin, epicatechin-3-gallate, gallic acid, quercetin, stigmasterol, stigmasterol-3-o-ß-D-glucopyranoside were identified. A total of 173 targets related to the bioactive components and 21,572 targets related to CRC were picked out through database searching. Based on the crossover targets of AGS and CRC, a protein-protein interaction network was built up by the String database, from which it was concluded that the core targets would be SRC, MAPK1, ESR1, HSP90AA1, MAPK8. Besides, GO analysis showed that the numbers of biological process, cellular component, and molecular function of AGS against CRC were 1079, 44, and 132, respectively, and KEGG pathway enrichment indicated that 96 signaling pathways in all would probably be involved in AGS against CRC, among which MAPK signaling pathway, lipid, and atherosclerosis, proteoglycans in cancer, prostate cancer, adherens junction would probably be the major pathways. The docking study verified that AGS had multiple ingredients and multiple targets against CRC. Molecular dynamics (MD) simulation analysis showed that the binding would be stable via forming hydrogen bonds. CONCLUSION: Our study showed that AGS had good anti-CRC potency with the characteristics of multi-ingredients, -targets, and -signaling pathways.

Bioaccessibility of arsenic, lead, and cadmium in contaminated mining/smelting soils: Assessment, modeling, and application for soil environment criteria derivation.

Soil environment criteria (SEC) are commonly derived from the total concentration of pollutants in soils, resulting in overly stringent values. Herein, we examined the feasibility of deriving the SEC by using the bioaccessibility of pollutants. In this regard, soil samples from 33 locations at 12 mining/smelting sites in China were collected and examined in terms of soil properties, chemical fraction distributions, and bioaccessibilities of cadmium (Cd), lead (Pb), and arsenic (As). The gastric (GP) and intestinal phases (IP) of the potentially hazardous trace elements (PHEs) were measured by in vitro assays, showing that these values varied from 11 % to 72 %, 1-79 %, and 2-27 % for Cd, Pb and As, respectively. Pearson analysis showed that the GP and IP bioaccessibilities of these PHEs were mainly influenced by soil pH, CEC, and clay fraction and positively correlated with the sequential extraction form. The random forest regression (RF) model showed excellent performance in predicting the gastric phase (GP) bioaccessibilities of Cd, Pb, and As, with a mean R2 and RMSE of 0.86 and 0.31, respectively. Both the measured and predicted bioaccessibilities were feasible to be used to derive SEC. This work will contribute to the development of regional soil environmental standards based on bioaccessibility for Cd-, Pb-, and As-contaminated mining/smelting soils.