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The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins. In recent years, toxins have been widely used as warheads for antibody‒drug conjugates (ADCs) due to their efficient killing activity against various cancer cells. Although ADCs confer certain targeting properties to the toxins, low drug loading capacity, possible immunogenicity, and other drawbacks also limit the potential application of ADCs. Recently, non-ADC delivery strategies for toxins have been extensively investigated. To further understand the application of toxins in anti-tumor, this paper provided an overview of prodrugs, nanodrug delivery systems, and biomimetic drug delivery systems. In addition, toxins and their combination strategies with other therapies were discussed. Finally, the prospect and challenge of toxins in cancer treatment were also summarized., (© 2024 The Authors.)

HOIL-1L and SHARPIN are two essential regulatory subunits of the linear ubiquitin chain assembly complex (LUBAC), which is the only known E3 ligase complex generating linear ubiquitin chains. In addition to their LUBAC-dependent functions, HOIL-1L and SHARPIN alone play crucial roles in many LUBAC-independent cellular processes. Importantly, deficiency of HOIL-1L or SHARPIN leads to severe disorders in humans or mice. However, the mechanistic bases underlying the multi-functions of HOIL-1L and SHARPIN are still largely unknown. Here, we uncover that HOIL-1L and SHARPIN alone can form homo-dimers through their LTM motifs. We solve two crystal structures of the dimeric LTM motifs of HOIL-1L and SHARPIN, which not only elucidate the detailed molecular mechanism underpinning the dimer formations of HOIL-1L and SHARPIN, but also reveal a general mode shared by the LTM motifs of HOIL-1L and SHARPIN for forming homo-dimer or hetero-dimer. Furthermore, we elucidate that the polyglucosan body myopathy-associated HOIL-1L A18P mutation disturbs the structural folding of HOIL-1L LTM, and disrupts the dimer formation of HOIL-1L. In summary, our study provides mechanistic insights into the homo-dimerization of HOIL-1L and SHARPIN mediated by their LTM motifs, and expands our understandings of the multi-functions of HOIL-1L and SHARPIN as well as the etiology of relevant human disease caused by defective HOIL-1L., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Arl8b, a specific Arf-like family GTPase present on lysosome, and plays critical roles in many lysosome-related cellular processes such as autophagy. The active Arl8b can be specifically recognized by the RUN domains of two Arl8b-effectors PLEKHM1 and SKIP, thereby regulating the autophagosome/lysosome membrane fusion and the intracellular lysosome positioning, respectively. However, the mechanistic bases underlying the interactions of Arl8b with the RUN domains of PLEKHM1 and SKIP remain elusive. Here, we report the two high-resolution crystal structures of the active Arl8b in complex with the RUN domains of PLEKHM1 and SKIP. In addition to elucidating the detailed molecular mechanism governing the specific interactions of the active Arl8b with the RUN domains of PLEKHM1 and SKIP, the determined complex structures also reveal a general binding mode shared by the PLEKHM1 and SKIP RUN domains for interacting with the active Arl8b. Furthermore, we uncovered a competitive relationship between the RUN domains of PLEKHM1 and SKIP in binding to the active Arl8b as well as a unique small GTPase-binding mode adopted by the PLEKHM1 and SKIP RUN domains, thereby enriching the repertoire of the RUN domain/small GTPase interaction modes. In all, our findings provide new mechanistic insights into the interactions of the active Arl8b with PLEKHM1 and SKIP, and are valuable for further understanding the working modes of these proteins in relevant cellular processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflict of interest The authors of this manuscript declare no relationship with any company, whose products or services may be related to the subject matter of the article. All authors have reviewed the final edition of the manuscript and approve it for publication. This manuscript has not been published previously and is not being considered concurrently by another publication. The authors disclose no conflicts.

The widespread presence and accumulation of microplastics (MPs) in organisms has led to their recognition as a major global ecological issue. There is a lot of data on how MPs affect the physiology and behavior of aquatic species, but the effects of MPs on poultry are less understood. Therefore, we aimed to explore the adverse effects and mechanisms of MPs exposure to chicken health. Results indicated that MPs exposure decreased growth performance and antioxidant ability and impaired chickens' intestine, liver, kidney, and spleen. Additionally, the gut microbiota in chickens exposed to MPs showed a significant decrease in alpha diversity, accompanied by significant alternations in taxonomic compositions. Microbial taxonomic investigation indicated that exposure to MPs resulted in a significant increase in the relative proportions of 11 genera and a distinct decline in the relative percentages of 3 phyla and 52 genera. Among decreased bacterial taxa, 11 genera even couldn't be detected in the gut microbiota of chickens exposed to MPs. Metabolomics analysis indicated that 2561 (1190 up-regulated, 1371 down-regulated) differential metabolites were identified, mainly involved in 5 metabolic pathways, including D-amino acid metabolism, ABC transporters, vitamin digestion and absorption, mineral absorption, and histidine metabolism. Taken together, this study indicated that MPs exposure resulted in adverse health outcomes for chickens by disturbing gut microbial homeostasis and intestinal metabolism. This study also provided motivation for environmental agencies worldwide to regulate the application and disposal of plastic products and decrease environmental contamination., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aflatoxin B1 (AFB1), the most harmful aflatoxins, is a frequent contamination in feed and food items, raising global concerns in animal production and human public health. Also, AFB1 induces oxidative stress, cytotoxicity, mutations, and DNA lesions through its metabolic transformation into aflatoxin B1-8,9-epoxide (AFBO) by cytochrome P450 (CYP450). Hedyotis diffusa (HD) is a traditional Chinese herbal medicine known for its multiple pharmacological activities, including antioxidant, anti-inflammatory, and immunomodulatory. Yet, the influence of HD on AFB1-induced liver injury in ducks is still unknown. Here, we investigated whether HD positively affects AFB1-induced liver injury in ducks. Results revealed that I) AFB1 caused significant changes in serum biochemical indices and decreased growth performance of ducks (such as ALT, AST, ALP, TP, ALB, final body weight, and body weight gain), whereas HD supplementation at 200 mg/kg mitigated these alterations. II) HD alleviated hepatic histopathological changes and liver index induced by AFB1 in ducks. III) HD significantly attenuated AFB1-induced oxidative stress, as measured by increased antioxidant enzyme activities such as SOD, GPx, and T-AOC and decreased MDA levels. Furthermore, HD reduced the level of AFB1-DNA adduct in duck liver. IV) HD significantly promoted the transcriptional expression of NF-E2-related nuclear factor 2 (Nrf2) and associated genes, including heme oxygenase 1 (HO-1), NAD(P)H dehydrogenase quinone 1 (NQO1), glutamate-cysteine ligase catalytic (GCLC). In conclusion, these results demonstrated that HD could activate the Nrf2 pathway in ducks to reduce the hepatotoxicity driven by AFB1. This finding also provides theoretical and data support for a deeper understanding of the toxic mechanisms of AFB1 and its prevention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Industrial production, ore smelting and sewage disposal plant can discharge large amounts of heavy metals every year, which may contaminate soil, water and air, posing a great threat to ecological environment and animal production. Hexavalent chromium [Cr (VI)], a recognized metallic contaminant, has been shown to impair kidney, liver and gastrointestinal tract of many species, but little is known about the gut microbial characteristics of chickens exposed to Cr (VI). Herein, this study characterized the gut microbial alternations of chickens exposed to Cr (VI). Results indicated that the gut microbial alpha-diversity in chickens exposed to Cr (VI) decreased significantly, accompanied by a distinct shifts in taxonomic composition. Microbial taxonomic analysis demonstrated that the preponderant phyla (Firmicutes, Bacteroidetes, Proteobacteria and Epsilonbacteraeota) were the same in both groups, but different in types and relative abundances of dominant genera. Moreover, some bacterial taxa including 2 phyla and 47 genera significantly decreased, whereas 3 phyla and 17 genera significantly increased during Cr (VI) exposure. Among decreased taxa, 9 genera (Coprobacter, Ruminococcus_1, Faecalicoccus, Eubacterium_nodatum_group, Parasutterella, Slackia, Barnesiella, Family_XIII_UCG-001 and Collinsella) even cannot be detected. In conclusion, this study revealed that Cr (VI) exposure dramatically decrased the gut microbial diversity and altered microbial composition of chickens. Additionally, this study also provided a theoretical basis for relieving Cr (VI) poisoning from the perspective of gut microbiota., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor metastasis is responsible for chemotherapeutic failure and cancer-related death. Moreover, circulating tumor cell (CTC) clusters play a pivotal role in tumor metastasis. Herein, we develop cancer-specific calcium nanoregulators to suppress the generation and circulation of CTC clusters by cancer membrane-coated digoxin (DIG) and doxorubicin (DOX) co-encapsulated PLGA nanoparticles (CPDDs). CPDDs could precisely target the homologous primary tumor cells and CTC clusters in blood and lymphatic circulation. Intriguingly, CPDDs induce the accumulation of intracellular Ca 2+ by inhibiting Na + /K + -ATPase, which help restrain cell-cell junctions to disaggregate CTC clusters. Meanwhile, CPDDs suppress the epithelial-mesenchymal transition (EMT) process, resulting in inhibiting tumor cells escape from the primary site. Moreover, the combination of DOX and DIG at a mass ratio of 5:1 synergistically induces the apoptosis of tumor cells. In vitro and in vivo results demonstrate that CPDDs not only effectively inhibit the generation and circulation of CTC clusters, but also precisely target and eliminate primary tumors. Our findings present a novel approach for anti-metastasis combinational chemotherapy., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX- S -DOX (PSD). The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu 2+ ) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu 2+ gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Gold nanoparticles (AuNPs) have been reported for their most desirable properties as compared to any other noble metal-based nanoparticles, which wider their applications in various fields including catalysis, bio-imaging, biosensors, medicine, biology, and material chemistry. In this study, the shape-dependent antibacterial activity of AuNPs: nanospheres (AuNSps), nanostars (AuNSts), and nanocubes (AuNCs) were investigated against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus at lower concentrations. The optical, crystallographic and morphological characterization of AuNPs was analyzed by UV-visible spectroscopy, X-ray diffraction spectroscopy, and transmission electron microscopy (TEM). Shape-dependent antibacterial qualitative and quantitative analyses revealed an effective bactericidal activity of AuNCs against the tested bacteria, followed by AuNSps and AuNSts. The study revealed that the AuNCs are effective bactericidal agents with 100% inactivation rate. The visual analysis confirmed the antibacterial activity of AuNCs and AuNSps by showing physical mutilated bacterial cells which involved cell loss, loosening of the cell wall, loss of flagella and cellular matrix. Finally, released nucleic acid was measured for the treated bacterial cells which support the physical mutilation by releasing 38 μg/mL (Pseudomonas aeruginosa) of cellular material after treating with AuNCs. It is concluded from this study that AuNPs showed the significant antibacterial property at lower concentrations. More applications can be explored including anti-infections, decontamination, and food safety., (Copyright © 2019. Published by Elsevier B.V.)

A single nanodrug delivery system for combined delivery of paclitaxel and doxorubicin that integrates high co-loading efficiency, synchronous co-delivery of combined drugs, controllable drug release, and maintains the drug combination at fixed synergistic ratios has been proven to be challenging. Here, we report a redox dual-responsive prodrug nanosystem consisting of a paclitaxel-doxorubicin heterodimeric prodrug with a thioether bond linkage to effectively co-deliver two therapeutic drugs. The heterodimeric prodrug could self-assemble into uniform nanoaggregates containing DSPE-PEG 2K with a precise drug co-loading ratio in water, and possessed a high co-loading content. We demonstrated that this nanosystem provided strong synergistic effects in MCF-7 and 4 T1 cells. In vivo, this nanosystem results in a long blood circulation, high accumulation in the tumor, and significant inhibition of tumor growth in BALB/c mice bearing 4 T1 tumors. Such a simple, safe, and efficient heterodimeric prodrug nanosystem exhibits great potential for clinical translation in future combination chemotherapy treatments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

TAX1BP1, a ubiquitin-binding adaptor, plays critical roles in the innate immunity and selective autophagy. During autophagy, TAX1BP1 may not only function as an autophagy receptor to recruit ubiquitylated substrates for autophagic degradation, but also serve as a Myosin VI cargo adaptor protein for mediating the maturation of autophagosome. However, the mechanistic basis underlying the specific interactions of TAX1BP1 with ubiquitin and Myosin VI remains elusive. Here, using biochemical, NMR and structural analyses, we elucidate the detailed binding mechanism and uncover the key determinants for the interaction between TAX1BP1 and ubiquitin. In addition, we reveal that both tandem zinc-fingers of TAX1BP1 and the conformational rigidity between them are required for the Myosin VI binding of TAX1BP1, and ubiquitin and Myosin VI are mutually exclusive in binding to TAX1BP1. Collectively, our findings provide mechanistic insights into the dual functions of TAX1BP1 in selective autophagy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Non-Camellia tea is a part of the colorful Chinese tea culture, and is also widely used as beverage and medicine in folk for disease prevention and treatment. In this study, 37 samples were collected, including 33 kinds of non-Camellia teas and 4 kinds of teas (Camellia). Traditional functions of non-Camellia teas were investigated. Furthermore, non-Camellia teas of original plants were characterized and identified by molecular methods. Four candidate regions (rbcL, matK, ITS2, psbA-trnH) were amplified by polymerase chain reaction. In addition, DNA barcodes were used for the first time to discriminate the commercial non-Camellia tea and their adulterants, and to evaluate their safety. This study showed that BLASTN and the relevant phylogenetic tree are efficient tools for identification of the commercial non-Camellia tea and their adulterants. However, some sequences from original plants have not been found and there is a limitation of sequence number of original plants in GenBank. Submitting more original plant sequences to the GenBank will be helpful for evaluating the safety of non-Camellia teas.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The mechanisms by which hepatoma cells resist apoptosis induced by doxorubicin are largely unknown. MAPKAPK5 (MK5), also named as p38-regulated/activated protein kinase (PRAK), has been identified as a crucial mediator of skin tumorigenesis in mouse and colon cancerogenesis in human. Here, we describe a novel role of MK5 in doxorubicin-induced apoptosis in human hepatoma cells. Expression of MK5 was highly upregulated in hepatoma cell lines. Doxorubicin rather than other chemotherapeutic drugs reduced MK5 protein level in a time- and concentration-dependent manner in hepatoma cells (HepG2 and Hep3B). We further showed that MK5 degradation induced by doxorubicin was via the 26S proteasome. Remarkably, stable overexpression of MK5 led to decreased cleavage of caspase-3 and PARP and attenuated doxorubicin-induced apoptosis, while stable knockdown of endogenous MK5 sensitized hepatoma cells to doxorubicin, which was coupled with increased cleavage of caspase-3 and PARP. Taken together, our results firstly demonstrate that MK5 is degraded in response to doxorubicin and negatively regulates doxorubicin-induced apoptosis, providing novel insights into the molecular mechanism of doxorubicin resistance in hepatoma cells., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In the current work, a one-step, washing-free, homogeneous nanosensor assay has been constructed to sensitively detect hepatitis B surface antigen (HBsAg) based on the light scattering property of gold nanoparticles (GNPs) through a sandwich model. The two nanoprobes in this study were designed by conjugating monoclonal and polyclonal hepatitis B surface antibody (HBsAb) onto the GNPs of different diameters. First, the detection behavior of the combinations of different sizes of GNPs was evaluated and the optimized combination was determined. In analyzing HBsAg in Tris-HCl buffer, such bioassay composed of GNPs of approximately 50 and 100 nm has a limit of detection (LOD) as high as 0.005 IU/ml and a dose-dependent response ranging from 0.005 to 1 IU/ml, which indicates its good diagnostic capability and provides a useful means to analyze protein biomarkers with low virus loads. Observation with transmission electron microscopy (TEM) provides direct evidence that the increase of hydrodynamic diameters resulted from the aggregation induced by immunological reactions. The bioassay also exhibits satisfactory specificity in analyzing HBsAg in serum media. Therefore, with its simple preparation, easy readout, and good stability, this bioassay has the potential to be developed into an automated and widely used biosensor assay., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The accumulation of unfolded protein in lumen of the endoplasmic reticulum (ER) triggers a cell stress response called ER stress, which induces the transcriptional up-regulation of a number of proteins, including molecular chaperones and folding enzymes, the global inhibition of protein synthesis, and the activation of apoptotic pathways. The molecular mechanism underlying the apoptotic response has remained largely elusive. AMP activated protein kinase (AMPK) has been implicated in ER stress-induced apoptosis through its role in attenuating ER stress. BRSK2 (brain selective kinase 2, also known as SAD-A) is a serine/threonine kinase of the AMPK family. Here, we demonstrate that the BRSK2 protein levels are significantly down-regulated in response to ER stress in PANC-1 and HeLa cells. Furthermore, we also observed that ER stress induces endogenous BRSK2 to localize to the ER. Importantly, knockdown of endogenous BRSK2 expression enhances ER stress-mediated apoptosis in cells while over express BRSK2 in wild type or kinase-dead type both reduce the apoptosis. BRSK2 knockdown increases the transcription of CHOP and the levels of cleaved caspase-3 in cells in response to ER stress while over expression of BRSK2 decrease CHOP mRNA and levels of cleaved caspase-3. Taken together, our findings demonstrate ER stress may reduce BRSK2 protein and change BRSK2 subcellular localization, which in turn alleviate ER stress-induced apoptosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Brain-specific kinase 2 (BRSK2) was classified as an AMP-activated protein kinase (AMPK)-related kinase and one of the substrates of LKB1. Studies on homologs of BRSK2 in mice, SADA and SADB, implied that it might be involved in the regulation of cell polarity and cell cycle. However, physiological functions and molecular regulatory mechanisms of BRSK2 are incompletely understood. In this study, we isolated a novel BRSK2-interacting protein, c-Jun activation domain-binding protein-1 (Jab1), which was reported to mediate degradation of multiple proteins and positively regulate cell cycle progression. GST pull-down and immunoprecipitation assays revealed the direct interaction between BRSK2 and Jab1 in vitro and in vivo, respectively. The co-localization between Jab1 and BRSK2 in the perinuclear region was observed. Intriguingly, Jab1 promoted the ubiquitination and proteasome-dependent degradation of BRSK2. Silencing of endogenous Jab1 increased the cellular BRSK2 protein level. Consistent with this, BRSK2-mediated cell cycle arrest at the G2/M phase in mammalian cells was reversed by exogenous Jab1. Taken together, our findings provide a novel regulatory mechanism of BRSK2 through direct interaction with Jab1., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The lack of robust small animal models has been an obstacle to the screening of Hepatitis C virus (HCV) NS3/4A protease inhibitors in vivo. Here, we described a reporter assay system for in vivo noninvasive imaging of NS3/4A serine protease activity using split firefly luciferase complementation strategy. The reporter construct ANluc(NS5A/B)BCluc constitutes the split N- and C-terminal fragments of luciferase, fused to interacting peptides, pepA and pepB, respectively, with an intervening HCV NS3/4A cleavage motif of NS5A/B. We proved that the reporter molecule could be proteolytically cleaved by NS3/4A at the NS5A/B motif in cells and living animals. Association of pepA and pepB brought inactive fragments of luciferase into close proximity, thereby restoring bioluminescence activity. The increase in luciferase activity was proportional to the dose of active NS3/4A protease. The ANluc(NS5A/B)BCluc reporter also could be used to detect the activity of NS3/4A-specific shRNA and IFN-alpha. Therefore, the reporter assay system using split firefly luciferase complementation strategy should prove useful for evaluating NS3/4A protease activity in cells and living animals., (2010 Elsevier B.V. All rights reserved.)

Brain selective kinase 2 (BRSK2) has been identified as a member of AMPK related kinases. LKB1 can phosphorylate the Thr174 of BRSK2, increasing its activity >50-fold. In this study, we identified cAMP-dependent protein kinase A (PKA) as another upstream kinase of BRSK2, which can phosphorylate BRSK2 at Thr260. The association between these two proteins was confirmed by GST pull-down. Furthermore, our study indicated that the kinase activity of BRSK2 can be increased through phosphorylation by PKA.