A polymeric nanocarrier that eradicates breast cancer stem cells and delivers chemotherapeutic drugs.

BACKGROUND: Drug nanocarriers can markedly reduce the toxicities and side effects of encapsulated chemotherapeutic drugs in the clinic. However, these drug nanocarriers have little effect on eradicating breast cancer stem cells (BCSCs). Although compounds that can inhibit BCSCs have been reported, these compounds are difficult to use as carriers for the widespread delivery of conventional chemotherapeutic drugs. METHODS: Herein, we synthesize a polymeric nanocarrier, hyaluronic acid-block-poly (curcumin-dithiodipropionic acid) (HA-b-PCDA), and explore the use of HA-b-PCDA to simultaneously deliver chemotherapeutic drugs and eradicate BCSCs. RESULTS: Based on molecular docking and molecular dynamics studies, HA-b-PCDA delivers 35 clinical chemotherapeutic drugs. To further verify the drug deliver ability of HA-b-PCDA, doxorubicin, paclitaxel, docetaxel, gemcitabine and camptothecin are employed as model drugs to prepare nanoparticles. These drug-loaded HA-b-PCDA nanoparticles significantly inhibit the proliferation and stemness of BCSC-enriched 4T1 mammospheres. Moreover, doxorubicin-loaded HA-b-PCDA nanoparticles efficiently inhibit tumor growth and eradicate approximately 95% of BCSCs fraction in vivo. Finally, HA-b-PCDA eradicates BCSCs by activating Hippo and inhibiting the JAK2/STAT3 pathway. CONCLUSION: HA-b-PCDA is a polymeric nanocarrier that eradicates BCSCs and potentially delivers numerous clinical chemotherapeutic drugs.

Mangrove degradation retarded microplastics weathering and affected metabolic activities of microplastics-associated microbes.

Currently, information on microplastics (MPs) weathering characteristics and ecological functions driven by MPs-associated microbes in mangrove ecosystems remains unclear, especially in the degraded areas. Herein, we compared the weathering characteristics of MPs in both undegraded and degraded mangrove sediments, and then explored the potential interactions between their weathering characteristics and microbially-driven functions. After 70 days of incubation, different MPs (including polyethylene PE, polystyrene PS, and polylactic acid PLA) were strongly weathered in mangrove sediments, with significant erosion features. Interestingly, more obvious weathering characteristics were found for MPs in the undegraded mangrove sediments. O/C ratio value of MPs in the undegraded sediments was 2.3-3.0 times greater than that in the degraded ones. Besides, mangrove degradation reduced network complexity among MPs-associated microorganisms and affected their metabolic activities. Bacteria involved in carbon cycle process enriched on nondegradable MPs, whereas abundant bacteria responsible for sulphur cycle were observed on PLA-MPs. Moreover, these relevant bacteria were more abundant on MPs in the undegraded mangrove sediments. Mangrove degradation could directly and indirectly affect MPs weathering process and microbially-driven functions through regulating sediment properties and MPs-associated microbes. During weathering, contact angle and roughness of MPs were key factors influencing the colonisation of hydrocarbon degradation bacteria on MPs.

Preparation and characterization of a high-affinity monoclonal antibody against nerve growth factor.

Nerve growth factor (NGF) is produced and released in injured tissues or chronic pain tissues caused by other diseases. Studies have shown that monoclonal antibodies targeting NGF have a good efficacy in the treatment of osteoarthritis (OA), low back pain and chronic pain, which may be a promising therapy. In this study, DNA sequences of NGF-his and NGF-hFc were synthesized using eukaryotic expression system and subcloned into pTT5 expression vector. After that, NGF proteins were expressed by transient expression in HEK293E cells. We immunized mice with NGF-hFc protein and fused mouse spleen cells to prepare hybridomas. NGF-His protein was used to screen out the hybridoma supernatant that could directly bind to NGF. Antibodies were purified from hybridioma supernatant. Futhermore, via surface plasmon resonance (SPR) screening, six anti-NGF mAbs were screened to block the binding of NGF and TrkA receptor in the treatment of chronic pain. Among them, 58F10G10H showed high affinity (KD = 1.03 × 10-9 M) and even better than that of positive control antibody Tanezumab (KD = 1.53 × 10-9 M). Moreover, the specific reactivity of 58F10G10H was demonstrated by TF-1 cell proliferation activity experiments, competitive binding Enzyme-linked immunosorbent assay (ELISA) and the arthritis animal models in mice, respectively. In conclusion, in this study, a method for the preparation of high-yield NGF-HFC and NGF-His proteins was designed, and a high-affinity monoclonal antibody against NGF with potential for basic research and clinical application was prepared.

Catalytic flexibility of rice glycosyltransferase OsUGT91C1 for the production of palatable steviol glycosides.

Steviol glycosides are the intensely sweet components of extracts from Stevia rebaudiana. These molecules comprise an invariant steviol aglycone decorated with variable glycans and could widely serve as a low-calorie sweetener. However, the most desirable steviol glycosides Reb D and Reb M, devoid of unpleasant aftertaste, are naturally produced only in trace amounts due to low levels of specific ß (1-2) glucosylation in Stevia. Here, we report the biochemical and structural characterization of OsUGT91C1, a glycosyltransferase from Oryza sativa, which is efficient at catalyzing ß (1-2) glucosylation. The enzyme's ability to bind steviol glycoside substrate in three modes underlies its flexibility to catalyze ß (1-2) glucosylation in two distinct orientations as well as ß (1-6) glucosylation. Guided by the structural insights, we engineer this enzyme to enhance the desirable ß (1-2) glucosylation, eliminate ß (1-6) glucosylation, and obtain a promising catalyst for the industrial production of naturally rare but palatable steviol glycosides.

Microplastics pollution in mangrove ecosystems: A critical review of current knowledge and future directions.

Over the last decade, microplastics (MPs, plastic particles <5 mm) as emerging contaminants have received a great deal of international attention, not only because of their continuous accumulation in both marine and terrestrial environment, but also due to their serious threats posed to the environment. Voluminous studies regarding sources, distribution characterization, and fate of MPs in the different environmental compartments (e.g., marine, freshwater, wastewater, and soil) have been reported since 2004, whereas MPs pollution in unique marine ecosystems (e.g., coastal mangrove habitat) receives little scientific attention. Mangrove ecosystem, an important buffer between the land and the sea, has been identified as a potential sink of MPs caused by both marine and land-based activities. Moreover, the source and distribution characteristics of MPs in this ecosystem are significantly different from other coastal habitats, mainly owing to its unique features of high productivity and biomass. With the impetus to provide a more integrated view of MPs pollution in mangrove habitats, a literature review was conducted based on the existing studies related to this topic. This is the first review to present the current state of MPs pollution in mangrove ecosystems, specially including (i) the possible sources of MPs in mangrove areas and their pathways entering into this habitat; (ii) MPs pollution in the different mangrove compartments (including surface seawater, sediments, and biotas); and (iii) factors influencing MPs distribution in mangrove areas. Toward that end, the research gaps are proposed to guide for future research priorities.

Extracellular vesicles transmitted miR-31-5p promotes sorafenib resistance by targeting MLH1 in renal cell carcinoma.

Sorafenib provides survival benefits in patients with advanced renal cell carcinoma (RCC), but its use is hampered by acquired drug resistance. It is important to fully clarify the molecular mechanisms of sorafenib resistance, which can help to avoid, delay or reverse drug resistance. Extracellular vesicles (EVs) can mediate intercellular communication by delivering effector molecules between cells. Here, we studied whether EVs are involved in sorafenib resistance of RCC and its possible molecular mechanisms. Using differential centrifugation, EVs were isolated from established sorafenib-resistant RCC cells (786-0 and ACHN), and EVs derived from sorafenib-resistant cells were uptaken by sensitive parental RCC cells and thus promoted drug resistance. Elevated exogenous miR-31-5p within EVs effectively downregulated MutL homolog 1 (MLH1) expression and thus promoted sorafenib resistance in vitro. Mice experiments also confirmed that miR-31-5p could mediate drug sensitivity in vivo. In addition, low expression of MLH1 was observed in sorafenib-resistant RCC cells and upregulation of MLH1 expression restored the sensitivity of resistant cell lines to sorafenib. Finally, miR-31-5p level in circulating EVs of RCC patients with progressive disease (PD) during sorafenib therapy was higher when compared to that in the pretherapy status. In conclusion, EVs shuttled miR-31-5p can transfer resistance information from sorafenib-resistant cells to sensitive cells by directly targeting MLH1, and thus magnify the drug resistance information to the whole tumor. Furthermore, miR-31-5p and MLH1 could be promising predictive biomarkers and therapeutic targets to prevent sorafenib resistance.

Proteomic analysis of cervical cancer cells treated with suberonylanilide hydroxamic acid.

Suberonylanilide hydroxamic acid (SAHA)is an orally administered histone deacetylase inhibitor (HDACI) that has shown significant antitumour activity in a variety of tumour cells.To identify proteins involved in its antitumour activity,we utilized a proteomic approach to reveal protein expression changes in the human cervical cancer cell line HeLa following SAHA treatment.Protein expression profiles were analysed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification was performed on a MALDI-Q-TOF MS/MS instrument.As a result,a total of nine differentially expressed proteins were visualized by 2-DE and Coomassie brilliant blue (CBB) staining.Further,all the changed proteins were positively identified via mass spectrometry (MS)/MS analysis. Of these,PGAM1 was significantly downregulated in HeLa cells after treatment with SAHA. Moreover,PGAM1 has been proven to be downregulated in another cervical cancer cell line (CaSki) by western blot analysis.Together,using proteomic tools,we identified several differentially expressed proteins that underwent SAHA-induced apoptosis. These changed proteins may provide some clues to a better understanding of the molecular mechanisms underlying SAHA-induced apoptosis in cervical cancer.