Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are being wildly used as target therapy in non-small-cell lung cancer (NSCLC). However, NSCLC patients with wild-type EGFR ...and KRAS mutation are primary resistant to EGFR-TKIs such as gefitinib. Curcumin has been known as a potential therapeutic agent for several major human cancers. In this study, we investigated the effect of curcumin on the reversal of gefitinib resistance in NSCLC cells as well as their molecular bases.
H157 (wild-type EGFR and KARS mutation) and H1299 (wild-type EGFR and HRAS mutation) cells were treated with gefitinib or curcumin alone, or the two combination, and then cell viability, EGFR activity, expressions of Sp1 and Sp1-dependent proteins and receptor tyrosine kinases, markers of autophagy and apoptosis were examined by using CCK-8, colony formation, immunoblot, quantitative PCR, immunofluoscence, and flow cytometry assays. Also xenograft experiments were conduced to test the synergism of curcumin to gefitinib.
Our results showed that curcumin significantly enhanced inhibitory effect of gefitinib on primary gefitinib-resistant NSCLC cell lines H157 and H1299. Combination treatment with curcumin and gefitinib markedly downregulated EGFR activity through suppressing Sp1 and blocking interaction of Sp1 and HADC1, and markedly suppressed receptor tyrosine kinases as well as ERK/MEK and AKT/S6K pathways in the resistant NSCLC cells. Meanwhile, combination treatment of curcumin and gefitinib caused dramatic autophagy induction, autophagic cell death and autophagy-mediated apoptosis, compared to curcumin or gefitinib treatment alone, as evidenced by the findings that curcumin and gefitinib combination treatment-produced synergistic growth inhibition and apoptosis activation can be reversed by pharmacological autophagy inhibitors (Baf A1 or 3-MA) or knockdown of Beclin-1 or ATG7, also can be partially returned by pan-caspase inhibitor (Z-VAD-FMK) in H157 and H1299 cells. Xenograft experiments in vivo yielded similar results.
These data indicate that the synergism of curcumin on gefitinib was autophagy dependent. Curcumin can be used as a sensitizer to enhance the efficacy of EGFR-TKIs and overcome the EGFR-TKI resistance in NSCLC patients with wild-type EGFR and/or KRAS mutation.
Polyhydroxyalkanoates (PHAs) are a diverse family of sustainable bioplastics synthesized by various bacteria, but their high production cost and unstable material properties make them challenging to ...use in commercial applications. Current industrial biotechnology (CIB) employs conventional microbial chassis, leading to high production costs. However, next-generation industrial biotechnology (NGIB) approaches, based on fast-growing and contamination-resistant extremophilic Halomonas spp., allow stable continuous processing and thus economical production of PHAs with stable properties. Halomonas spp. designed and constructed using synthetic biology not only produce low-cost intracellular PHAs but also secrete extracellular soluble products for improved process economics. Next-generation industrial biotechnology is expected to reduce the bioproduction cost and process complexity, leading to successful commercial production of PHAs.
The high production cost, poor thermal and mechanical properties, and unstable quality of polyhydroxyalkanoates (PHAs) are the grand challenges to be addressed before industrialization.Next-generation industrial biotechnology (NGIB) based on extremophiles is emerging to meet most of these challenges.Fast-growing and contamination-resistant Halomonas spp. allow open, unsterile, and continuous fermentations to produce PHAs with low-cost and stable properties.Halomonas spp. constructed by synthetic biology generate large sizes for PHA accumulation and gravity separation or coproduction of extracellular soluble products.
Biopolyesters polyhydroxyalkanoates (PHA) produced by many bacteria have been investigated by microbiologists, molecular biologists, biochemists, chemical engineers, chemists, polymer experts and ...medical researchers. PHA applications as bioplastics, fine chemicals, implant biomaterials, medicines and biofuels have been developed and are covered in this critical review. Companies have been established or involved in PHA related R&D as well as large scale production. Recently, bacterial PHA synthesis has been found to be useful for improving robustness of industrial microorganisms and regulating bacterial metabolism, leading to yield improvement on some fermentation products. In addition, amphiphilic proteins related to PHA synthesis including PhaP, PhaZ or PhaC have been found to be useful for achieving protein purification and even specific drug targeting. It has become clear that PHA and its related technologies are forming an industrial value chain ranging from fermentation, materials, energy to medical fields (142 references).
Chiral conjugated polymer has promoted the development of the efficient circularly polarized electroluminescence (CPEL) device, nevertheless, it remains a challenge to develop chiral polymers with ...high electroluminescence performance. Herein, by the acceptor copolymerization of axially chiral biphenyl emitting skeleton and benzophenone, a pair of axially chiral conjugated polymers namely R‐PAC and S‐PAC are synthesized. The target polymers exhibit obvious thermally activated delayed fluorescence (TADF) activities with high photoluminescence quantum yields of 81%. Moreover, the chiral polymers display significant circularly polarized luminescence features, with luminescence dissymmetry factor (|glum|) of nearly 3 × 10−3. By using the chiral polymers as emitters, the corresponding circularly polarized organic light‐emitting diodes (CP‐OLEDs) exhibit efficient CPEL signals with electroluminescence dissymmetry factor |gEL| of 3.4 × 10−3 and high maximum external quantum efficiency (EQEmax) of 17.8%. Notably, considering both EQEmax and |gEL| comprehensively, the device performance of R‐PAC and S‐PAC is the best among all the reported CP‐OLEDs with chiral conjugated polymers as emitters. This work provides a facile approach to constructing chiral conjugated TADF polymers and discloses the potential of axially chiral conjugated luminescent skeletons in architecting high‐performance CP‐OLEDs.
Axially chiral conjugated polymers with thermally activated delayed fluorescence features are synthesized by copolymerizing chiral unit and benzophenone acceptor. By using the obtained polymers as emitters, high‐performance solution‐processed circularly polarized organic light‐emitting diodes are fabricated featuring efficient circularly polarized electroluminescence properties with the maximum external quantum efficiency and dissymmetry factor of up to 17.8% and 3.4 × 10‐3, respectively.
Next generation industrial biotechnology (NGIB) based on extremophilic bacteria grown under unsterile and continuous way in plastic transparent bioreactors.▪
•Low petroleum prices require innovations ...to make bio-production competitive.•Contamination resistant extremophilic microorganisms can simplify bioprocessing.•Next generation industrial biotechnology (NGIB) is energy and fresh water saving.•NGIB should be operated under open and continuous conditions and easily automated.•NGIB should make bulk chemical production as competitive as chemical processes.
Industrial biotechnology aims to produce bulk chemicals including polymeric materials and biofuels based on bioprocessing sustainable agriculture products such as starch, fatty acids and/or cellulose. However, traditional bioprocesses require bioreactors made of stainless steel, complicated sterilization, difficult and expensive separation procedures as well as well-trained engineers that are able to conduct bioprocessing under sterile conditions, reducing the competitiveness of the bio-products. Amid the continuous low petroleum price, next generation industrial biotechnology (NGIB) allows bioprocessing to be conducted under unsterile (open) conditions using ceramic, cement or plastic bioreactors in a continuous way, it should be an energy, water and substrate saving technology with convenient operation procedure. NGIB also requires less capital investment and reduces demand on highly trained engineers. The foundation for the simplified NGIB is microorganisms that resist contaminations by other microbes, one of the examples is rapid growing halophilic bacteria inoculated under high salt concentration and alkali pH. They have been engineered to produce multiple products in various scales.
To avoid large open surgery using scaffold transplants, small‐sized cell carriers are employed to repair complexly shaped tissue defects. However, most cell carriers show poor cell adherences and ...viability. Therefore, polyhydroxyalkanoate (PHA), a natural biopolymer, is used to prepare highly open porous microspheres (OPMs) of 300–360 µm in diameter, combining the advantages of microspheres and scaffolds to serve as injectable carriers harboring proliferating stem cells. In addition to the convenient injection to a defected tissue, and in contrast to poor performances of OPMs made of polylactides (PLA OPMs) and traditional less porous hollow microspheres (PHA HMs), PHA OPMs present suitable surface pores of 10–60 µm and interconnected passages with an average size of 8.8 µm, leading to a high in vitro cell adhesion of 93.4%, continuous proliferation for 10 d and improved differentiation of human bone marrow mesenchymal stem cells (hMSCs). PHA OPMs also support stronger osteoblast‐regeneration compared with traditional PHA HMs, PLA OPMs, commercial hyaluronic acid hydrogels, and carrier‐free hMSCs in an ectopic bone‐formation mouse model. PHA OPMs protect cells against stresses during injection, allowing more living cells to proliferate and migrate to damaged tissues. They function like a micro‐Noah's Ark to safely transport cells to a defect tissue.
Combining the advantages of microspheres and scaffolds, highly open porous microspheres (OPMs) made of polyhydroxyalkanoate (PHA) are developed as injectable carriers harboring growing stem cells. The PHA OPMs protect the stem cells from stresses during injection, allowing more living cells to proliferate and migrate to damaged tissues, functioning like a micro‐Noah's Ark to safely transport cells to a designated tissue location for regeneration.
The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin ...compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future ferroptosis-inducing cancer therapies.
Polyhydroxyalkanoates (PHAs) are a diverse family of biopolyesters synthesized by many natural or engineered bacteria. Synthetic biology and DNA-editing approaches have been adopted to engineer cells ...for more efficient PHA production. Recent advances in synthetic biology applied to improve PHA biosynthesis include ribosome-binding site (RBS) optimization, promoter engineering, chromosomal integration, cell morphology engineering, cell growth behavior reprograming, and downstream processing. More importantly, the genome-editing tool clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has been applied to optimize the PHA synthetic pathway, regulate PHA synthesis-related metabolic flux, and control cell shapes in model organisms, such as Escherichia coli, and non-model organisms, such as Halomonas. These synthetic biology methods and genome-editing tools contribute to controllable PHA molecular weights and compositions, enhanced PHA accumulation, and easy downstream processing.
The bioplastic PHA, which features biodegradability, biocompatibility, and thermoprocessibility, is moving toward low-cost microbial production to replace nondegradable petrochemical plastics.Wild-type or weakly engineered bacteria are insufficient to meet demands for improved PHA structures and low production cost.Synthetic biology and genome-editing approaches can promote PHA synthesis, enlarge cells for more PHA storage, control shape changes, accelerate growth, aid the co-production of multiple products, direct flux toward final products, and make product recovery more convenient.Optimized promoters and RBSs increase the expression of PHA synthesis genes.CRISPR interference and CRISPR/Cas9 are useful for downregulating the expression of multiple genes simultaneously, allowing more flux to be directed to PHA synthesis in an optimized strain.
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