Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance.

ROS and the DNA damage response in cancer.

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19-related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that (a) coronaviruses activate multiple complement pathways; (b) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.

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The complement system in COVID-19: friend and foe?

Near-infrared II fluorescence imaging holds great promise for in vivo imaging and imaging-guided surgery with deep penetration and high spatiotemporal resolution. However, most NIR-II aromatic luminophores suffer from the notorious aggregation-caused quenching (ACQ) effect in the aqueous solution, which largely hinders their biomedical application in vivo. In this study, the first NIR-II organic aggregation-induced emission (AIE) fluorophore (HLZ-BTED), encapsulated as nanoparticles (HLZ-BTED dots) for in vivo biomedical imaging, was designed and synthesized. The NIR-II AIE HLZ-BTED dots showed high temporal resolution, high photostability, outstanding water-solubility and biocompatibility in vitro and in vivo. The HLZ-BTED dots were further used for long-term breast tumor imaging and visualizing tumor-feeding blood vessels, long-term hind limb vasculature and incomplete hind limb ischemia. More importantly, as a proof-of-concept, this is the first time that non-invasive and real-time NIR-II imaging of the gastrointestinal tract in health and disease has been performed, making the AIE dots a promising tool for gastrointestinal (GI) tract research, such as understanding the healthy status of GI peristalsis, diagnosing and evaluating intestinal motility dysfunction, and assessing drug effects on intestinal obstruction.

/pdf/novel-near-infrared-ii-aggregation-induced-emission-dots-for-op5fvu6p5q.pdf

Novel near-infrared II aggregation-induced emission dots for in vivo bioimaging

NIR-II fluorophores have shown great promise for biomedical applications with superior in vivo optical properties. To date, few small-molecule NIR-II fluorophores have been discovered with donor-acceptor-donor (D-A-D) or symmetrical structures, and upconversion-mitochondria-targeted NIR-II dyes have not been reported. Herein, we report development of D-A type thiopyrylium-based NIR-II fluorophores with frequency upconversion luminescence (FUCL) at ~580 nm upon excitation at ~850 nm. H4-PEG-PT can not only quickly and effectively image mitochondria in live or fixed osteosarcoma cells with subcellular resolution at 1 nM, but also efficiently convert optical energy into heat, achieving mitochondria-targeted photothermal cancer therapy without ROS effects. H4-PEG-PT has been further evaluated in vivo and exhibited strong tumor uptake, specific NIR-II signals with high spatial and temporal resolution, and remarkable NIR-II image-guided photothermal therapy. This report presents the first D-A type thiopyrylium NIR-II theranostics for synchronous upconversion-mitochondria-targeted cell imaging, in vivo NIR-II osteosarcoma imaging and excellent photothermal efficiency. Currently available mitochondria-targeted fluorescent dyes emit only one color in the visible or NIR-I and their applications are limited. Here, the authors develop upconversion mitochondria-targeted NIR-II fluorophores for synchronous upconversion-mitochondria-targeted cell imaging, in vivo NIR-II osteosarcoma imaging and photothermal efficiency

/pdf/upconversion-nir-ii-fluorophores-for-mitochondria-targeted-4zrt43bwoo.pdf

Upconversion NIR-II fluorophores for mitochondria-targeted cancer imaging and photothermal therapy.

Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000–1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine green structure, a series of polymethine dyes with both absorption and emission in the NIR-II window have been developed for NIR-II imaging, providing the feasibility to directly compare optical imaging in the NIR-IIa (1300–1400 nm) subwindow under 1064 nm excitation with that in the NIR-II window under 808 nm excitation. The signal–background ratio and the tumor–normal tissue ratio achieved great improvement under 1064 nm excitation in the imaging of mouse blood pool and U87 glioma tumors. Our study not only introduces a broadband emission fluorophore for both NIR-II and NIR-IIa imaging, but also reveals the advantages of NIR-II excitation over NIR-I in in vivo imaging.

Polymethine Thiopyrylium Fluorophores with Absorption beyond 1000 nm for Biological Imaging in the Second Near-Infrared Subwindow

Accurate identification of novel peptides remains challenging because of the lack of evaluation criteria in large-scale proteogenomic studies. Mirror proteases of trypsin and lysargiNase can generate complementary b/y ion series, providing the opportunity to efficiently assess authentic novel peptides in experiments other than filter potential targets by different false discovery rates (FDRs) ranking. In this study, a pair of in-house developed acetylated mirror proteases, Ac-Trypsin and Ac-LysargiNase, were used in Mycolicibacterium smegmatis MC2 155 for proteogenomic analysis. The mirror proteases accurately identified 368 novel peptides, exhibiting 75–80% b and y ion coverages against 65–68% y or b ion coverages of Ac-Trypsin (38.9% b and 68.3% y) or Ac-LysargiNase (65.5% b and 39.6% y) as annotated peptides from M. smegmatis MC2 155. The complementary b and y ion series largely increased the reliability of overlapped sequences derived from novel peptides. Among these novel peptides, 311 peptides were annotated in other public M. smegmatis strains, and 57 novel peptides with more continuous b and y pairs were obtained for further analysis after spectral quality assessment. This enabled mirror proteases to successfully correct six annotated proteins' N-termini and detect 17 new coding open reading frames (ORFs). We believe that mirror proteases will be an effective strategy for novel peptide detection in both prokaryotic and eukaryotic proteogenomics.

/pdf/mirror-proteases-of-ac-trypsin-and-ac-lysarginase-precisely-2440x418.pdf

Mirror proteases of Ac-Trypsin and Ac-LysargiNase precisely improve novel event identifications in Mycolicibacterium smegmatis MC2 155 by proteogenomic analysis

Ubiquitin ligases (E3s) serve as key regulators for the ubiquitylation-mediated pathway. The identification of the corresponding relationship between E3 and its substrates is challenging but required for understanding the regulatory network of ubiquitylation. The low abundance of ubiquitinated conjugates and high redundancy of E3 substrate regulation made the screening pretty hard. Herein, we combined SILAC-based quantitative proteomics with two contrary genetic methods (overexpression and knockout) in theory for E3 (Hrt3, the F-box subunit of the SCF complex) substrate screening. The knockout method could not overcome the constraint mentioned above, while the overexpression approach turned on the access to the potential substrates of E3. Subsequently, we obtained 77 candidates, which are involved in many critical biological processes and need to be verified in the future. Within these candidates, we confirmed the relationship between one of the candidates Nce103 and Hrt3 and linked Hrt3 with oxygen sensitivity and oxidative stress response in which Nce103 took part as well. This research is also beneficial for understanding the impact of oxygen supply on regulation of yeast growth through the ubiquitination of Nce103.

Quantitative Proteomics Combined with Two Genetic Strategies for Screening Substrates of Ubiquitin Ligase Hrt3.

By revealing the close relationship between CTSS protein and liver cirrhosis or fibrosis, uses of CTSS protein in diagnosis and treatment of liver cirrhosis/ fibrosis are proposed, a diagnostic reagent and a kit are provided, and therapeutic use of CTSS protein or a gene coding same is also provided.

Ctss protein and use of gene coding same

Type 2 diabetes mellitus (T2DM) is a global metabolic disease with potentially life- threatening complications. Liver metabolism plays a vital role in the occurrence and development of diabetes mellitus. It has been reported that the Chinese medicinal Anemarrhenae rhizoma (AR) can relieve insulin resistance and diabetes mellitus. However, the effect on abnormal liver metabolism in diabetes mellitus is still unclear. Therefore, we extracted liver proteins of T2DM rats induced by high-fat diet (HFD) and streptozotocin (STZ), T2DM rats treated with AR extract (ARE), obesity rats (fed with HFD), and normal control rats (fed with normal diet). Then, through tandem mass tag (TMT) labeling combined with mass spectrometry (MS), we obtained the quantitative proteomic data. Bioinformatics software was used for hierarchical cluster analysis and principal component analysis of the data in each group. The volcano map for differentially expressed proteins (P < 0.05, fold change > 1.5) was plotted. It was found that the treatment group was closer to the normal control group, indicating that the quantitative proteomic data of liver tissue can reflect the therapeutic effect of ARE on T2DM rats. Key protein clusters closely related to the treatment of ARE were screened out. The Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the protein clusters were analyzed by David, and the result showed that AR's alleviation of abnormal fatty acid metabolism in livers of T2DM rats may be related to the regulation of the expression of key proteins Ndufa6 and Prkar2b.

[Quantitative proteomics reveals the abnormal liver metabolism-relieving effect of Anemarrhenae rhizoma in type 2 diabetes mellitus rats].

The invention relates to a preparation method for a human HNP-1 protein. An escherichia coli expression system can be constructed and used to prepare a mature human HNP-1 protein with biological activity. A prokaryotic system is firstly utilized to express the HNP-1 protein with activity in this field.

Lei Chang

Papers

Mirror proteases of Ac-Trypsin and Ac-LysargiNase precisely improve novel event identifications in Mycolicibacterium smegmatis MC2 155 by proteogenomic analysis

Quantitative Proteomics Combined with Two Genetic Strategies for Screening Substrates of Ubiquitin Ligase Hrt3.

Ctss protein and use of gene coding same

[Quantitative proteomics reveals the abnormal liver metabolism-relieving effect of Anemarrhenae rhizoma in type 2 diabetes mellitus rats].

Preparation for bioactive recombinant human HNP-1 protein