scholarly journals Mitochondria structural integrity is essential for the protection of mitochondrial transplantation against UV-induced cell death

2021 ◽  
Author(s):  
Shan-Shan Hu ◽  
Ruo-Yun Li ◽  
Xin-Hui Cao ◽  
Jing-Jing Liu ◽  
Zhen-Hua Wang ◽  
...  
Keyword(s):  
Animal Models ◽  
Small Molecules ◽  
Uv Irradiation ◽  
Structural Integrity ◽  
Thermal Inactivation ◽  
Cell Model ◽  
Irradiation Damage ◽  
Cerebral Stroke ◽  
Irradiation Effect ◽  
Short Period

Abstract Background: Mitochondrial transplantation (MT) is a new technology developed in recent years, which injects healthy mitochondria directly into damaged tissues or blood vessels to play a therapeutic role. It has been studied in many animal models of various diseases, such as myocardial ischemia, cerebral stroke, liver and lung injury, and even has been successfully used in the treatment of childhood heart disease. MT can quickly improve tissue function within a few minutes after injection. This fast response is what is frequently questioned, for it is hard to understand how the whole mitochondria transport to the damaged sites, enter cells and function within such a short period of time. Are there any small molecules of mitochondrial component rather than the whole mitochondria that being responsible for the function of MT? To test this hypothesis, we established a much simple ultra-violet (UV)-irradiated HeLa cell model instead of the more complex animal models.Results: The results of colony formation, sulforhodamine B (SRB), and Hoechst 33342/PI double staining assay strongly indicated that MT exhibited a significant protective effect on UV irradiation damage. The UV irradiation-induced cell cycle arrest at S phase, apoptosis, mitochondrial membrane potential (MMP) decreasing, and the related apoptosis signalling factors p-IKKα, p-p65, I-κB and the activation of caspase3 were all reversed by MT treatments to some extent. Furthermore, mechanisms of MT were evaluated through comparing the effect of thermal inactivation, ultrasonic crushing, and repeated freezing and thawing treatments on MT function. The results denied the above hypothesis that mitochondrial component may function to MT, excluded the function of ATP, mtDNA and other small molecules, and indicated that the mitochondria structural integrity is essential.Conclusions: Our data support a potent anti-UV irradiation effect of MT, and structural integrity of mitochondria is critical for its function.

AlphaFill: enriching the AlphaFold models with ligands and co-factors

2021 ◽  
Author(s):  
Maarten L Hekkelman ◽  
Ida de de Vries ◽  
Robbie P Joosten ◽  
Anastassis Perrakis
Keyword(s):  
Small Molecules ◽  
Structural Integrity ◽  
Biological Function ◽  
Protein Structures ◽  
Molecular Function ◽  
Structure Database ◽  
Zinc Finger Motifs ◽  
Structure Similarity ◽  
Protein Models ◽  
Design Experiments

Artificial intelligence (AI) methods for constructing structural models of proteins on the basis of their sequence are having a transformative effect in biomolecular sciences. The AlphaFold protein structure database makes available hundreds of thousands of protein structures. However, all these structures lack cofactors essential for their structural integrity and molecular function (e.g. hemoglobin lacks a bound heme), key ions essential for structural integrity (e.g. zinc-finger motifs) or catalysis (e.g. Ca2+ or Zn2+ in metalloproteases), and ligands that are important for biological function (e.g. kinase structures lack ADP or ATP). Here, we present AlphaFill, an algorithm based on sequence and structure similarity, to "transplant" such "missing" small molecules and ions from experimentally determined structures to predicted protein models. These publicly available structural annotations are mapped to predicted protein models, to help scientists interpret biological function and design experiments.

scholarly journals Improving Precise CRISPR Genome Editing by Small Molecules: Is there a Magic Potion?

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1318 ◽  
Author(s):  
Nadja Bischoff ◽  
Sandra Wimberger ◽  
Marcello Maresca ◽  
Cord Brakebusch
Keyword(s):  
Gene Therapy ◽  
Dna Repair ◽  
Animal Models ◽  
Molecular Biology ◽  
Small Molecules ◽  
Genome Editing ◽  
Drug Targets ◽  
Targeted Mutagenesis ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome editing has become a standard method in molecular biology, for the establishment of genetically modified cellular and animal models, for the identification and validation of drug targets in animals, and is heavily tested for use in gene therapy of humans. While the efficiency of CRISPR mediated gene targeting is much higher than of classical targeted mutagenesis, the efficiency of CRISPR genome editing to introduce defined changes into the genome is still low. Overcoming this problem will have a great impact on the use of CRISPR genome editing in academic and industrial research and the clinic. This review will present efforts to achieve this goal by small molecules, which modify the DNA repair mechanisms to facilitate the precise alteration of the genome.

Target engagement approaches for pharmacological evaluation in animal models

2019 ◽  
Vol 55 (63) ◽  
pp. 9241-9250 ◽  
Author(s):  
James E. Kath ◽  
Aleksandra Baranczak
Keyword(s):  
Animal Models ◽  
Small Molecules ◽  
Chemical Biology ◽  
Target Engagement ◽  
Pharmacological Evaluation

We highlight recent applications of chemical biology approaches to measure target engagement of small molecules in animal models to support the nomination of clinical candidates.

scholarly journals Effect of UV Ageing on the fatigue life of bulk polyethylene

2018 ◽  
Vol 165 ◽  
pp. 08002 ◽  
Author(s):  
Hamza Lamnii ◽  
Moussa Nait-Abdelaziz ◽  
Georges Ayoub ◽  
Jean-Michel Gloaguen ◽  
Ulrich Maschke ◽  
...  
Keyword(s):  
Fatigue Life ◽  
Uv Irradiation ◽  
Chemical Structure ◽  
Fatigue Behavior ◽  
Crystalline Polymer ◽  
Fatigue Loading ◽  
Chain Scission ◽  
Fatigue Tests ◽  
Fatigue Properties ◽  
Irradiation Effect

Polymers operating in various weathering conditions must be assessed for lifetime performance. Particularly, ultraviolet (UV) radiations alters the chemical structure and therefore affect the mechanical and fatigue properties. The UV irradiation alters the polymer chemical structure, which results into a degradation of the mechanical and fatigue behavior of the polymer. The polymer properties degradation due to UV irradiation is the result of a competitive process of chain scission versus post-crosslinking. Although few studied investigated the effect of UV irradiation on the mechanical behaviour of thermoplastics, fewer examined the UV irradiation effect on the fatigue life of polymers. This study focuses on investigating the effect of UV irradiation on the fatigue properties of bulk semi-crystalline polymer; the low density Polyethylene (LDPE). Tensile specimens were exposed to different dose values of UV irradiation then subjected to fatigue loading. The fatigue tests were achieved under constant stress amplitude at a frequency of 1Hz. The results show an important decrease of the fatigue limit with increasing absorbed UV irradiation dose.

scholarly journals ESR Study on the UV-Irradiation Effect of Higher PolyolhydrogenPeroxide Systems

1962 ◽  
Vol 83 (6) ◽  
pp. 652-655 ◽  
Author(s):  
Keiji KUWATA ◽  
Takahisa ICHIKAWA ◽  
Kozo HIROTA
Keyword(s):  
Uv Irradiation ◽  
Irradiation Effect

Protein degradation: a validated therapeutic strategy with exciting prospects

2017 ◽  
Vol 61 (5) ◽  
pp. 517-527 ◽  
Author(s):  
Honorine Lebraud ◽  
Tom D. Heightman
Keyword(s):  
Animal Models ◽  
Protein Degradation ◽  
Small Molecules ◽  
Cancer Patients ◽  
Clinical Efficacy ◽  
Therapeutic Strategy ◽  
Substrate Recognition ◽  
Pharmacological Targets ◽  
Preclinical Animal Models

In a time of unprecedented challenges in developing potent, selective and well-tolerated protein inhibitors as therapeutics, drug hunters are increasingly seeking alternative modalities to modulate pharmacological targets. Selective inhibitors are achievable for only a fraction of the proteome, and are not guaranteed to elicit the desired response in patients, especially when pursuing targets identified through genetic knockdown. Targeted protein degradation holds the potential to expand the range of proteins that can be effectively modulated. Drugs inducing protein degradation through misfolding or by modulating cereblon (CRBN) substrate recognition are already approved for treatment of cancer patients. The last decade has seen the development of proteolysis targeting chimeras (PROTACs), small molecules that elicit proteasomal degradation by causing protein polyubiquitination. These have been used to degrade a range of disease-relevant proteins in cells, and some show promising efficacy in preclinical animal models, although their clinical efficacy and tolerability is yet to be proven. This review introduces current strategies for protein degradation with an emphasis on PROTACs and the role of click chemistry in PROTAC research through the formation of libraries of preclicked PROTACs or in-cell click-formed PROTACs (CLIPTACs).

scholarly journals Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I

2016 ◽  
Vol 291 (33) ◽  
pp. 17165-17177 ◽  
Author(s):  
Ruben Herrendorff ◽  
Maria Teresa Faleschini ◽  
Adeline Stiefvater ◽  
Beat Erne ◽  
Tatiana Wiktorowicz ◽  
...  
Keyword(s):  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Therapeutic Potential ◽  
Cell Model ◽  
Type I ◽  
Myotonic Dystrophy Type ◽  
Kinase Gene ◽  
Causal Treatment ◽  
Protein Kinase Gene ◽  
Dystrophia Myotonica Protein Kinase

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3′ UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases.

Sign in / Sign up

Export Citation Format

Share Document