6-Shogaol induces apoptosis in acute lymphoblastic leukaemia cells by targeting p53 signalling pathway and generation of reactive oxygen species

Combination therapies, using medicinal herbs, are broadly recommended to attenuate the chemotherapy adverse effects. Based on our previous findings considering the anti-leukaemic effects of ginger extract on acute lymphoblastic leukaemia (ALL) cells, the present study was aimed to investigate the anti-cancer role of this pharmaceutical plant on ALL mice models. Moreover, we worked towards identifying the most anti-leukaemic derivative of ginger and the mechanism through which it may exert its cytotoxic impact. In vivo experiments were performed using five groups of six C57BL/6 nude mice, and the anti-leukaemic activity of ginger extract alone or in combination with methotrexate (MTX) was examined. Results showed increased survival rate and reduced damages in mice brain and liver tissues. Subsequently, MTT assay demonstrated synergistic growth inhibitory effect of 6-shogaol (6Sh) and MTX on ALL cell lines and patients primary cells. Eventually, the molecular anti-neoplastic mechanism of 6Sh was evaluated using Bioinformatics. Flow cytometry illustrated 6Sh-mediated apoptosis in Nalm-6 cells confirmed by Western blotting and RT-PCR assays. Further analyses exhibited the generation of reactive oxygen species (ROS) through 6Sh. The current study revealed the in vivo novel anti-leukaemic role of ginger extract, promoted by MTX. Moreover, 6-shogaol was introduced as the major player of ginger cytotoxicity through inducing p53 activity and ROS generation.     

DNA repair in human promyelocytic cell line, HL-60.

The human promyelocytic cell line, HL-60, shows large changes in endogenous poly(ADP-ribose) and in nuclear ADP-ribosyl transferase activity (ADPRT) during its induced myelocytic differentiation. DNA strand-breaks are an essential activator for this enzyme; and transient DNA strand breaks occur during the myelocytic differentiation of HL-60 cells. We have tested the hypothesis that these post-mitotic, terminally differentiating cells are less efficient in DNA repair, and specifically in DNA strand rejoining, than their proliferating precursor cells. We have found that this hypothesis is not tenable. We observe that there is no detectable reduction in the efficiency of DNA excision repair after exposure to either dimethyl sulphate or gamma-irradiation in HL-60 cells induced to differentiate by dimethyl sulphoxide. Moreover, the efficient excision repair of either dimethyl sulphate or gamma-irradiation induced lesions, both in the differentiated and undifferentiated HL-60 cells, is blocked by the inhibition of ADPRT activity.     

Enhancement of seminiferous tubular growth and spermatogenesis in testes of rats recovering from early hypothyroidism: a quantitative study

Testicular weight and DNA content were markedly reduced (63 and 69%) in weanling Long-Evans rat pups rendered hypothyroid from birth by administration of propylthiouracil (PTU), a reversible goitrogen. These growth deficits worsened to >80% by continuing hypothyroidism beyond weaning, to days 50 and 90. Recovery of thyroid function, brought about by discontinuing PTU at weaning, resulted in a paradoxical stimulation of testis growth, amounting to increased weight (40%), DNA content (60%) and size by 90 days, compared to age-matched controls. In the 25-day or older hypothyroid rats, testicular structure was immature and spermatogenesis markedly delayed, as evident by closed lumen and significantly reduced diameter of seminiferous tubules (38%), thickness of germinal layer (70%), and number of primary spermatocytes (86%), compared to control. Hypothyroidism did not alter the number of tubules per testis cross section. In the 90-day recovery rats, numbers of seminiferous tubules were unchanged but tubular diameter was significantly (20%) larger than in controls and spermatogenesis appeared very active as indicated by significantly increased germinal layer thickness (22%) and total number and density of primary spermatocytes (55% and 40%). The results show that although postnatal hypothyroidism is deleterious for testicular growth and spermatogenesis, recovery from this condition leads to enhanced seminiferous tubular growth and spermatogenesis.     

The Human Cathelicidin LL-37, a Defensive Peptide Against Rotavirus Infection

International Journal of Peptide Research and Therapeutics - LL-37 is a 37 amino acid long cationic peptide belonging to the cathelicidin family of antimicrobial peptides. Limited investigations...     

The next step of neurogenesis in the context of Alzheimer’s disease

Molecular Biology Reports - Among different pathological mechanisms, neuronal loss and neurogenesis impairment in the hippocampus play important roles in cognitive decline in Alzheimer’s...     

Liquid–liquid phase separation of Tau by self and complex coacervation

The liquid–liquid phase separation (LLPS) of Tau has been postulated to play a role in modulating the aggregation property of Tau, a process known to be critically associated with the pathology of a broad range of neurodegenerative diseases including Alzheimer''s Disease. Tau can undergo LLPS by homotypic interaction through self‐coacervation (SC) or by heterotypic association through complex‐coacervation (CC) between Tau and binding partners such as RNA. What is unclear is in what way the formation mechanisms for self and complex coacervation of Tau are similar or different, and the addition of a binding partner to Tau alters the properties of LLPS and Tau. A combination of in vitro experimental and computational study reveals that the primary driving force for both Tau CC and SC is electrostatic interactions between Tau‐RNA or Tau‐Tau macromolecules. The liquid condensates formed by the complex coacervation of Tau and RNA have distinctly higher micro‐viscosity and greater thermal stability than that formed by the SC of Tau. Our study shows that subtle changes in solution conditions, including molecular crowding and the presence of binding partners, can lead to the formation of different types of Tau condensates with distinct micro‐viscosity that can coexist as persistent and immiscible entities in solution. We speculate that the formation, rheological properties and stability of Tau droplets can be readily tuned by cellular factors, and that liquid condensation of Tau can alter the conformational equilibrium of Tau.     

The effect of inflammatory factors and their inhibitors on the hematopoietic stem cells fate

Inflammatory cytokines exert different effects on hematopoietic stem cells (HSCs), lead to the development of various cell lineages in bone marrow (BM) and are thus a differentiation axis for HSCs. The content used in this article has been obtained by searching PubMed database and Google Scholar search engine of English-language articles (1995–2020) using “Hematopoietic stem cell,” “Inflammatory cytokine,” “Homeostasis,” and “Myelopoiesis.” Inflammatory cytokines are involved in the differentiation and proliferation of hematopoietic progenitors to compensate for cellular death due to inflammation. Since each of these cytokines differentiates HSCs into a specific cell line, the difference in the effect of these cytokines on the fate of HSC progenitors can be predicted. Inhibitors of these cytokines can also control the inflammatory process as well as the cells involved in leukemic conditions. In general, inflammatory signaling can specify the dominant cell line in BM to counteract inflammation and leukemic condition via stimulating or inhibiting hematopoietic progenitors. Therefore, detection of the effects of inflammatory cytokines on the differentiation of HSCs can be an appropriate approach to check inflammatory and leukemic conditions and the suppression of these cytokines by their inhibitors allows for control of homeostasis in stressful conditions.     

The role of Pro-P5C Cycle in chs mutants of Arabidopsis under cold stress

Proline metabolism is implicated in plant responses to abiotic stresses, including the chilling stress. During proline catabolism, the two-step oxidation of proline is performed by the continuous actions of proline dehydrogenase (ProDH), which produces Δ¹-pyrroline-5-carboxylate (P5C), and P5C dehydrogenase (P5CDH), which oxidizes P5C to glutamate. The Arabidopsis thaliana chilling mutants chs1 and chs2 are sensitive to chilling temperatures of 13–18°C. For a better understanding of Arabidopsis responses to chilling stress, 4-week-old wild-type (WT) and chs1 and chs2 lines, with three plants in each group, were subjected to chilling stress (13°C), cold stress (4°C), or remained under normal conditions (23°C); and several factors including the expression of ProDH2 and P5CDH genes, POX (peroxidase) and SOD (superoxide dismutase) activities, as well as MDA and proline contents were examined. Our results showed an increase in the proline content in all lines under chilling conditions. In addition, a greater expression of ProDH2 and a lower expression of P5CDH were observed, leading us to speculate a greater breakdown of proline into P5C and a consequent overproduction of ROS in the ETC cycle. The higher POX and SOD activities and a higher MDA content in chs mutants at 13°C are in line with this speculation. Finally, cold-treated plants (4°C) only showed an increase in proline levels.     

Heat-Induced Conformational Unfolding of Fatty Acid-Free and Fatted Camel Serum Albumin: A Comparative Study

Albumin is a multifunctional non-glycosylated, negatively charged plasma protein, with extraordinary ligand-binding and transport properties, antioxidant functions, and enzymatic activities. Physiologically, albumin transports free fatty acids in plasma and contributes in maintaining colloid osmotic pressure. Recent progresses in using albumin as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein-based drugs, increased the attempts for improving albumin stability. Studying the thermal stability of camel albumin may provide us not only new clues for designing recombinant albumins, but also molecular insights on camel physiology. This study aims to determine the thermal stability of camel albumin. Fatted camel serum albumin (FCSA) was purified from blood via combination of Cohn’s method and anion-exchange chromatography. Activated charcoal treatment was used to obtain defatted camel serum albumin (CSA). Fluorescence spectroscopy and differential scanning calorimetry (DSC) were used to study thermal denaturation of this protein. The set of fluorescence spectra were deconvoluted using the convex constraint analysis method (CCA). The results from deconvolution of fluorescence spectroscopy and DSC showed three and two components for CSA and FCSA, respectively. The bimodal DSC transition can be attributed to a crevice between domains I and II and formation of two independent thermodynamic domains. The crevice formation can be prevented by fatty acid binding between domains I and II. The calculated values of ?H _v/?H _cal, approximately 0.4 for CSA and near 1 for FCSA, confirmed the presence of at least one intermediate in thermal unfolding of CSA and the absence of the intermediate for FCSA. The obtained midpoint transition temperature (T _m) of FCSA was about 20 °C higher than that of CSA. Such enormous stabilizing effect may be attributed to the fact that fatty acid serves as glue which preserves different domains beside each other and prevents formation of the mentioned intermediate.