scholarly journals Utilizing Developmentally Essential Secreted Peptides Such As Thymosin Beta-4 to Remind the Adult Organs of Their Embryonic State—New Directions in Anti-Aging Regenerative Therapies

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1343
Author(s):  
Klaudia Maar ◽  
Roland Hetenyi ◽  
Szabolcs Maar ◽  
Gabor Faskerti ◽  
Daniel Hanna ◽  
...  
Keyword(s):  
Small Molecules ◽  
Progenitor Cells ◽  
Aging Process ◽  
The Body ◽  
Routine Practice ◽  
Molecular Alterations ◽  
Thymosin Beta 4 ◽  
New Directions ◽  
Secreted Peptides ◽  
Regenerative Therapies

Our dream of defeating the processes of aging has occupied the curious and has challenged scientists globally for hundreds of years. The history is long, and sadly, the solution is still elusive. Our endeavors to reverse the magnitude of damaging cellular and molecular alterations resulted in only a few, yet significant advancements. Furthermore, as our lifespan increases, physicians are facing more mind-bending questions in their routine practice than ever before. Although the ultimate goal is to successfully treat the body as a whole, steps towards regenerating individual organs are even considered significant. As our initial approach to enhance the endogenous restorative capacity by delivering exogenous progenitor cells appears limited, we propose, utilizing small molecules critical during embryonic development may prove to be a powerful tool to increase regeneration and to reverse the processes associated with aging. In this review, we introduce Thymosin beta-4, a 43aa secreted peptide fulfilling our hopes and capable of numerous regenerative achievements via systemic administration in the heart. Observing the broad capacity of this small, secreted peptide, we believe it is not the only molecule which nature conceals to our benefit. Hence, the discovery and postnatal administration of developmentally relevant agents along with other approaches may result in reversing the aging process.

scholarly journals How Small Molecules Affect the Thermo-Oxidative Aging Mechanism of Polypropylene: A Reactive Molecular Dynamics Study

Polymers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1243
Author(s):  
Fan Zhang ◽  
Yufei Cao ◽  
Xuan Liu ◽  
Huan Xu ◽  
Diannan Lu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Acetic Acid ◽  
Small Molecules ◽  
Aging Process ◽  
Experimental Studies ◽  
Hydroxyl Group ◽  
Oxidative Aging ◽  
Reactive Molecular Dynamics ◽  
Aging Mechanism ◽  
Effects Of Temperature

Understanding the aging mechanism of polypropylene (PP) is fundamental for the fabrication and application of PP-based materials. In this paper, we present our study in which we first used reactive molecular dynamics (RMD) simulations to explore the thermo-oxidative aging of PP in the presence of acetic acid or acetone. We studied the effects of temperature and oxygen on the aging process and discussed the formation pathways of typical small molecule products (H2, CO, CO2, CH4, C2H4, and C2H6). The effect of two infection agents, acetic acid and acetone, on the aging reaction was analyzed emphatically. The simulation results showed that acetone has a weak impact on accelerating the aging process, while acetic acid has a significant effect, consistent with previous experimental studies. By tracking the simulation trajectories, both acetic acid and acetone produced small active free radicals to further react with other fragment products, thus accelerating the aging process. The first reaction step of acetic acid is often the shedding of the H atom on the hydroxyl group, while the reaction of acetone is often the shedding of the H atom or the methyl. The latter requires higher energy at lower temperatures. This is why the acceleration effect of acetone for the thermo-oxidative aging of PP was not so significant compared to acetic acid in the experimental temperature (383.15 K).

scholarly journals Humans accumulate microsatellite instability with acquired loss of MLH1 protein in hematopoietic stem and progenitor cells as a function of age

Blood ◽  
2012 ◽  
Vol 120 (16) ◽  
pp. 3229-3236 ◽  
Author(s):  
Jonathan Kenyon ◽  
Pingfu Fu ◽  
Karen Lingas ◽  
Emily Thomas ◽  
Anshul Saurastri ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Progenitor Cells ◽  
Aging Process ◽  
Early Event ◽  
Human Aging ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Normal Human ◽  
Mlh1 Protein

AbstractHematopoietic stem and progenitor cells (HPCs) are necessary for long-term survival. Genomic instability and persistent DNA damage may cause loss of adult stem cell function. The mismatch repair (MMR) pathway increases replication fidelity and defects have been implicated in malignant hematopoietic diseases. Little, however, is known about the role MMR pathway failure plays in the aging process of human HPCs. We hypothesized that loss of MMR occurs in HPCs as a process of human aging. We examined microsatellite instability and expression of the MMR genes MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in HPCs and colony-forming cell-derived clones (CFCs) from human donors aged 0 to 86 years. CFCs from donors > 45 years had a greater frequency of microsatellite instability and CD34+ progenitors lacking MLH1 expression and protein than individuals ≤ 45 years. Loss of MSH2 did not correlate with age. Thus, a potentially early event in the normal human aging process is microsatellite instability accumulation in normal human HPCs associated with the loss of MLH1 protein expression.

Abstract 2671: Thymosin Beta 4 Induced Oligodendrogenesis Is Associated With Upregulation Of Serum Response Factor

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Daniel C Morris ◽  
Benjamin Buller ◽  
Manoranjan Santra ◽  
Michael Chopp ◽  
Zheng Gang Zhang
Keyword(s):  
Western Blot ◽  
Progenitor Cells ◽  
Rat Model ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Embolic Stroke ◽  
Early Gene ◽  
Dependent Manner ◽  
Thymosin Beta 4 ◽  
Serum Response

Background: Thymosin beta 4 (Tβ4) is a G-actin sequestering peptide that improves neurological functional outcome when administered 24 hours after onset of stroke to a rat model of embolic stroke. Tβ4 increases the number of oligodendrocyte progenitor cells (OPCs) as well as mature oligodendrocytes (OLs). Mechanisms of Tβ4 induced oligodendrogenesis (OLG) remain unclear. Serum response growth factor (SRF) is a transcriptional factor which binds with ternary complex co-factors to primarily convey an immediate early gene response to influence and orchestrate neuronal migration and differentiation. Hypothesis: We tested the hypothesis that Tβ4 upregulates SRF with subsequent increase in the markers of OL differentiation. Results: We employed a mouse OPC line (N20.1) to investigate the mechanisms of Tβ4-induced OLG. The cells were plated at a density of 100,000 cells/ml and grown in the presence of 0, 12.5, 25 and 50 ng/ml of Tβ4 (RegeneRx Biopharmaceuticals, Inc.) for 14 days (n=3). Western blot analysis revealed that SRF was dose-dependently upregulated by a factor of 4. Quantitative real time PCR and Western blot analysis showed that Tβ4 treatment induced myelin basic protein (MBP) and 2’, 3’-cyclic nucleotide, 3’-phosphodiesterase (CNPase) expression in a dose-dependent manner by ∼2 fold, indicating the stimulation of OLG. In order to independently demonstrate that SRF promotes the differentiation of progenitor cells into mature oligodendrocytes, SRF was over expressed in the N20.1 cells using a plasmid encoding the SRF gene. After six days SRF over expressed N20.1 cells (n=3) demonstrated an increase of expression of MBP (26 ± 3%) and CNPase (23 ± 3%) when compared to cells transfected with an empty expression plasmid (n=3, MBP, 14 ± 3% and CNPase, 10 ± 4%, p<0.05). Conclusions: In this mouse model of OPCs, SRF was upregulated by Tβ4 and may be involved in Tβ4 induced OLG. Further in vivo investigation of SRF is warranted in our rat model of embolic stroke.

scholarly journals Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2076-2086 ◽  
Author(s):  
Britta Will ◽  
Li Zhou ◽  
Thomas O. Vogler ◽  
Susanna Ben-Neriah ◽  
Carolina Schinke ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Genetic Alterations ◽  
Fish Analysis ◽  
Exact Nature ◽  
Clinical Relapse ◽  
Hematopoietic Stem ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Stem And Progenitor Cells ◽  
Specific Expansion

Abstract Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage−/CD34+/CD38−/CD90+) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

scholarly journals Current perspectives concerning the multimodal therapy in Glioblastoma

2015 ◽  
Vol 22 (1) ◽  
pp. 3-19
Author(s):  
Florina Grigore ◽  
Felix Mircea Brehar ◽  
Mircea Radu Gorgan
Keyword(s):  
Multimodal Therapy ◽  
Tumor Biology ◽  
Primary Brain Tumor ◽  
Average Life ◽  
Average Life Expectancy ◽  
Molecular Alterations ◽  
The Past ◽  
Dismal Prognosis ◽  
New Directions ◽  
Set Up

Abstract GBM (Glioblastoma) is the most common, malignant type of primary brain tumor. It has a dismal prognosis, with an average life expectancy of less than 15 months. A better understanding of the tumor biology of GBM has been achieved in the past decade and set up new directions in the multimodal therapy by targeting the molecular paths involved in tumor initiation and progression. Invasion is a hallmark of GBM, and targeting the complex invasive mechanism of the tumor is mandatory in order to achieve a satisfactory result in GBM therapy. The goal of this review is to describe the tumor biology and key features of GBM and to provide an up-to-date overview of the current identified molecular alterations involved both in tumorigenesis and tumor progression.

A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1211-1223 ◽  
Author(s):  
T.P. Yamaguchi ◽  
A. Bradley ◽  
A.P. McMahon ◽  
S. Jones
Keyword(s):  
Progenitor Cells ◽  
Primitive Streak ◽  
The Body ◽  
Loss Of Function ◽  
Proliferating Cells ◽  
Precise Control ◽  
Cellular Processes ◽  
Cell Proliferation And Differentiation ◽  
Primary Body ◽  
Multiple Structures

Morphogenesis depends on the precise control of basic cellular processes such as cell proliferation and differentiation. Wnt5a may regulate these processes since it is expressed in a gradient at the caudal end of the growing embryo during gastrulation, and later in the distal-most aspect of several structures that extend from the body. A loss-of-function mutation of Wnt5a leads to an inability to extend the A-P axis due to a progressive reduction in the size of caudal structures. In the limbs, truncation of the proximal skeleton and absence of distal digits correlates with reduced proliferation of putative progenitor cells within the progress zone. However, expression of progress zone markers, and several genes implicated in distal outgrowth and patterning including Distalless, Hoxd and Fgf family members was not altered. Taken together with the outgrowth defects observed in the developing face, ears and genitals, our data indicates that Wnt5a regulates a pathway common to many structures whose development requires extension from the primary body axis. The reduced number of proliferating cells in both the progress zone and the primitive streak mesoderm suggests that one function of Wnt5a is to regulate the proliferation of progenitor cells.

Cough

Asthma ◽  
2014 ◽  
pp. 161-171
Author(s):  
Pramod Kelkar ◽  
Alan Goldsobel ◽  
Riccardo Polosa
Keyword(s):  
Cost Effectiveness ◽  
Physical Examination ◽  
Defense Mechanism ◽  
The Body ◽  
Lower Airway ◽  
Future Research ◽  
Routine Practice ◽  
Over The Counter ◽  
Closed Glottis ◽  
Habit Cough

Cough results from forced expulsion, usually against a closed glottis, creating a characteristic sound. It is a natural reflex and defense mechanism that helps the body clear excessive secretions and prevents foreign material from entering the respiratory tract. At times, cough can become excessive, nonproductive, disturbing to the patient, and potentially harmful. Cough is a complex symptom and often requires a multidisciplinary approach to ascertain its cause and effective treatment. Evaluation should be guided by a thorough history and physical examination, and testing should be individualized for cost effectiveness. Habit cough and unexplained cough are diagnoses of exclusion, and any tendency to underdiagnose or overdiagnose these conditions should be avoided. Most over-the-counter cough suppressants are not as effective as previously thought, and their use in routine practice should be minimized. Future research should be conducted to elucidate the mechanisms of cough production and to develop cough-suppressive pharmacotherapy. Allergists, as experts in the management of upper and lower airway disorders, should play a central role in the diagnosis and management of cough.

scholarly journals Insulin Signaling in Intestinal Stem and Progenitor Cells as an Important Determinant of Physiological and Metabolic Traits in Drosophila

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 803 ◽  
Author(s):  
Olha M. Strilbytska ◽  
Uliana V. Semaniuk ◽  
Kenneth B. Storey ◽  
Ihor S. Yurkevych ◽  
Oleh Lushchak
Keyword(s):  
Progenitor Cells ◽  
Insulin Signaling ◽  
Egf Receptor ◽  
The Body ◽  
Receptor Ligands ◽  
Adipokinetic Hormone ◽  
Peripheral Tissues ◽  
Genes Encoding ◽  
Stem And Progenitor Cells ◽  
Multicellular Organisms

The insulin–IGF-1 signaling (IIS) pathway is conserved throughout multicellular organisms and regulates many traits, including aging, reproduction, feeding, metabolism, stress resistance, and growth. Here, we present evidence of a survival-sustaining role for IIS in a subset of gut cells in Drosophila melanogaster, namely the intestinal stem cells (ISCs) and progenitor cells. Using RNAi to knockdown the insulin receptor, we found that inhibition of IIS in ISCs statistically shortened the lifespan of experimental flies compared with non-knockdown controls, and also shortened their survival under starvation or malnutrition conditions. These flies also showed decreased reproduction and feeding, and had lower amounts of glycogen and glucose in the body. In addition, increased expression was observed for the Drosophila transcripts for the insulin-like peptides dilp2, dilp5, and dilp6. This may reflect increased insulin signaling in peripheral tissues supported by up-regulation of the target of the brain insulin gene (tobi). In contrast, activation of IIS (via knockdown of the insulin pathway inhibitor PTEN) in intestinal stem and progenitor cells decreased fly resistance to malnutrition, potentially by affecting adipokinetic hormone signaling. Finally, Pten knockdown to enhance IIS also activated JAK–STAT signaling in gut tissue by up-regulation of upd2, upd3, and soc36 genes, as well as genes encoding the EGF receptor ligands spitz and vein. These results clearly demonstrate that manipulating insulin levels may be used to modulate various fly traits, which are important determinants of organismal survival.

Small-Molecule Immuno-Oncology Therapy: Advances, Challenges and New Directions

2019 ◽  
Vol 19 (3) ◽  
pp. 180-185 ◽  
Author(s):  
Shulun Chen ◽  
Zilan Song ◽  
Ao Zhang
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Future Research ◽  
Checkpoint Proteins ◽  
Adaptive Immune ◽  
Superior Efficacy ◽  
Adaptive Immune Cells ◽  
New Directions ◽  
Clinical Responses ◽  
Remarkable Progress

Oncology immunotherapy has gained significant advances in recent years and benefits cancer patients with superior efficacy and superior clinical responses. Currently over ten immune checkpoint antibodies targeting CTLA-4 and PD-1/PD-L1 have received regulatory approval worldwide and over thousands are under active clinical trials. However, compared to the rapid advance of Monoclonal Antibody (mAb), studies on immunotherapeutic small molecules have far lagged behind. Small molecule immunotherapy not only can target immunosuppressive mechanisms similar to mAbs, but also can stimulate intracellular pathways downstream of checkpoint proteins in innate or adaptive immune cells that mAbs are unable to access. Therefore, small molecule immunotherapy can provide an alternative treatment modality either alone or complementary to or synergistic with extracellular checkpoint mAbs to address low clinical response and drug resistance. Fortunately, remarkable progress has achieved recently in the pursuit of small molecule immunotherapy. This review intends to provide a timely highlight on those clinically investigated small molecules targeting PD-1/PD-L1, IDO1, and STING. The most advanced IDO1 inhibitor epacadostat have been aggressively progressed into multiple clinical testings. Small molecule PD-1/PD-L1 inhibitors and STING activators are still in a premature state and their decisive application needs to wait for the ongoing clinical outcomes. Since no small molecule immunotherapy has been approved yet, the future research should continue to focus on discovery of novel small molecules with distinct chemo-types and higher potency, identification of biomarkers to precisely stratify patients, as well as validation of many other immune-therapeutic targets, such as LAG3, KIRs, TIM-3, VISTA, B7-H3, and TIGIT.

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