scholarly journals Senescence under appraisal: hopes and challenges revisited

2021 ◽  
Author(s):  
Camilla S. A. Davan-Wetton ◽  
Emanuela Pessolano ◽  
Mauro Perretti ◽  
Trinidad Montero-Melendez
Keyword(s):  
Cellular Senescence ◽  
Clinical Success ◽  
Immune Surveillance ◽  
Favourable Outcome ◽  
Cellular Growth ◽  
Therapeutic Approaches ◽  
Cycle Arrest ◽  
Therapeutic Development ◽  
The Right ◽  
Inflammation Resolution

AbstractIn recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called ‘zombie cells’ are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies.

scholarly journals Immune Surveillance of Senescent Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 248-248
Author(s):  
Scott Lowe
Keyword(s):  
Cellular Senescence ◽  
Immune Surveillance ◽  
Therapeutic Benefit ◽  
Tumor Evolution ◽  
Laboratory Studies ◽  
Conventional Chemotherapy ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Car T

Abstract Cellular senescence involves a stable cell cycle arrest and a secretory program that modulates the tissue environment. In cancer, senescence acts as a potent barrier to tumorigenesis and, though many cancers evade senescence during the course of tumor evolution, ionizing radiation and conventional chemotherapy can, to varying degrees, induce senescence in tumor cells leading to potent anticancer effects. Conversely, the aberrant accumulation of senescent cells can reduce regenerative capacity and lead to tissue decline, contributing to tissue pathologies associated with age or the debilitating side-effects of cancer therapy. Our laboratory studies mechanisms of cellular senescence with the ultimate goal of developing strategies to modulate senescence for therapeutic benefit. We have focused on how senescent cells trigger immune surveillance to facilitate their own elimination or, when that fails, how synthetic immune cells (i.e. CAR T cells) can be directed to eliminate senescent cells. Recent advances in understanding senescent cell surveillance by the immune system will be discussed.

Alkylphospholipids are Signal Transduction Modulators with Potential for Anticancer Therapy

2019 ◽  
Vol 19 (1) ◽  
pp. 66-91 ◽  
Author(s):  
Ferda Kaleağasıoğlu ◽  
Maya M. Zaharieva ◽  
Spiro M. Konstantinov ◽  
Martin R. Berger
Keyword(s):  
Clinical Success ◽  
Phase Cell ◽  
Akt Phosphorylation ◽  
Cycle Arrest ◽  
M Phase ◽  
Mtor Phosphorylation ◽  
Antiviral Activities ◽  
Bone Marrow Sparing ◽  
Membrane Components ◽  
The Way

Background:Alkylphospholipids (APLs) are synthetically derived from cell membrane components, which they target and thus modify cellular signalling and cause diverse effects. This study reviews the mechanism of action of anticancer, antiprotozoal, antibacterial and antiviral activities of ALPs, as well as their clinical use.Methods:A literature search was used as the basis of this review.Results:ALPs target lipid rafts and alter phospholipase D and C signalling cascades, which in turn will modulate the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways. By feedback coupling, the SAPK/JNK signalling chain is also affected. These changes lead to a G2/M phase cell cycle arrest and subsequently induce programmed cell death. The available knowledge on inhibition of AKT phosphorylation, mTOR phosphorylation and Raf down-regulation renders ALPs as attractive candidates for modern medical treatment, which is based on individualized diagnosis and therapy. Corresponding to their unusual profile of activities, their side effects result from cholinomimetic activity mainly and focus on the gastrointestinal tract. These aspects together with their bone marrow sparing features render APCs well suited for modern combination therapy. Although the clinical success has been limited in cancer diseases so far, the use of miltefosine against leishmaniosis is leading the way to better understanding their optimized use.Conclusion:Recent synthetic programs generate congeners with the increased therapeutic ratio, liposomal formulations, as well as diapeutic (or theranostic) derivatives with optimized properties. It is anticipated that these innovative modifications will pave the way for the further successful development of ALPs.

scholarly journals Cost comparison between botulinum neurotoxin and surgery in the treatment of infantile esotropia in a tertiary public hospital

2021 ◽  
Vol 6 (1) ◽  
pp. e000766
Author(s):  
Ismail Mayet ◽  
Shelley-Ann McGee ◽  
Naseer Ally ◽  
Hassan Dawood Alli ◽  
Mohammed Tikly ◽  
...  
Keyword(s):  
Botulinum Neurotoxin ◽  
Clinical Success ◽  
Cost Benefit ◽  
Randomised Clinical Trial ◽  
Primary Treatment ◽  
Favourable Outcome ◽  
Cost Comparison ◽  
Infantile Esotropia ◽  
Satisfactory Outcome ◽  
Mean Cost

ObjectiveTo compare the cost implications of botulinum neurotoxin (BNT) injection to surgery in infantile esotropia (IE) in a public/government funded hospital.Methods and analysisA simple costing comparison was undertaken for a randomised clinical trial in IE. Patients were randomised to receive either BNT or standard surgery. The participants in the BNT arm were further subdivided into subgroups based on their age in months and degree of esotropia in prism dioptres (PD) at presentation: G1 ≤60 PD/24 months, G2 ≤24 months/>60 PD, G3 >24 months/≤60 PD, G4 >24 months/>60 PD. The costs were calculated for each arm from primary treatment to eventual satisfactory outcome defined as orthophoria or microtropia (≤10 PD). A bottom-up costing analysis was done for single and multiple procedures for each arm. Comprehensive variable costs as well as fixed costs were calculated at each point of intervention and expressed in local currency ZAR (US$1=ZAR15.00). Costing was analysed for surgery and BNT subgroups (based on clinical success)ResultsThere were 101 patients enrolled in the trial. 54 in the BNT arm and 47 in the surgery arm. Cost for single surgery and single BNT was ZAR 7743.04 and 1713.14, respectively. A favourable clinical outcome was achieved in 72% of surgery arm and 37% of BNT arm. The mean cost for eventual favourable outcome in BNT arm was ZAR9158.08 and in surgery arm ZAR9124.27 (p=0.26). Mean cost in G1 was ZAR6328.45, in G2 ZAR7197.45, in G3 ZAR11891.93 and G4 ZAR12882.44 (p=0.018).ConclusionBNT has a cost–benefit in IE and is a viable option in the primary treatment of IE in resource constrained regions. Clinical outcomes and economic benefit in smaller angle of esotropia and younger patients are comparable to surgery.

scholarly journals Leishmania mexicana in a central Texas cat: clinical presentation, molecular identification, sandfly vector collection and novel management

2021 ◽  
Vol 7 (1) ◽  
pp. 205511692199959
Author(s):  
Kaitlin Hopke ◽  
Alyssa Meyers ◽  
Lisa Auckland ◽  
Sarah Hamer ◽  
David Florin ◽  
...  
Keyword(s):  
Case Report ◽  
Clinical Success ◽  
Leishmania Species ◽  
Canine Leishmaniosis ◽  
Leishmania Mexicana ◽  
Cutaneous Lesions ◽  
Clinical Appearance ◽  
Significant Clinical Improvement ◽  
Central Texas ◽  
The Right

Case summary This case report documents the clinical appearance, diagnosis and novel treatment of a central Texas cat with cutaneous leishmaniosis. The cat presented with a linear erosion on the right pinnal margin, an ulcerated exophytic nodule on the right hock and a swelling in the right nostril. Cytological and histopathological findings were consistent with leishmaniosis. PCR confirmed the presence of Leishmania mexicana, a species endemic to Texas. An epidemiological investigation was conducted by trapping sandflies from the cat’s environment. Sandflies collected were identified as Lutzomyia species, known vectors of Leishmania species. Given the lack of validated medical therapies for L mexicana in cats, treatments typically prescribed for canine leishmaniosis were administered. Allopurinol achieved clinical success but was discontinued due to suspected drug-related neutropenia. Topical imiquimod also improved lesional skin but was not sustainable due to application difficulty. Oral administration of artemisinin resulted in significant clinical improvement of cutaneous lesions without reported adverse events. Nearly 8 months after the initiation of artemisinin therapy, the cat remained systemically healthy with stable lesions. Relevance and novel information This case report demonstrates endemic feline leishmaniosis in central Texas and provides the clinician with alternative therapeutic options for medical management.

scholarly journals Cellular Senescence in Liver Disease and Regeneration

2021 ◽  
Author(s):  
Sofia Ferreira-Gonzalez ◽  
Daniel Rodrigo-Torres ◽  
Victoria L. Gadd ◽  
Stuart J. Forbes
Keyword(s):  
Cell Cycle ◽  
Liver Disease ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Cellular Senescence ◽  
Cell Populations ◽  
Cycle Arrest ◽  
Relevant Role ◽  
Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

Systems Biology Technologies Enable Personalized Traditional Chinese Medicine: A Systematic Review

2012 ◽  
Vol 40 (06) ◽  
pp. 1109-1122 ◽  
Author(s):  
Xijun Wang ◽  
Aihua Zhang ◽  
Hui Sun ◽  
Ping Wang
Keyword(s):  
Systems Biology ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Disease Diagnosis ◽  
Modern Medicine ◽  
Therapeutic Approaches ◽  
Current Trends ◽  
Close Relationship ◽  
The Right ◽  
Personalize Medicine

Traditional Chinese medicine (TCM), an alternative medicine, focuses on the treatment of human disease via the integrity of the close relationship between body and syndrome analysis. It remains a form of primary care in most Asian countries and its characteristics showcase the great advantages of personalized medicine. Although this approach to disease diagnosis, prognosis and treatment has served the medical establishment well for thousands of years, it has serious shortcomings in the era of modern medicine that stem from its reliance on reductionist principles of experimentation and analysis. In this way, systems biology offers the potential to personalize medicine, facilitating the provision of the right care to the right patient at the right time. We expect that systems biology will have a major impact on future personalized therapeutic approaches which herald the future of medicine. Here we summarize current trends and critically review the potential limitations and future prospects of such treatments. Some characteristic examples are presented to highlight the application of this groundbreaking platform to personalized TCM as well as some of the necessary milestones for moving systems biology of a state-of-the-art nature into mainstream health care.

Struma Ovarii: Clinico-Morphological Features and Therapeutic Experience of a Romanian Institution over 20 Years

2021 ◽  
Vol 11 (20) ◽  
pp. 9427
Author(s):  
Mihaela Camelia Tîrnovanu ◽  
Vlad Gabriel Tîrnovanu ◽  
Bogdan Florin Toma ◽  
Elena Cojocaru ◽  
Carmen Ungureanu ◽  
...  
Keyword(s):  
Rare Condition ◽  
Diagnostic Algorithm ◽  
Complete Information ◽  
Published Data ◽  
Struma Ovarii ◽  
Therapeutic Approaches ◽  
Diagnostic Challenge ◽  
Benign Ovarian Tumors ◽  
The Right ◽  
Clinical Conditions

Struma ovarii is a rare condition with scarce published data regarding clinical, morphological, and therapeutic approaches. This study reports the experience of 25 patients with struma ovarii who received surgical treatment in a gynecology department in Romania. The study was conducted from January 1999 to September 2021 and included patients with confirmed struma ovarii whose medical records were retrospectively reviewed and evaluated. Struma ovarii represented 2.8% of the total number of benign ovarian tumors treated by surgery. The age of the patients was between 24 and 71 years. The tumor was unilateral in 24 cases, 13 cases on the left ovary, 11 on the right side, and bilateral in 1 case. Tumor dimensions ranged between 1 cm and 20 cm. In two cases, the patients had symptoms of hyperthyroidism. The procedure was performed on four women for diagnoses other than an ovarian tumor. In another five situations, there was suspicion of ovarian malignancy. In addition, struma ovarii was associated with other clinical conditions in 22 cases. These lesions represent a diagnostic challenge with heterogeneous clinical and imaging manifestations. Complete information of clinical, morphologic, and surgical findings may improve the diagnostic algorithm and better predict patient outcomes.

scholarly journals Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e42150 ◽  
Author(s):  
Sascha Schäuble ◽  
Karolin Klement ◽  
Shiva Marthandan ◽  
Sandra Münch ◽  
Ines Heiland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Quantitative Model ◽  
Cycle Arrest

scholarly journals In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2171
Author(s):  
Saori Deguchi ◽  
Fumihiko Ogata ◽  
Mizuki Yamaguchi ◽  
Misa Minami ◽  
Hiroko Otake ◽  
...  
Keyword(s):  
Therapeutic Approaches ◽  
In Situ Gel ◽  
Retinal Dysfunction ◽  
Atp Production ◽  
Oletf Rats ◽  
Bead Mill ◽  
Long Evans ◽  
The Right ◽  
In Situ Gelling

We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.

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