scholarly journals Pharmacological Activation of Autophagy Restores Cellular Homeostasis in Ultraviolet-(B)-Induced Skin Photodamage

2021 ◽  
Vol 11 ◽  
Author(s):  
Sheikh Ahmad Umar ◽  
Naikoo Hussain Shahid ◽  
Lone Ahmad Nazir ◽  
Malik Ahmad Tanveer ◽  
Gupta Divya ◽  
...  
Keyword(s):  
Dna Damage ◽  
Er Stress ◽  
Stress Responses ◽  
Repair Process ◽  
Dermal Fibroblasts ◽  
Ultraviolet B ◽  
Cellular Damage ◽  
Great Promise ◽  
Independent Manner ◽  
Photo Damage

Ultraviolet (UV) exposure to the skin causes photo-damage and acts as the primary etiological agent in photo-carcinogenesis. UV-B exposure induces cellular damage and is the major factor challenging skin homeostasis. Autophagy allows the fundamental adaptation of cells to metabolic and oxidative stress. Cellular dysfunction has been observed in aged tissues and in toxic insults to cells undergoing stress. Conversely, promising anti-aging strategies aimed at inhibiting the mTOR pathway have been found to significantly improve the aging-related disorders. Recently, autophagy has been found to positively regulate skin homeostasis by enhancing DNA damage recognition. Here, we investigated the geno-protective roles of autophagy in UV-B-exposed primary human dermal fibroblasts (HDFs). We found that UV-B irradiation to HDFs impairs the autophagy response in a time- and intensity-independent manner. However, improving autophagy levels in HDFs with pharmacological activators regulates the UV-B-induced cellular stress by decreasing the induction of DNA photo-adducts, promoting the DNA repair process, alleviating oxidative and ER stress responses, and regulating the expression levels of key cell cycle regulatory proteins. Autophagy also prevents HDFs from UV-B-induced nuclear damage as is evident in TUNEL assay and Acridine Orange/Ethidium Bromide co-staining. Salubrinal (an eIF2α phosphatase inhibitor) relieves ER stress response in cells and also significantly alleviates DNA damage and promotes the repair process in UV-B-exposed HDFs. P62-silenced HDFs show enhanced DNA damage response and also disturb the tumor suppressor PTEN/pAKT signaling axis in UV-B-exposed HDFs whereas Atg7-silenced HDFs reveal an unexpected consequence by decreasing the UV-B-induced DNA damage. Taken together, these results suggest that interventional autophagy offers significant protection against UV-B radiation-induced photo-damage and holds great promise in devising it as a suitable therapeutic strategy against skin pathological disorders.

scholarly journals Deciphering the Genome Protection Roles of Autophagy in Primary Human Dermal Fibroblasts (HDFs) against Ultraviolet-(B) –Induced Skin Photodamage

2020 ◽  
Author(s):  
Sheikh Ahmad Umar ◽  
Sheikh Abdullah Tasduq
Keyword(s):  
Dna Damage ◽  
Stress Response ◽  
Er Stress ◽  
Dna Damage Response ◽  
Dermal Fibroblasts ◽  
Ultraviolet B ◽  
Great Promise ◽  
Er Stress Response ◽  
Damage Response ◽  
Photo Damage

AbstractUltraviolet-B (UV-B) exposure to skin causes photo-damage and acts as the primary etiological agent in photo-carcinogenesis. UV-B exposure induces photodamage in epidermal cells and is the major factor that challenges skin homeostasis. Autophagy allows fundamental adaptation of cells to metabolic needs and stresses. Cellular dysfunction is observed in aged tissues and in toxic insults to cells that undergo through stress. Conversely, promising anti-aging strategies aimed at inhibiting the mTOR pathway has been found to significantly improve the aging related disorders. Recently, autophagy has been found to positively regulate skin homeostasis by enhancing DNA damage recognition. Here we investigated the Geno-protective roles of autophagy in UV-B exposed primary HDFs. We found that improving autophagy levels in HDFs regulates UV-B mediated cellular stress by decreasing the formation of DNA photo adducts, alleviates oxidative and ER stress response and by regulating the expression levels of cell cycle regulatory proteins P21 and P27. Autophagy also prevents HDFs from UV-B -induced nuclear damage as is evident from Tunnel assay and Acridine Orange/Ethidium Bromide co-staining. Salubrinal, (an eIf2α inhibitor) significantly decreases the DNA damage response in HDFs. P62 silenced HDFs show enhanced DNA damage response and disturbs the tumor suppressor axis PTEN/pAKT towards damage whereas ATG7 silenced HDFs reveal an unexpected consequence by decreasing the UV-B -induced DNA damage compared to UV-B treated HDFs. Together, our results suggest that autophagy is essential in protecting skin cells from UV-B radiation -induced photo-damage and holds great promise in devising it as a suitable therapeutic strategy against skin photo-damage.HighlightsAutophagy is an immediate molecular event induced following exposure of primary HDFs to UV-B –irradiationAutophagy offers pro-survival capacity to HDFs under UV-B induced genotoxic stressAutophagy regulates DNA Damage Response via regulation of oxidative and ER stress in UV-B exposed HDFsRelieving ER stress response offers significant protection to primary HDFs from UV-B by decreasing the DNA damageAutophagy deprivation to HDFs via P62 silencing potentiates UV-B -induced DNA damage responseATG7 silencing in UV-B exposed HDFs unexpectedly alleviates the DNA Damage Response in primary HDFs

scholarly journals Fanconi anemia A protein participates in nucleolar homeostasis maintenance and ribosome biogenesis

2021 ◽  
Vol 7 (1) ◽  
pp. eabb5414
Author(s):  
Anna Gueiderikh ◽  
Frédérique Maczkowiak-Chartois ◽  
Guillaume Rouvet ◽  
Sylvie Souquère-Besse ◽  
Sébastien Apcher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Fanconi Anemia ◽  
Stress Responses ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Loss Of Function ◽  
Independent Manner ◽  
Ribosomal Subunits ◽  
Nucleolar Proteins ◽  
Nucleolar Stress

Fanconi anemia (FA), the most common inherited bone marrow failure and leukemia predisposition syndrome, is generally attributed to alterations in DNA damage responses due to the loss of function of the DNA repair and replication rescue activities of the FANC pathway. Here, we report that FANCA deficiency, whose inactivation has been identified in two-thirds of FA patients, is associated with nucleolar homeostasis loss, mislocalization of key nucleolar proteins, including nucleolin (NCL) and nucleophosmin 1 (NPM1), as well as alterations in ribosome biogenesis and protein synthesis. FANCA coimmunoprecipitates with NCL and NPM1 in a FANCcore complex–independent manner and, unique among the FANCcore complex proteins, associates with ribosomal subunits, influencing the stoichiometry of the translational machineries. In conclusion, we have identified unexpected nucleolar and translational consequences specifically associated with FANCA deficiency that appears to be involved in both DNA damage and nucleolar stress responses, challenging current hypothesis on FA physiopathology.

scholarly journals Genome protection: histone H4 and beyond

2020 ◽  
Vol 66 (5) ◽  
pp. 945-950
Author(s):  
Kundan Kumar ◽  
Romila Moirangthem ◽  
Rupinder Kaur
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Stress Responses ◽  
Gene Dosage ◽  
Repair Process ◽  
Histone H4 ◽  
Pathogenic Yeast ◽  
Protein Levels ◽  
Genome Protection

Abstract Histone proteins regulate cellular factors’ accessibility to DNA, and histone dosage has previously been linked with DNA damage susceptibility and efficiency of DNA repair pathways. Surplus histones are known to impede the DNA repair process by interfering with the homologous recombination-mediated DNA repair in Saccharomyces cerevisiae. Here, we discuss the recent finding of association of methyl methanesulfonate (MMS) resistance with the reduced histone H4 gene dosage in the pathogenic yeast Candida glabrata. We have earlier shown that while the low histone H3 gene dosage led to MMS susceptibility, the lack of two H4-encoding ORFs, CgHHF1 and CgHHF2, led to resistance to MMS-induced DNA damage. This resistance was linked with a higher rate of homologous recombination (HR). Taking these findings further, we review the interactome analysis of histones H3 and H4 in C. glabrata. We also report that the arginine residue present at the 95th position in the C-terminal tail of histone H4 protein is required for complementation of the MMS resistance in the Cghhf1Δhhf2Δ mutant, thereby pointing out a probable role of this residue in association with HR factors. Additionally, we present evidence that reduction in H4 protein levels may constitute an important part of varied stress responses in C. glabrata. Altogether, we present an overview of histone H4 dosage, HR-mediated repair of damaged DNA and stress resistance in this opportunistic human fungal pathogen.

scholarly journals Extract of Deschampsia antarctica (EDA) Prevents Dermal Cell Damage Induced by UV Radiation and 2,3,7,8-Tetrachlorodibenzo-p-dioxin

2019 ◽  
Vol 20 (6) ◽  
pp. 1356 ◽  
Author(s):  
Alicia Zamarrón ◽  
Esther Morel ◽  
Silvia Lucena ◽  
Manuel Mataix ◽  
Azahara Pérez-Davó ◽  
...  
Keyword(s):  
Stress Responses ◽  
Nuclear Translocation ◽  
Cell Damage ◽  
Skin Barrier ◽  
Hair Follicles ◽  
Ultraviolet B ◽  
Cellular Damage ◽  
Deschampsia Antarctica ◽  
Ecm Remodeling ◽  
Predominant Component

Exposure to natural and artificial light and environmental pollutants are the main factors that challenge skin homeostasis, promoting aging or even different forms of skin cancer through a variety of mechanisms that include accumulation of reactive oxygen species (ROS), engagement of DNA damage responses, and extracellular matrix (ECM) remodeling upon release of metalloproteases (MMPs). Ultraviolet A radiation is the predominant component of sunlight causative of photoaging, while ultraviolet B light is considered a potentiator of photoaging. In addition, different chemicals contribute to skin aging upon penetration through skin barrier disruption or hair follicles, aryl hydrocarbon receptors (AhR) being a major effector mechanism through which toxicity is exerted. Deschampsia antarctica is a polyextremophile Gramineae capable of thriving under extreme environmental conditions. Its aqueous extract (EDA) exhibits anti- photoaging in human skin cells, such as inhibition of MMPs, directly associated with extrinsic aging. EDA prevents cellular damage, attenuating stress responses such as autophagy and reducing cellular death induced by UV. We demonstrate that EDA also protects from dioxin-induced nuclear translocation of AhR and increases the production of loricrin, a marker of homeostasis in differentiated keratinocytes. Thus, our observations suggest a potential use exploiting EDA’s protective properties in skin health supplements.

scholarly journals Restoration of skeletal muscle homeostasis by hydrogen sulfide during hyperhomocysteinemia-mediated oxidative/ER stress condition

2019 ◽  
Vol 97 (6) ◽  
pp. 441-456 ◽  
Author(s):  
Avisek Majumder ◽  
Mahavir Singh ◽  
Akash K. George ◽  
Suresh C. Tyagi
Keyword(s):  
Skeletal Muscle ◽  
Hydrogen Sulfide ◽  
Er Stress ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Cellular Damage ◽  
Bidirectional Regulation ◽  
Muscle Homeostasis ◽  
Jnk Activation

Elevated homocysteine (Hcy), i.e., hyperhomocysteinemia (HHcy), causes skeletal muscle myopathy. Among many cellular and metabolic alterations caused by HHcy, oxidative and endoplasmic reticulum (ER) stress are considered the major ones; however, the precise molecular mechanism(s) in this process is unclear. Nevertheless, there is no treatment option available to treat HHcy-mediated muscle injury. Hydrogen sulfide (H2S) is increasingly recognized as a potent anti-oxidant, anti-apoptotic/necrotic/pyroptotic, and anti-inflammatory compound and also has been shown to improve angiogenesis during ischemic injury. Patients with CBS mutation produce less H2S, making them vulnerable to Hcy-mediated cellular damage. Many studies have reported bidirectional regulation of ER stress in apoptosis through JNK activation and concomitant attenuation of cell proliferation and protein synthesis via PI3K/AKT axis. Whether H2S mitigates these detrimental effects of HHcy on muscle remains unexplored. In this review, we discuss molecular mechanisms of HHcy-mediated oxidative/ER stress responses, apoptosis, angiogenesis, and atrophic changes in skeletal muscle and how H2S can restore skeletal muscle homeostasis during HHcy condition. This review also highlights the molecular mechanisms on how H2S could be developed as a clinically relevant therapeutic option for chronic conditions that are aggravated by HHcy.

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