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Entanglement of UPR <sup>ER</sup> in Aging Driven Neurodegenerative Diseases
Rahman, Safikur,Jan, Arif Tasleem,Ayyagari, Archana,Kim, Jiwoo,Kim, Jihoe,Minakshi, Rinki Frontiers Media S.A. 2017 FRONTIERS IN AGING NEUROSCIENCE Vol.9 No.-
<P>The endoplasmic reticulum (ER) is an indispensable cellular organelle that remains highly active in neuronal cells. The ER bears the load of maintaining protein homeostasis in the cellular network by managing the folding of incoming nascent peptides; however, the stress imposed by physiological/environmental factors can cause ER dysfunctions that lead to the activation of ER unfolded protein response (UPR<SUP>ER</SUP>). Aging leads to deterioration of several cellular pathways and therefore weakening of the UPR<SUP>ER</SUP>. The decline in functioning of the UPR<SUP>ER</SUP> during aging results in accumulation of misfolded proteins that becomes intracellular inclusions in neuronal cells, resulting in toxicity manifested as neurodegenerative diseases. With ascension in cases of neurodegenerative diseases, understanding the enigma behind aging driven UPR<SUP>ER</SUP> dysfunction may lead to possible treatments.</P>
Rinki Minakshi,Safikur Rahman,Arif Tasleem Jan,Ayyagari Archana,김지회 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-
The endoplasmic reticulum (ER) is an important subcellular organelle that is involved in numerous activities required to achieve and maintain functional proteins in addition to its role in the biosynthesis of lipids and as a repository of intracellular Ca2+. The inability of the ER to cope with protein folding beyond its capacity causes disturbances that evoke ER stress. Cells possess molecular mechanisms aimed at clearing unwanted cargo from the ER lumen as an adaptive response, but failing to do so navigates the system towards cell death. This systemic approach is called the unfolded protein response. Aging insults cells through various perturbations in homeostasis that involve curtailing ER function by mitigating the expression of its resident chaperones and enzymes. Here the unfolded protein response (UPR) cannot protect the cell due to the weakening of its protective arm, which exacerbates imbalanced homeostasis. Aging predisposed breast malignancy activates the UPR, but tumor cells maneuver the mechanistic details of the UPR, favoring tumorigenesis and thereby eliciting a treacherous condition. Tumor cells exploit UPR pathways via crosstalk involving various signaling cascades that usher tumor cells to immortality. This review aims to present a collection of data that can delineate the missing links of molecular signatures between aging and breast cancer.
Minakshi, Rinki,Rahman, Safikur,Jan, Arif Tasleem,Archana, Ayyagari,Kim, Jihoe Nature Publishing Group 2017 Experimental and molecular medicine Vol.49 No.11
<P>The endoplasmic reticulum (ER) is an important subcellular organelle that is involved in numerous activities required to achieve and maintain functional proteins in addition to its role in the biosynthesis of lipids and as a repository of intracellular Ca<SUP>2+</SUP>. The inability of the ER to cope with protein folding beyond its capacity causes disturbances that evoke ER stress. Cells possess molecular mechanisms aimed at clearing unwanted cargo from the ER lumen as an adaptive response, but failing to do so navigates the system towards cell death. This systemic approach is called the unfolded protein response. Aging insults cells through various perturbations in homeostasis that involve curtailing ER function by mitigating the expression of its resident chaperones and enzymes. Here the unfolded protein response (UPR) cannot protect the cell due to the weakening of its protective arm, which exacerbates imbalanced homeostasis. Aging predisposed breast malignancy activates the UPR, but tumor cells maneuver the mechanistic details of the UPR, favoring tumorigenesis and thereby eliciting a treacherous condition. Tumor cells exploit UPR pathways via crosstalk involving various signaling cascades that usher tumor cells to immortality. This review aims to present a collection of data that can delineate the missing links of molecular signatures between aging and breast cancer.</P>
Baig, Mohammad Hassan,Rahman, Safikur,Rabbani, Gulam,Imran, Mohd,Ahmad, Khurshid,Choi, Inho MDPI 2019 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.20 No.3
<P>Cyclobenzaprine hydrochloride (CBH) is a well-known muscle relaxant that is widely used to relieve muscle spasms and other pain associated with acute musculoskeletal conditions. In this study, we elucidated the binding characteristics of this muscle relaxant to human serum albumin (HSA). From a pharmaceutical and biochemical viewpoint, insight into the structure, functions, dynamics, and features of HSA-CBH complex holds great importance. The binding of CBH with this major circulatory transport protein was studied using a combination of biophysical approaches such as UV-VIS absorption, fluorescence quenching, and circular dichroism (CD) spectroscopy. Various <I>in silico</I> techniques, molecular docking and molecular dynamics, were also used to gain deeper insight into the binding. A reduction in the fluorescence intensities of HSA-CBH complex with a constant increase in temperature, revealed the static mode of protein fluorescence quenching upon CBH addition, which confirmed the formation of the HSA-CBH ground state complex. The alteration in the UV-VIS and far-UV CD spectrum indicated changes in both secondary and tertiary structures of HSA upon binding of CBH, further proving CBH binding to HSA. The analysis of thermodynamic parameters ∆H° and ∆S° showed that binding of CBH to HSA was dominated by intermolecular hydrophobic forces. The results of the molecular docking and molecular dynamics simulation studies also confirmed the stability of the complex and supported the experimental results.</P>
Adipogenic function of tetranectin mediated by enhancing mitotic clonal expansion via ERK signaling
( Seulgi Go ),( Jihyun Park ),( Safikur Rahman ),( Juno Jin ),( Inho Choi ),( Jihoe Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2021 BMB Reports Vol.54 No.7
Tetranectin (TN), an adipogenic serum protein, enhances adipocyte differentiation, however, its functional mechanism has yet to be elucidated. In the present study, we investigated the adipogenic function of TN by using medium containing TN-depleted fetal bovine serum (TN-del-FBS) and recombinant mouse TN (mTN). The adipocyte differentiation of 3T3-L1 cells was significantly enhanced by mTN supplementation essentially at differentiation induction, which indicated a potential role of the protein in the early differentiation phase. The adipogenic effect of mTN was more significant with insulin in the differentiation induction cocktail, implicating their close functional relationship. mTN enhanced not only the proliferation of growing cells, but also mitotic clonal expansion (MCE) that is a prerequisite for adipocyte differentiation in the early phase. Consistently, mTN increased the phosphorylation of ERK in the early phase of adipocyte differentiation. Results of this study demonstrate that the adipogenic function of mTN is mediated by enhancing MCE via ERK signaling. [BMB Reports 2021; 54(7): 374-379]
Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal
Jan, Arif Tasleem,Malik, Mudasir A.,Rahman, Safikur,Yeo, Hye R.,Lee, Eun J.,Abdullah, Tasduq S.,Choi, Inho Frontiers Media S.A. 2017 FRONTIERS IN AGING NEUROSCIENCE Vol.9 No.-
<P>Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB), exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in different neurodegenerative diseases, and the possibilities of using them as diagnostic biomarkers of disease progression, drug delivery vehicles and in gene therapy.</P>
Adipogenic function of mouse tetranectin and identification of its functional domain
Park, Jihyun,Ryu, Da-young,Rahman, Safikur,Kim, Jihoe Elsevier 2019 Biochemical and biophysical research communication Vol.519 No.3
<P><B>Abstract</B></P> <P>Tetranectin (TN), a plasminogen (Plg) binding protein, enhances the Plg activator (PA)-catalyzed activation of Plg to plasmin (Pln). Previously, TN was identified as an adipogenic serum protein, which promotes adipocyte differentiation. In the present study, we investigated the adipogenic function of mouse TN using recombinant proteins (rmTNs) in full-length and domain-truncated forms. Adipocyte differentiation in TN-depleted-FBS-media was significantly enhanced by rmTNs supplementation. The adipogenic effect of rmTNs was found to be dependent on the presence of a Plg binding domain, indicating the domain is essential for the adipogenic function of mTN. In addition, these results suggested the involvement of Plg activation, however Plg, PA and Pln appeared to have no direct effect on adipocyte differentiation. This study demonstrates the adipogenic function of mTN, which is dependent on the Plg binding domain as its functional domain.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Tetranectin, a serum protein, promotes adipocyte differentiation. </LI> <LI> Exogenous tetranectin supplementation enhances adipocyte differentiation. </LI> <LI> Plasminogen binding domain is essential for the adipogenic function of tetranectin. </LI> </UL> </P>
Jan, Arif Tasleem,Azam, Mudsser,Rahman, Safikur,Almigeiti, Angham M. S.,Choi, Duk Hwan,Lee, Eun Ju,Haq, Qazi Mohd Rizwanul,Choi, Inho Frontiers Media S.A. 2017 FRONTIERS IN AGING NEUROSCIENCE Vol.9 No.-
<P>Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of β-amyloid fibrils and abnormal tau proteins in and outside of neurons. Representing a common form of dementia, aggravation of AD with age increases the morbidity rate among the elderly. Although, mutations in the ApoE4 act as potent risk factors for sporadic AD, familial AD arises through malfunctioning of APP, PSEN-1, and−2 genes. AD progresses through accumulation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) in brain, which interfere with neuronal communication. Cellular stress that arises through mitochondrial dysfunction, endoplasmic reticulum malfunction, and autophagy contributes significantly to the pathogenesis of AD. With high accuracy in disease diagnostics, Aβ deposition and phosphorylated tau (p-tau) are useful core biomarkers in the cerebrospinal fluid (CSF) of AD patients. Although five drugs are approved for treatment in AD, their failures in achieving complete disease cure has shifted studies toward a series of molecules capable of acting against Aβ and p-tau. Failure of biologics or compounds to cross the blood-brain barrier (BBB) in most cases advocates development of an efficient drug delivery system. Though liposomes and polymeric nanoparticles are widely adopted for drug delivery modules, their use in delivering drugs across the BBB has been overtaken by exosomes, owing to their promising results in reducing disease progression.</P>