Publications by authors named "Ramesh Kandimalla"

63 Publications

Autoimmunity roots of the thrombotic events after COVID-19 vaccination.

Autoimmun Rev 2021 Sep 9:102941. Epub 2021 Sep 9.

Department of Molecular Medicine, University of South Florida, Tampa, FL, United States. Electronic address:

Although vaccination represents the most promising way to stop or contain the coronavirus disease 2019 (COVID-19) pandemic and safety and effectiveness of available vaccines were proven, a small number of individuals who received anti-SARS-CoV-2 vaccines developed a prothrombotic syndrome. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can be triggered by the adenoviral vector-based vaccine, whereas lipid nanoparticle-mRNA-based vaccines can induce rare cases of deep vein thrombosis (DVT). Although the main pathogenic mechanisms behind this rare phenomenon have not yet been identified, both host and vaccine factors might be involved, with pathology at least in part being related to the vaccine-triggered autoimmune reaction. In this review, we are considering some aspects related to pathogenesis, major risk factors, as well as peculiarities of diagnosis and treatment of this rare condition.
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http://dx.doi.org/10.1016/j.autrev.2021.102941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426137PMC
September 2021

COVID-19 Vaccines and Thrombosis-Roadblock or Dead-End Street?

Biomolecules 2021 07 13;11(7). Epub 2021 Jul 13.

Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA-based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines.
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http://dx.doi.org/10.3390/biom11071020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301964PMC
July 2021

Emerging COVID-19 Neurological Manifestations: Present Outlook and Potential Neurological Challenges in COVID-19 Pandemic.

Mol Neurobiol 2021 Jun 24. Epub 2021 Jun 24.

Texas Tech University Health Sciences Center, Lubbock, TX, USA.

The unremitting coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marked a year-long phase of public health adversaries and has severely compromised healthcare globally. Early evidence of COVID-19 noted its impact on the pulmonary and cardiovascular functions, while multiple studies in recent time shed light on its substantial neurological complications, though a comprehensive understanding of the cause(s), the mechanism(s), and their neuropathological outcomes is scarce. In the present review, we conferred evidence of neurological complications in COVID-19 patients and shed light on the SARS-CoV-2 infection routes including the hematogenous, direct/neuronal, lymphatic tissue or cerebrospinal fluid, or infiltration through infected immune cells, while the underlying mechanism of SARS-CoV-2 invasion to the central nervous system (CNS) was also discussed. In an up-to-date manner, we further reviewed the impact of COVID-19 in developing diverse neurologic manifestations associated with CNS, peripheral nervous system (PNS), skeletal muscle, and also pre-existing neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and myasthenia gravis. Furthermore, we discussed the involvement of key factors including age, sex, comorbidity, and disease severity in exacerbating the neurologic manifestations in COVID-19 patients. An outlook of present therapeutic strategies and state of existing challenges in COVID-19 management was also accessed. Conclusively, the present report provides a comprehensive review of COVID-19-related neurological complications and emphasizes the need for their early clinical management in the ongoing COVID-19 pandemic.
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http://dx.doi.org/10.1007/s12035-021-02450-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224263PMC
June 2021

COVID-19, Neuropathology, and Aging: SARS-CoV-2 Neurological Infection, Mechanism, and Associated Complications.

Front Aging Neurosci 2021 3;13:662786. Epub 2021 Jun 3.

Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, India.

The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) pandemic has been diverse and complex. Besides the evident pulmonary and cardiovascular threats, accumulating clinical data points to several neurological complications, which are more common in elderly COVID-19 patients. Recent pieces of evidence have marked events of neuro infection and neuroinvasion, producing several neurological complications in COVID-19 patients; however, a systematic understanding of neuro-pathophysiology and manifested neurological complications, more specifically in elderly COVID-19 patients is largely elusive. Since the elderly population gradually develops neurological disorders with aging, COVID-19 inevitably poses a higher risk of neurological manifestations to the aged patients. In this report, we reviewed SARS-CoV-2 infection and its role in neurological manifestations with an emphasis on the elderly population. We reviewed neuropathological events including neuroinfection, neuroinvasion, and their underlying mechanisms affecting neuromuscular, central- and peripheral- nervous systems. We further assessed the imminent neurological challenges in the COVID-19 exposed population, post-SARS-CoV-2-infection. Given the present state of clinical preparedness, the emerging role of AI and machine learning was also discussed concerning COVID-19 diagnostics and its management. Taken together, the present review summarizes neurological outcomes of SARS-CoV-2 infection and associated complications, specifically in elderly patients, and underlines the need for their clinical management in advance.
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http://dx.doi.org/10.3389/fnagi.2021.662786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209245PMC
June 2021

The Emerging Role of HDACs: Pathology and Therapeutic Targets in Diabetes Mellitus.

Cells 2021 May 28;10(6). Epub 2021 May 28.

Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, India.

Diabetes mellitus (DM) is one of the principal manifestations of metabolic syndrome and its prevalence with modern lifestyle is increasing incessantly. Chronic hyperglycemia can induce several vascular complications that were referred to be the major cause of morbidity and mortality in DM. Although several therapeutic targets have been identified and accessed clinically, the imminent risk of DM and its prevalence are still ascending. Substantial pieces of evidence revealed that histone deacetylase (HDAC) isoforms can regulate various molecular activities in DM via epigenetic and post-translational regulation of several transcription factors. To date, 18 HDAC isoforms have been identified in mammals that were categorized into four different classes. Classes I, II, and IV are regarded as classical HDACs, which operate through a Zn-based mechanism. In contrast, class III HDACs or Sirtuins depend on nicotinamide adenine dinucleotide (NAD) for their molecular activity. Functionally, most of the HDAC isoforms can regulate β cell fate, insulin release, insulin expression and signaling, and glucose metabolism. Moreover, the roles of HDAC members have been implicated in the regulation of oxidative stress, inflammation, apoptosis, fibrosis, and other pathological events, which substantially contribute to diabetes-related vascular dysfunctions. Therefore, HDACs could serve as the potential therapeutic target in DM towards developing novel intervention strategies. This review sheds light on the emerging role of HDACs/isoforms in diabetic pathophysiology and emphasized the scope of their targeting in DM for constituting novel interventional strategies for metabolic disorders/complications.
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http://dx.doi.org/10.3390/cells10061340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228721PMC
May 2021

A unique view of SARS-CoV-2 through the lens of ORF8 protein.

Comput Biol Med 2021 06 15;133:104380. Epub 2021 Apr 15.

Center for IPS Cell Research and Application, Kyoto University, Kyoto, 606-8397, Japan.

Immune evasion is one of the unique characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attributed to its ORF8 protein. This protein modulates the adaptive host immunity through down-regulation of MHC-1 (Major Histocompatibility Complex) molecules and innate immune responses by surpassing the host's interferon-mediated antiviral response. To understand the host's immune perspective in reference to the ORF8 protein, a comprehensive study of the ORF8 protein and mutations possessed by it have been performed. Chemical and structural properties of ORF8 proteins from different hosts, such as human, bat, and pangolin, suggest that the ORF8 of SARS-CoV-2 is much closer to ORF8 of Bat RaTG13-CoV than to that of Pangolin-CoV. Eighty-seven mutations across unique variants of ORF8 in SARS-CoV-2 can be grouped into four classes based on their predicted effects (Hussain et al., 2021) [1]. Based on the geo-locations and timescale of sample collection, a possible flow of mutations was built. Furthermore, conclusive flows of amalgamation of mutations were found upon sequence similarity analyses and consideration of the amino acid conservation phylogenies. Therefore, this study seeks to highlight the uniqueness of the rapidly evolving SARS-CoV-2 through the ORF8.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049180PMC
June 2021

Notable sequence homology of the ORF10 protein introspects the architecture of SARS-CoV-2.

Int J Biol Macromol 2021 Jun 16;181:801-809. Epub 2021 Apr 16.

University of Pittsburgh School of Medicine, Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address:

The current Coronavirus Disease 19 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) shows similar pathology to MERS and SARS-CoV, with a current estimated fatality rate of 1.4%. Open reading frame 10 (ORF10) is a unique SARS-CoV-2 accessory protein, which contains eleven cytotoxic T lymphocyte (CTL) epitopes each of nine amino acids in length. Twenty-two unique SARS-CoV-2 ORF10 variants have been identified based on missense mutations found in sequence databases. Some of these mutations are predicted to decrease the stability of ORF10 in silico physicochemical and structural comparative analyses were carried out on SARS-CoV-2 and Pangolin-CoV ORF10 proteins, which share 97.37% amino acid (aa) homology. Though there is a high degree of ORF10 protein similarity of SARS-CoV-2 and Pangolin-CoV, there are differences of these two ORF10 proteins related to their sub-structure (loop/coil region), solubility, antigenicity and shift from strand to coil at aa position 26 (tyrosine). SARS-CoV-2 ORF10, which is apparently expressed in vivo since reactive T cell clones are found in convalescent patients should be monitored for changes which could correlate with the pathogenesis of COVID-19.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.03.199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051021PMC
June 2021

Autophagy in the diabetic heart: A potential pharmacotherapeutic target in diabetic cardiomyopathy.

Ageing Res Rev 2021 07 7;68:101338. Epub 2021 Apr 7.

Department of Biochemistry, Kakatiya Medical College, Warangal, 506007, Telangana, India; Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad, 50000, Telangana, India. Electronic address:

Association of diabetes with an elevated risk of cardiac failure has been clinically evident. Diabetes potentiates diastolic and systolic cardiac failure following the myocardial infarction that produces the cardiac muscle-specific microvascular complication, clinically termed as diabetic cardiomyopathy. Elevated susceptibility of diabetic cardiomyopathy is primarily caused by the generation of free radicals in the hyperglycemic milieu, compromising the myocardial contractility and normal cardiac functions with increasing redox insult, impaired mitochondria, damaged organelles, apoptosis, and cardiomyocytes fibrosis. Autophagy is essentially involved in the recycling/clearing the damaged organelles, cytoplasmic contents, and aggregates, which are frequently produced in cardiomyocytes. Although autophagy plays a vital role in maintaining the cellular homeostasis in diligent cardiac tissues, this process is frequently impaired in the diabetic heart. Given its clinical significance, accumulating evidence largely showed the functional aspects of autophagy in diabetic cardiomyopathy, elucidating its intricate protective and pathogenic outcomes. However, etiology and molecular readouts of these contrary autophagy activities in diabetic cardiomyopathy are not yet comprehensively assessed and translated. In this review, we attempted to assess the role of autophagy and its adaptations in the diabetic heart. To delineate the molecular consequences of these events, we provided detailed insights into the autophagy regulation pieces of machinery including the mTOR/AMPK, TFEB/ZNSCAN3, FOXOs, SIRTs, PINK1/Parkin, Nrf2, miRNAs, and others in the diabetic cardiomyopathy. Given the clinical significance of autophagy in the diabetic heart, we further discussed the potential pharmacotherapeutic strategies towards targeting autophagy. Taken together, the present report meticulously assessed autophagy, its adaptations, and molecular regulations in diabetic cardiomyopathy and reviewed the current autophagy-targeting strategies.
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http://dx.doi.org/10.1016/j.arr.2021.101338DOI Listing
July 2021

Carbon-Based Nanomaterials: Promising Antiviral Agents to Combat COVID-19 in the Microbial-Resistant Era.

ACS Nano 2021 05 7;15(5):8069-8086. Epub 2021 Apr 7.

University of Pittsburgh School of Medicine, Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania 15232, United States.

Therapeutic options for the highly pathogenic human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic coronavirus disease (COVID-19) are urgently needed. COVID-19 is associated with viral pneumonia and acute respiratory distress syndrome causing significant morbidity and mortality. The proposed treatments for COVID-19 have shown little or no effect in the clinic so far. Additionally, bacterial and fungal pathogens contribute to the SARS-CoV-2-mediated pneumonia disease complex. The antibiotic resistance in pneumonia treatment is increasing at an alarming rate. Therefore, carbon-based nanomaterials (CBNs), such as fullerene, carbon dots, graphene, and their derivatives constitute a promising alternative due to their wide-spectrum antimicrobial activity, biocompatibility, biodegradability, and capacity to induce tissue regeneration. Furthermore, the antimicrobial mode of action is mainly physical (, membrane distortion), characterized by a low risk of antimicrobial resistance. In this Review, we evaluated the literature on the antiviral activity and broad-spectrum antimicrobial properties of CBNs. CBNs had antiviral activity against 13 enveloped positive-sense single-stranded RNA viruses, including SARS-CoV-2. CBNs with low or no toxicity to humans are promising therapeutics against the COVID-19 pneumonia complex with other viruses, bacteria, and fungi, including those that are multidrug-resistant.
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http://dx.doi.org/10.1021/acsnano.1c00629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043205PMC
May 2021

Urgent Need for Field Surveys of Coronaviruses in Southeast Asia to Understand the SARS-CoV-2 Phylogeny and Risk Assessment for Future Outbreaks.

Biomolecules 2021 03 9;11(3). Epub 2021 Mar 9.

UPMC Hillman Cancer Center, Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Phylogenetic analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is focused on a single isolate of bat coronaviruses (bat CoVs) which does not adequately represent genetically related coronaviruses (CoVs) [...].
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http://dx.doi.org/10.3390/biom11030398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999587PMC
March 2021

Protective effects of a mitochondria-targeted small peptide SS31 against hyperglycemia-induced mitochondrial abnormalities in the liver tissues of diabetic mice, Tallyho/JngJ mice.

Mitochondrion 2021 05 25;58:49-58. Epub 2021 Feb 25.

Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States; Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States; Cell Biology & Biochemistry Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States; Pharmacology & Neuroscience Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States; Neurology Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States; Speech, Language and Hearing Sciences Departments, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States. Electronic address:

Type 2 Diabetes mellitus (T2DM) has become a major public health issue associated with a high risk of late-onset Alzheimer's disease (LOAD). Mitochondrial dysfunction is one of the molecular events that occur in the LOAD pathophysiology. The present study was planned to investigate the molecular alterations induced by hyperglycemia in the mitochondria of diabetic mice and further explore the possible ameliorative role of the mitochondria-targeted small peptide, SS31 in diabetic mice. For this purpose, we used a polygenic mouse model of type 2 diabetes, TALLYHO/JngJ (TH), and nondiabetic, SWR/J mice strains. The diabetic status in TH mice was confirmed at 8 weeks of age. The 24 weeks old experimental animals were segregated into three groups: Non-diabetic controls (SWR/J mice), diabetic (TH mice) and, SS31 treated diabetic TH mice. The mRNA and protein expression levels of mitochondrial proteins were investigated in all the study groups in the liver tissues using qPCR and immunoblot analysis. Also, the mitochondrial functions including H2O2 production, ATP generation, and lipid peroxidation were assessed in all the groups. Mitochondrial dysfunction was observed in TH mice as evident by significantly elevated H2O2 production, lipid peroxidation, and reduced ATP production. The mRNA expression and Western blot analysis of mitochondrial dynamics (Drp1 and Fis1 - fission; Mfn1, Mfn2, and Opa1 -fusion), and biogenesis (PGC-1α, Nrf1, Nrf2, and TFAM) genes were significantly altered in diabetic TH mice. Furthermore, SS31 treatment significantly reduced the mitochondrial abnormalities and restore mitochondrial functions in diabetic TH mice.
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http://dx.doi.org/10.1016/j.mito.2021.02.007DOI Listing
May 2021

Engaging the spikes: heparan sulfate facilitates SARS-CoV-2 spike protein binding to ACE2 and potentiates viral infection.

Signal Transduct Target Ther 2021 01 29;6(1):39. Epub 2021 Jan 29.

Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad, Telangana State, India.

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http://dx.doi.org/10.1038/s41392-021-00470-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844799PMC
January 2021

Mitochondrial dysfunction, mitophagy, and role of dynamin-related protein 1 in Alzheimer's disease.

J Neurosci Res 2021 04 19;99(4):1120-1135. Epub 2021 Jan 19.

Department of Physics, National Institute of Technology-Warangal, Warangal, India.

Alzheimer's disease (AD) is the most common type of dementia and progressive neurodegenerative disease. The presence of β-amyloid (Aβ) plaques and phosphorylated Tau tangles are considered to be the two main hallmarks of AD. Recent findings have shown that different changes in the structure and dynamics of mitochondria play an important role in AD pathology progression. Mitochondrial changes in AD are expressed as enhanced mitochondrial fragmentation, altered mitochondrial dynamics, and changes in the expression of mitochondrial biogenesis genes in vitro and in vivo models. Therefore, targeting mitochondria and associated mitochondrial proteins seems to be a promising alternative instead of targeting Aβ and Tau in the prevention of Alzheimer's disease. The dynamin-related protein (Drp1) is one such protein that plays an important role in the regulation of mitochondrial division and maintenance of mitochondrial structures. Few researchers have shown that inhibition of Drp1 GTPase activity in neuronal cells rescues excessive mitochondrial fragmentation. In addition, the growing evidence revealed that Drp1 can interact with both Aβ and Tau protein in human brain tissues and mouse models. In this review, we would like to update existing knowledge about various changes in and around mitochondria related to the pathogenesis of Alzheimer's disease, with particular emphasis on mitophagy and autophagy.
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http://dx.doi.org/10.1002/jnr.24781DOI Listing
April 2021

Possible Transmission Flow of SARS-CoV-2 Based on ACE2 Features.

Molecules 2020 Dec 13;25(24). Epub 2020 Dec 13.

Division of Hematology/Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22-42, aa 79-84, and aa 330-393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.
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http://dx.doi.org/10.3390/molecules25245906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763092PMC
December 2020

The structural basis of accelerated host cell entry by SARS-CoV-2†.

FEBS J 2021 09 14;288(17):5010-5020. Epub 2020 Dec 14.

Department of Physiology, Michigan State University, East Lansing, MI, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19) that exhibits an overwhelming contagious capacity over other human coronaviruses (HCoVs). This structural snapshot describes the structural bases underlying the pandemic capacity of SARS-CoV-2 and explains its fast motion over respiratory epithelia that allow its rapid cellular entry. Based on notable viral spike (S) protein features, we propose that the flat sialic acid-binding domain at the N-terminal domain (NTD) of the S1 subunit leads to more effective first contact and interaction with the sialic acid layer over the epithelium, and this, in turn, allows faster viral 'surfing' of the epithelium and receptor scanning by SARS-CoV-2. Angiotensin-converting enzyme 2 (ACE-2) protein on the epithelial surface is the primary entry receptor for SARS-CoV-2, and protein-protein interaction assays demonstrate high-affinity binding of the spike protein (S protein) to ACE-2. To date, no high-frequency mutations were detected at the C-terminal domain of the S1 subunit in the S protein, where the receptor-binding domain (RBD) is located. Tight binding to ACE-2 by a conserved viral RBD suggests the ACE2-RBD interaction is likely optimal. Moreover, the viral S subunit contains a cleavage site for furin and other proteases, which accelerates cell entry by SARS-CoV-2. The model proposed here describes a structural basis for the accelerated host cell entry by SARS-CoV-2 relative to other HCoVs and also discusses emerging hypotheses that are likely to contribute to the development of antiviral strategies to combat the pandemic capacity of SARS-CoV-2.
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http://dx.doi.org/10.1111/febs.15651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753708PMC
September 2021

Viewpoint: Origin of SARS-CoV-2.

Viruses 2020 10 22;12(11). Epub 2020 Oct 22.

UPMC Hillman Cancer Center, Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

The origin of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) virus causing the COVID-19 pandemic has not yet been fully determined. Despite the consensus about the SARS-CoV-2 origin from bat CoV RaTG13, discrepancy to host tropism to other human Coronaviruses exist. SARS-CoV-2 also possesses some differences in its S protein receptor-binding domain, glycan-binding N-terminal domain and the surface of the sialic acid-binding domain. Despite similarities based on cryo-EM and biochemical studies, the SARS-CoV-2 shows higher stability and binding affinity to the ACE2 receptor. The SARS-CoV-2 does not appear to present a mutational "hot spot" as only the D614G mutation has been identified from clinical isolates. As laboratory manipulation is highly unlikely for the origin of SARS-CoV-2, the current possibilities comprise either natural selection in animal host before zoonotic transfer or natural selection in humans following zoonotic transfer. In the former case, despite SARS-CoV-2 and bat RaTG13 showing 96% identity some pangolin Coronaviruses exhibit very high similarity to particularly the receptor-binding domain of SARS-CoV-2. In the latter case, it can be hypothesized that the SARS-CoV-2 genome has adapted during human-to-human transmission and based on available data, the isolated SARS-CoV-2 genomes derive from a common origin. Before the origin of SARS-CoV-2 can be confirmed additional research is required.
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http://dx.doi.org/10.3390/v12111203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690418PMC
October 2020

Mitochondria-Targeted Small Peptide, SS31 Ameliorates Diabetes Induced Mitochondrial Dynamics in Male TallyHO/JngJ Mice.

Mol Neurobiol 2021 Feb 7;58(2):795-808. Epub 2020 Oct 7.

Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX, 79430, USA.

The escalating burden of type 2 diabetes (T2D) and its related complications has become a major public health challenge worldwide. Substantial evidence indicates that T2D is one of the culprits for the high prevalence of Alzheimer's disease (AD) in diabetic subjects. This study aimed to investigate the possible mitochondrial alterations in the pancreas induced by hyperglycemia in diabetes. We used a diabetic TallyHO/JngJ (TH) and non-diabetic, SWR/J mice strains. The diabetic and non-diabetic status in animals was assessed by performing intraperitoneal glucose tolerance test at four time points, i.e., 4, 8, 16, and 24 weeks of age. We divided 24-week-old TH and SWR/J mice into 3 groups: controls, diabetic TH mice, and diabetic TH mice treated with SS31 peptide. After the treatment of male TH mice with SS31, intraperitoneally, for 4 weeks, we studied mitochondrial dynamics, biogenesis, and function. The mRNA and protein expression levels of mitochondrial proteins were evaluated using qPCR and immunoblot analysis. The diabetic mice after 24 weeks of age showed overt pancreatic injury as demonstrated by disintegration and atrophy of β cells with vacuolization and reduced islet size. Mitochondrial dysfunction was observed in TH mice, as evidenced by significantly elevated HO production, lipid peroxidation, and reduced ATP production. Furthermore, mRNA expression and immunoblot analysis of mitochondrial dynamics genes were significantly affected in diabetic mice, compared with controls. However, treatment of animals with SS31 reduced mitochondrial dysfunction and restored most of the mitochondrial functions and mitochondrial dynamics processes to near normal in TH mice. In conclusion, mitochondrial dysfunction is established as one of the molecular events that occur in the pathophysiology of T2D. Further, SS31 treatment may confer protection against the mitochondrial alterations induced by hyperglycemia in diabetic TallyHO/JngJ mice.
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http://dx.doi.org/10.1007/s12035-020-02142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856017PMC
February 2021

Screening of potential drug for Alzheimer's disease: a computational study with GSK-3 β inhibition through virtual screening, docking, and molecular dynamics simulation.

J Biomol Struct Dyn 2020 Aug 11:1-15. Epub 2020 Aug 11.

Department of Biotechnology, School of Bio and Chemical Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, India.

The global impact of Alzheimer's disease (AD) necessitates intensive research to find appropriate and effective drugs. Many studies in AD suggested beta-amyloid plaques and neurofibrillary tangles-associated tau protein as the key targets for drug development. On the other hand, it is proved that triggering of Glycogen Synthase Kinase-3β (GSK-3β) also cause AD, therefore, GSK-3β is a potential drug target to combat AD. We, in this study, investigated the ability of small molecules to inhibit GSK-3β through virtual screening, Absorption, Distribution, Metabolism, and Excretion (ADME), induced-fit docking (IFD), molecular dynamics simulation, and binding free energy calculation. Besides, molecular docking was performed to reveal the binding and interaction of the ligand at the active site of GSK-3β. We found two compounds such as 6961 and 6966, which exhibited steady-state interaction with GSK-3β for 30 ns in molecular dynamics simulation. The compounds (6961 and 6966) also achieved a docking score of -9.05 kcal/mol and -8.11 kcal/mol, respectively, which is relatively higher than the GSK-3β II inhibitor (-6.73 kcal/mol). The molecular dynamics simulation revealed that the compounds have a stable state during overall simulation time, and lesser root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) values compared with co-crystal. In conclusion, we suggest the two compounds (6966 and 6961) as potential leads that could be utilized as effective inhibitors of GSK-3β to combat AD.
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http://dx.doi.org/10.1080/07391102.2020.1805362DOI Listing
August 2020

Current Status of Multiple Drug Molecules, and Vaccines: An Update in SARS-CoV-2 Therapeutics.

Mol Neurobiol 2020 Oct 15;57(10):4106-4116. Epub 2020 Jul 15.

Internal Medicine, Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.

The coronavirus disease of 2019 (COVID-19) is a pandemic disease that has taken the lives of many around the world. It is caused by severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). To date, the USA, Italy, Spain, France, Russia, and the UK have been hit the hardest by the virus. However, death counts are still rising. Some nations have managed to "flatten" the death rate via protective measures such physical distancing, quarantine measures, and therapeutic management. The structure of the SARS-CoV-2 virus comprises of S proteins, M proteins, E proteins, hemagglutinin esterases, nucleocapsid proteins, and a 30-kb RNA genome. Viral proteases cleave these polyproteins and RNA-dependent polymerases replicate the genome. Currently, there are no effective therapies against this new disease. Numerous investigators are developing novel protease inhibitors, some of which have made it into clinical trials. Researchers are also attempting to develop a vaccine. In this review paper, we discuss the latest therapeutic developments against COVID-19. Graphical Abstract.
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http://dx.doi.org/10.1007/s12035-020-02022-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360695PMC
October 2020

SARS-CoV-2, ACE2, and Hydroxychloroquine: Cardiovascular Complications, Therapeutics, and Clinical Readouts in the Current Settings.

Pathogens 2020 Jul 7;9(7). Epub 2020 Jul 7.

Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India.

The rapidly evolving coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome coronavirus 2- SARS-CoV-2), has greatly burdened the global healthcare system and led it into crisis in several countries. Lack of targeted therapeutics led to the idea of repurposing broad-spectrum drugs for viral intervention. In vitro analyses of hydroxychloroquine (HCQ)'s anecdotal benefits prompted its widespread clinical repurposing globally. Reports of emerging cardiovascular complications due to its clinical prescription are revealing the crucial role of angiotensin-converting enzyme 2 (ACE2), which serves as a target receptor for SARS-CoV-2. In the present settings, a clear understanding of these targets, their functional aspects and physiological impact on cardiovascular function are critical. In an up-to-date format, we shed light on HCQ's anecdotal function in stalling SARS-CoV-2 replication and immunomodulatory activities. While starting with the crucial role of ACE2, we here discuss the impact of HCQ on systemic cardiovascular function, its associated risks, and the scope of HCQ-based regimes in current clinical settings. Citing the extent of HCQ efficacy, the key considerations and recommendations for the use of HCQ in clinics are further discussed. Taken together, this review provides crucial insights into the role of ACE2 in SARS-CoV-2-led cardiovascular activity, and concurrently assesses the efficacy of HCQ in contemporary clinical settings.
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http://dx.doi.org/10.3390/pathogens9070546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400328PMC
July 2020

SARS-CoV-2 pathophysiology and assessment of coronaviruses in CNS diseases with a focus on therapeutic targets.

Biochim Biophys Acta Mol Basis Dis 2020 10 27;1866(10):165889. Epub 2020 Jun 27.

Department of Biochemistry, Kakatiya Medical College, Warangal 506007, Telangana, India; Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India. Electronic address:

The novel Coronavirus disease of 2019 (nCOV-19) is a viral outbreak noted first in Wuhan, China. This disease is caused by Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2. In the past, other members of the coronavirus family, such as SARS and Middle East Respiratory Syndrome (MERS), have made an impact in China and the Arabian peninsula respectively. Both SARS and COVID-19 share similar symptoms such as fever, cough, and difficulty in breathing that can become fatal in later stages. However, SARS and MERS infections were epidemic diseases constrained to limited regions. By March 2020 the SARS-CoV-2 had spread across the globe and on March 11th, 2020 the World Health Organization (WHO) declared COVID-19 as pandemic disease. In severe SARS-CoV-2 infection, many patients succumbed to pneumonia. Higher rates of deaths were seen in older patients who had co-morbidities such as diabetes mellitus, hypertension, cardiovascular disease (CVD), and dementia. In this review paper, we discuss the effect of SARS-CoV-2 on CNS diseases, such as Alzheimer's-like dementia, and diabetes mellitus. We also focus on the virus genome, pathophysiology, theranostics, and autophagy mechanisms. We will assess the multiorgan failure reported in advanced stages of SARS-CoV-2 infection. Our paper will provide mechanistic clues and therapeutic targets for physicians and investigators to combat COVID-19.
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http://dx.doi.org/10.1016/j.bbadis.2020.165889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320676PMC
October 2020

Vitamins (A&D) and Isoprenoid (Chenodeoxycholic acid) molecules are accompanied by Th1 immunostimulatory response and therapeutic cure in vivo: possible antileishmanial drugs.

Sci Rep 2019 06 12;9(1):8531. Epub 2019 Jun 12.

Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, 160012, Chandigarh, India.

Investigation of immune modulatory anti-leishmanial molecules is now being strongly encouraged to overcome the immunosuppression manifested during visceral leishmaniasis (VL), resistance, toxicity and high cost associated with conventional therapeutics. In the present study, we explored the protective efficacy of vitamin D, retinoic acid and isoprenoid chenodeoxycholic acid (CDCA) combinations against L. donovani infected BALB/c mice. We also probed the immune modulatory response (Th1 & Th2 cytokines) and infection dynamics following experimental infections with drug treated animals. Our results indicate that Vit.D/RA and CDCA/RA combination treatment led to significant inhibition of parasite load on days 21 and 28 post treatment. Furthermore, there was a marked inhibition of Th2 type immune responses in IL-4, IL-5 and polarization of Th1 biased immunity along with upregulation of IL-1, IFN-γ, and TNF-α levels on day 28 post treatment. In addition, mice treated with Vit.D/RA and CDCA/RA demonstrates here that splenic histological recovery against the virulent challenge of L. donovani by day 28 was comparable to control group. The conclusions derived from this study suggests that a combination of vitamin A, D and isoprenoids may have a potential immunomodulatory therapeutic role against leishmaniasis.
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http://dx.doi.org/10.1038/s41598-019-44630-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562038PMC
June 2019

Current Status of Healthy Aging and Dementia Research: A Symposium Summary.

J Alzheimers Dis 2019 ;72(s1):S11-S35

Garrison Institute on Aging, Texas Tech University Health Science Center, Lubbock, TX, USA.

The purpose of the 'First Regional Healthy Aging and Dementia Research Symposium' was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24-25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion.
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http://dx.doi.org/10.3233/JAD-190252DOI Listing
November 2020

Liquid Crystals: A Novel Approach for Cancer Detection and Treatment.

Cancers (Basel) 2018 Nov 21;10(11). Epub 2018 Nov 21.

Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA.

Liquid crystals are defined as the fourth state of matter forming between solid and liquid states. Earlier the applications of liquid crystals were confined to electronic instruments, but recent research findings suggest multiple applications of liquid crystals in biology and medicine. Here, the purpose of this review article is to discuss the potential biological impacts of liquid crystals in the diagnosis and prognosis of cancer along with the risk assessment. In this review, we also discussed the recent advances of liquid crystals in cancer biomarker detection and treatment in multiple cell line models. Cases reviewed here will demonstrate that cancer diagnostics based on the multidisciplinary technology and intriguingly utilization of liquid crystals may become an alternative to regular cancer detection methodologies. Additionally, we discussed the formidable challenges and problems in applying liquid crystal technologies. Solving these problems will require great effort and the way forward is through the multidisciplinary collaboration of physicists, biologists, chemists, material-scientists, clinicians, and engineers. The triumphant outcome of these liquid crystals and their applications in cancer research would be convenient testing for the detection of cancer and may result in treating the cancer patients non-invasively.
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http://dx.doi.org/10.3390/cancers10110462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267481PMC
November 2018

Corrigendum: Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity.

Hum Mol Genet 2019 Mar;28(5):875-876

Garrison Institute on Aging, Texas Tech University Health Sciences Center, MS, Lubbock, TX, USA.

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http://dx.doi.org/10.1093/hmg/ddy399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381310PMC
March 2019

Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity.

Hum Mol Genet 2019 01;28(2):177-199

Garrison Institute on Aging, Texas Tech University Health Sciences Center, MS, Lubbock, TX, USA.

The purpose of our study was to better understand the effects of mitochondrial-division inhibitor 1 (Mdivi-1) on mitochondrial fission, mitochondrial biogenesis, electron transport activities and cellular protection. In recent years, researchers have found excessive mitochondrial fragmentation and reduced fusion in a large number of diseases with mitochondrial dysfunction. Therefore, several groups have developed mitochondrial division inhibitors. Among these, Mdivi-1 was extensively studied and was found to reduce dynamin-related protein 1 (Drp1) levels and excessive mitochondrial fission, enhance mitochondrial fusion activity and protect cells. However, a recent study by Bordt et al. (1) questioned earlier findings of the beneficial, inhibiting effects of Mdivi-1. In the current study, we studied the protective effects of Mdivi-1 by studying the following: mRNA and protein levels of electron transport chain (ETC) genes; mitochondrial dynamics and biogenesis genes; enzymatic activities of ETC complexes I, II, III and IV; the mitochondrial network; mitochondrial size & number; Drp1 GTPase enzymatic activity and mitochondrial respiration (1) in N2a cells treated with Mdivi-1, (2) overexpressed with full-length Drp1 + Mdivi-1-treated N2a cells and (3) Drp1 RNA silenced+Mdivi-1-treated N2a cells. We found reduced levels of the fission genes Drp1 and Fis1 levels; increased levels of the fusion genes Mfn1, Mfn2 and Opa1; and the biogenesis genes PGC1α, nuclear respiration factor 1, nuclear respiratory factor 2 and transcription factor A, mitochondrial. Increased levels mRNA and protein levels were found in ETC genes of complexes I, II and IV genes. Immunoblotting data agreed with mRNA changes. Transmission electron microscopy analysis revealed reduced numbers of mitochondria and increased length of mitochondria (1) in N2a cells treated with Mdivi-1, (2) cells overexpressed with full-length Drp1 + Mdivi-1-treated N2a cells and (3) Drp1 RNA silenced+Mdivi-1-treated N2a cells. Immunofluorescence analysis revealed that mitochondrial network was increased. Increased levels of complex I, II and IV enzymatic activities were found in all three groups of cells treated with low concentration of Mdivi-1. Mitochondrial function was increased and GTPase Drp1 activity was decreased in all three groups of N2a cells. These observations strongly suggest that Mdivi-1 is a Drp1 inhibitor and directly reduces mitochondrial fragmentation and further, Mdivi-1 is a promising molecule to treat human diseases with ETC complexes, I, II and IV.
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http://dx.doi.org/10.1093/hmg/ddy335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322070PMC
January 2019

Conformational transition pathway of R308K mutant glucokinase in the presence of the glucokinase activator YNKGKA4.

FEBS Open Bio 2018 Aug 6;8(8):1202-1208. Epub 2018 Jul 6.

Garrison Institute on Aging Texas Tech University of Health Science Centre Lubbock TX USA.

Glucokinase (GK) plays a vital role in the control of blood glucose levels and its altered activity can lead to the development of forms of diabetes. We have previously identified a mutant GK (R308K) in patients with type 2 diabetes with reduced enzyme activity. In the present study, the activation mechanism of GK from super-open to the closed state under wild-type and mutant conditions in the presence of the novel aminophosphonate derivative YNKGKA4 (an allosteric activator of GK) was characterized via a series of molecular dynamics simulations. A reliable conformational transition pathway of GK was observed from super-open to closed state during trajectory analysis. Glucose was also observed to modulate its binding orientation in the active site but with stable moments in the cavity. These observations provide insights into the complicated conformational transitions in the presence of YNKGKA4 and the molecular mechanism of GK activators for the allosteric regulation of mutant forms of GK.
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http://dx.doi.org/10.1002/2211-5463.12255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070654PMC
August 2018

Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease.

Alzheimers Dement 2018 07 28;14(7):913-924. Epub 2018 Mar 28.

Department of Nuclear Medicine, Technische Universitaet München, Munich, Germany.

Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location.

Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.

Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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http://dx.doi.org/10.1016/j.jalz.2018.02.009DOI Listing
July 2018
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