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  1. Article ; Online: Computational benchmarking of putative KIFC1 inhibitors.

    Sharma, Nivya / Setiawan, Dani / Hamelberg, Donald / Narayan, Rishikesh / Aneja, Ritu

    Medicinal research reviews

    2022  Volume 43, Issue 2, Page(s) 293–318

    Abstract: The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and ... ...

    Abstract The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and numerical abnormalities in the centrosome can cause chromosomal instability and dysregulation of the cell cycle, leading to cancer development and metastasis. However, disturbances caused by centrosome amplification can also limit cancer cell survival by activating mitotic checkpoints and promoting mitotic catastrophe. As a smart escape, cancer cells cluster their surplus of centrosomes into pseudo-bipolar spindles and progress through the cell cycle. This phenomenon, known as centrosome clustering (CC), involves many proteins and has garnered considerable attention as a specific cancer cell-targeting weapon. The kinesin-14 motor protein KIFC1 is a minus end-directed motor protein that is involved in CC. Because KIFC1 is upregulated in various cancers and modulates oncogenic signaling cascades, it has emerged as a potential chemotherapeutic target. Many molecules have been identified as KIFC1 inhibitors because of their centrosome declustering activity in cancer cells. Despite the ever-increasing literature in this field, there have been few efforts to review the progress. The current review aims to collate and present an in-depth analysis of known KIFC1 inhibitors and their biological activities. Additionally, we present computational docking data of putative KIFC1 inhibitors with their binding sites and binding affinities. This first-of-kind comparative analysis involving experimental biology, chemistry, and computational docking of different KIFC1 inhibitors may help guide decision-making in the selection and design of potent inhibitors.
    MeSH term(s) Animals ; Benchmarking ; Neoplasms/pathology ; Centrosome/metabolism ; Binding Sites ; Microtubules
    Language English
    Publishing date 2022-09-14
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 603210-2
    ISSN 1098-1128 ; 0198-6325
    ISSN (online) 1098-1128
    ISSN 0198-6325
    DOI 10.1002/med.21926
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Chitosan derivatives: A suggestive evaluation for novel inhibitor discovery against wild type and variants of SARS-CoV-2 virus.

    Modak, Chandrima / Jha, Anubhuti / Sharma, Nivya / Kumar, Awanish

    International journal of biological macromolecules

    2021  Volume 187, Page(s) 492–512

    Abstract: With increasing global cases and mortality rates due to COVID-19 infection, finding effective therapeutic interventions has become a top priority. Marine resources are not explored much and to be taken into consideration for exploring antiviral potential. ...

    Abstract With increasing global cases and mortality rates due to COVID-19 infection, finding effective therapeutic interventions has become a top priority. Marine resources are not explored much and to be taken into consideration for exploring antiviral potential. Chitosan (carbohydrate polymer) is one such bioactive glycan found ubiquitously in marine organisms. The presence of reactive amine/hydroxyl groups, with low toxicity/allergenicity, compels us to explore it against SARS-CoV-2. We have screened a library of chitosan derivatives by site-specific docking at not only spike protein Receptor Binding Domain (RBD) of wild type SARS-CoV-2 but also on RBD of B.1.1.7 (UK) and P.1 (Brazil) SARS-CoV-2 variants. The obtained result was very interesting and ranks N-benzyl-O-acetyl-chitosan, Imino-chitosan, Sulfated-chitosan oligosaccharides derivatives as a potent antiviral candidate due to its high binding affinity of the ligands (-6.0 to -6.6 kcal/mol) with SARS-CoV-2 spike protein RBD and they critically interacting with amino acid residues Tyr 449, Asn 501, Tyr 501, Gln 493, Gln 498 and some other site-specific residues associated with higher transmissibility and severe infection. Further ADMET analysis was done and found significant for exploration of the future therapeutic potential of these three ligands. The obtained results are highly encouraging in support for consideration and exploration in further clinical studies of these chitosan derivatives as anti-SARS-CoV-2 therapeutics.
    MeSH term(s) Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Binding Sites ; Brazil ; Chitosan/chemistry ; Chitosan/pharmacology ; Genetic Variation ; Models, Molecular ; Molecular Docking Simulation ; Protein Binding ; Protein Conformation/drug effects ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; United Kingdom ; Virus Internalization/drug effects
    Chemical Substances Antiviral Agents ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Chitosan (9012-76-4)
    Language English
    Publishing date 2021-07-27
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2021.07.144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Chitosan derivatives: A suggestive evaluation for novel inhibitor discovery against wild type and variants of SARS-CoV-2 virus

    Modak, Chandrima / Jha, Anubhuti / Sharma, Nivya / Kumar, Awanish

    International journal of biological macromolecules. 2021 Sept. 30, v. 187

    2021  

    Abstract: With increasing global cases and mortality rates due to COVID-19 infection, finding effective therapeutic interventions has become a top priority. Marine resources are not explored much and to be taken into consideration for exploring antiviral potential. ...

    Abstract With increasing global cases and mortality rates due to COVID-19 infection, finding effective therapeutic interventions has become a top priority. Marine resources are not explored much and to be taken into consideration for exploring antiviral potential. Chitosan (carbohydrate polymer) is one such bioactive glycan found ubiquitously in marine organisms. The presence of reactive amine/hydroxyl groups, with low toxicity/allergenicity, compels us to explore it against SARS-CoV-2. We have screened a library of chitosan derivatives by site-specific docking at not only spike protein Receptor Binding Domain (RBD) of wild type SARS-CoV-2 but also on RBD of B.1.1.7 (UK) and P.1 (Brazil) SARS-CoV-2 variants. The obtained result was very interesting and ranks N-benzyl-O-acetyl-chitosan, Imino-chitosan, Sulfated-chitosan oligosaccharides derivatives as a potent antiviral candidate due to its high binding affinity of the ligands (-6.0 to -6.6 kcal/mol) with SARS-CoV-2 spike protein RBD and they critically interacting with amino acid residues Tyr 449, Asn 501, Tyr 501, Gln 493, Gln 498 and some other site-specific residues associated with higher transmissibility and severe infection. Further ADMET analysis was done and found significant for exploration of the future therapeutic potential of these three ligands. The obtained results are highly encouraging in support for consideration and exploration in further clinical studies of these chitosan derivatives as anti-SARS-CoV-2 therapeutics.
    Keywords COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; allergenicity ; amino acids ; chitosan ; ligands ; mortality ; oligosaccharides ; polymers ; therapeutics ; toxicity ; viruses ; Brazil
    Language English
    Dates of publication 2021-0930
    Size p. 492-512.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2021.07.144
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Underscoring the immense potential of chitosan in fighting a wide spectrum of viruses: A plausible molecule against SARS-CoV-2?

    Sharma, Nivya / Modak, Chandrima / Singh, Pankaj Kumar / Kumar, Rahul / Khatri, Dharmender / Singh, Shashi Bala

    International journal of biological macromolecules

    2021  Volume 179, Page(s) 33–44

    Abstract: Chitosan is a deacetylated polycationic polysaccharide derived from chitin. It is structurally constituted of N-acetyl-D-glucosamine and β-(1-4)-linked D-glucosamine where acetyl groups are randomly distributed across the polymer. The parameters of ... ...

    Abstract Chitosan is a deacetylated polycationic polysaccharide derived from chitin. It is structurally constituted of N-acetyl-D-glucosamine and β-(1-4)-linked D-glucosamine where acetyl groups are randomly distributed across the polymer. The parameters of deacetylation and depolymerization process greatly influence various physico-chemical properties of chitosan and thus, offer a great degree of manipulation to synthesize chitosan of interest for various industrial and biomedical applications. Chitosan and its various derivatives have been a potential molecule of investigation in the area of anti-microbials especially anti-fungal, anti-bacterial and antiviral. The current review predominantly highlights and discusses about the antiviral activities of chitosan and its various substituted derivatives against a wide spectrum of human, animal, plants and bacteriophage viruses. The extrinsic and intrinsic factors that affect antiviral efficacy of chitosan have also been talked about. With the rapid unfolding of COVID-19 pandemic across the globe, we look for chitosan as a plausible potent antiviral molecule for fighting this disease. Through this review, we present enough literature data supporting role of chitosan against different strains of SARS viruses and also chitosan targeting CD147 receptors, a novel route for invasion of SARS-CoV-2 into host cells. We speculate the possibility of using chitosan as potential molecule against SARS-CoV-2 virus.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; COVID-19/drug therapy ; COVID-19/virology ; Chitin/chemistry ; Chitin/pharmacology ; Chitosan/chemistry ; Chitosan/pharmacology ; Humans ; Pandemics/prevention & control ; SARS-CoV-2/drug effects
    Chemical Substances Antiviral Agents ; Chitin (1398-61-4) ; Chitosan (9012-76-4)
    Language English
    Publishing date 2021-02-16
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2021.02.090
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Natural product topical therapy in mitigating imiquimod-induced psoriasis-like skin inflammation-underscoring the anti-psoriatic potential of Nimbolide.

    More, Nilesh Barku / Sharma, Nivya / Pulivendala, Gauthami / Bale, Swarna / Godugu, Chandraiah

    Indian journal of pharmacology

    2021  Volume 53, Issue 4, Page(s) 278–285

    Abstract: Background: Psoriasis is a chronic inflammatory dermatological disorder having complex pathophysiology with autoimmune and genetic factors being the major players. Despite the availability of a gamut of therapeutic strategies, systemic toxicity, poor ... ...

    Abstract Background: Psoriasis is a chronic inflammatory dermatological disorder having complex pathophysiology with autoimmune and genetic factors being the major players. Despite the availability of a gamut of therapeutic strategies, systemic toxicity, poor efficacy, and treatment tolerance due to genetic variability among patients remain the major challenges. This calls for effective intervention with the superior pharmacological profile. Nimbolide (NIM), a major limonoid is an active chemical constituent found in the leaves of the Indian Neem tree, Azadirachta indica. It has gained immense limelight in the past decades for the treatment of various diseases owing to its anti-proliferative, anti-inflammatory, and anti-cancer potentials.
    Objective: The present study was centered around evaluating the anti-psoriatic effect of NIM in the experimental model of Imiquimod (IMQ)-induced psoriasis-like inflammation model.
    Materials and methods: Application of IMQ topically on the dorsum of Balb/c mice from day 0-6 prompted psoriasis-like inflammatory symptoms. Treatment groups included topical administration of NIM incorporated carbopol gel formulation and NIM free drug given through subcutaneous route. Protein expression studies such as immunohistochemistry, Western blotting, and ELISA were employed.
    Results: It was clearly observed from our results that NIM significantly ameliorated the expression of inflammatory and proliferation mediators. Further, NIM in the treatment groups significantly improved classic Psoriasis Area Severity Index scoring when compared to IMQ administered group.
    Conclusion: It is noteworthy that NIM showed a predominant therapeutic effect as compared to other treatment group. To recapitulate, NIM has shown promising activity as an anti-psoriatic agent by remarkably ameliorating inflammation and associated proliferation.
    MeSH term(s) Administration, Topical ; Animals ; Biological Products/administration & dosage ; Disease Models, Animal ; Imiquimod/adverse effects ; Intercellular Adhesion Molecule-1/physiology ; Limonins/administration & dosage ; Mice ; Mice, Inbred BALB C ; NF-kappa B/physiology ; Psoriasis/chemically induced ; Psoriasis/drug therapy ; Severity of Illness Index
    Chemical Substances Biological Products ; Limonins ; NF-kappa B ; Intercellular Adhesion Molecule-1 (126547-89-5) ; nimbolide (25990-37-8) ; Imiquimod (P1QW714R7M)
    Language English
    Publishing date 2021-08-20
    Publishing country India
    Document type Journal Article
    ZDB-ID 605829-2
    ISSN 1998-3751 ; 0253-7613
    ISSN (online) 1998-3751
    ISSN 0253-7613
    DOI 10.4103/ijp.IJP_591_20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1α-dependent Induction of Polo-Like Kinase 4.

    Mittal, Karuna / Kaur, Jaspreet / Sharma, Shaligram / Sharma, Nivya / Wei, Guanhao / Choudhary, Ishita / Imhansi-Jacob, Precious / Maganti, Nagini / Pawar, Shrikant / Rida, Padmashree / Toss, Michael S / Aleskandarany, Mohammed / Janssen, Emiel A / Søiland, Håvard / Gupta, Meenakshi V / Reid, Michelle D / Rakha, Emad A / Aneja, Ritu

    Molecular cancer research : MCR

    2022  Volume 20, Issue 4, Page(s) 596–606

    Abstract: Centrosome amplification (CA) has been implicated in the progression of various cancer types. Although studies have shown that overexpression of PLK4 promotes CA, the effect of tumor microenvironment on polo-like kinase 4 (PLK4) regulation is ... ...

    Abstract Centrosome amplification (CA) has been implicated in the progression of various cancer types. Although studies have shown that overexpression of PLK4 promotes CA, the effect of tumor microenvironment on polo-like kinase 4 (PLK4) regulation is understudied. The aim of this study was to examine the role of hypoxia in promoting CA via PLK4. We found that hypoxia induced CA via hypoxia-inducible factor-1α (HIF1α). We quantified the prevalence of CA in tumor cell lines and tissue sections from breast cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and prostate cancer and found that CA was prevalent in cells with increased HIF1α levels under normoxic conditions. HIF1α levels were correlated with the extent of CA and PLK4 expression in clinical samples. We analyzed the correlation between PLK4 and HIF1A mRNA levels in The Cancer Genome Atlas (TCGA) datasets to evaluate the role of PLK4 and HIF1α in breast cancer and PDAC prognosis. High HIF1A and PLK4 levels in patients with breast cancer and PDAC were associated with poor overall survival. We confirmed PLK4 as a transcriptional target of HIF1α and demonstrated that in PLK4 knockdown cells, hypoxia-mimicking agents did not affect CA and expression of CA-associated proteins, underscoring the necessity of PLK4 in HIF1α-related CA. To further dissect the HIF1α-PLK4 interplay, we used HIF1α-deficient cells overexpressing PLK4 and showed a significant increase in CA compared with HIF1α-deficient cells harboring wild-type PLK4. These findings suggest that HIF1α induces CA by directly upregulating PLK4 and could help us risk-stratify patients and design new therapies for CA-rich cancers.
    Implications: Hypoxia drives CA in cancer cells by regulating expression of PLK4, uncovering a novel HIF1α/PLK4 axis.
    MeSH term(s) Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Cell Hypoxia ; Cell Line, Tumor ; Centrosome/metabolism ; Enzyme Induction ; Humans ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Male ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Protein Serine-Threonine Kinases/biosynthesis ; Protein Serine-Threonine Kinases/genetics ; Tumor Microenvironment
    Chemical Substances HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; PLK4 protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2022-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2098788-2
    ISSN 1557-3125 ; 1541-7786
    ISSN (online) 1557-3125
    ISSN 1541-7786
    DOI 10.1158/1541-7786.MCR-20-0798
    Database MEDical Literature Analysis and Retrieval System OnLINE

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