Browsing by Author "Gill, Balraj Singh"

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Antioxidant potential of ganoderic acid in Notch-1 protein in neuroblastoma
(Springer, 2018) Gill, Balraj Singh; Navgeet; Kuamr, Sanjeev
Neuroblastoma is a childhood tumor arising from developing a sympathetic nervous system and causes around 10% of pediatric tumors. Despite advancement in the use of sophisticated techniques in molecular biology, neuroblastoma patient's survivability rate is very less. Notch pathway is significant in upholding cell maintenance and developmental process of organs. Notch-1 proteins are a ligand-activated transmembrane receptor which decides the fate of the cell. Notch signaling leads to transcription of genes which indulged in numerous diseases including tumor progression. Ganoderic acid, a lanosterol triterpene, isolated from fungus Ganoderma lucidum with a wide range of medicinal values. In the present study, various isoforms of the ganoderic acid and natural inhibitors were docked by molecular docking using Maestro 9 in the Notch-1 signaling pathway. The receptor-based molecular docking exposed the best binding interaction of Notch-1 with ganoderic acid A with GScore (- 8.088), kcal/mol, Lipophilic EvdW (- 1.74), Electro (- 1.18), Glide emodel (- 89.944) with the active participation of Arg 189, Arg 199, Glu 232 residues. On the other hand natural inhibitor, curcumin has GScore (- 7.644), kcal/mol, Lipophilic EvdW (- 2.19), Electro (- 0.73), Glide emodel (- 70.957) with Arg 75 residues involved in docking. The ligand binding affinity of ganoderic acid A in Notch-1 is calculated using MM-GBSA (- 76.782), whereas curcumin has (- 72.815) kcal/mol. The QikProp analyzed the various drug-likeness parameters such as absorption, distribution, metabolism, excretion, and toxicity (ADME/T) and isoforms of ganoderic acid require some modification to fall under Lipinski rule. The ganoderic acid A and curcumin were the best-docked among different compounds and exhibits downregulation in Notch-1 mRNA expression and inhibits proliferation, viability, and ROS activity in IMR-32 cells.
Chemical profiling of ganoderma lucidum of bathinda region
(Central University of Punjab, 2013) Gill, Balraj Singh; Kumar, Sanjeev
Ganoderma lucidum is a basidiomycete's fungus with numerous pharmacological properties. The important ingredients of Ganoderma lucidum are terpenoids and polysaccharides etc. which play momentous role in immunomodulating, anti-inflammatory, anti-cancer, anti-diabetic and anti-oxidative. Mechanism of anticancer is still unrevealed. Aim of the present study was to analyse phytochemical difference in the Ganoderma lucidum growing on different hosts in Malwa region. Biomolecules play an imperative role in growth and development. Stress condition remodels the physiology, morphology and development of plant. To combat with stress, plants evolve with time and synthesize secondary metabolites. Stress tolerance ability is generated by overexpression of isoenzyme, intracellular targeting of anti-oxidants and overexpression ability of anti-oxidative enzyme. Ganoderma lucidum was analysed for different parameters such as total sugars, reducing sugars, starch, proteins, phenols, antioxidant property and flavonoids by standard procedures which was collected in different stages of development on different hosts, such as Azadirachta, Acacia, Bauhinia, Melia, and Dalbergia spp. It manifests fungus-host relationship and amount of phytoconstituent synthesized. The biochemical estimation showed 38.1±0.0481 g/100g of total sugars, 19±5.925 g/100g of reducing sugars, 57.3±3.333 g/100g of starch, 42±4.2% of proteins, 9.7±0.066% of phenols, 86.31%±5.480 scavenging activity in term of % inhibition and 5.26 ±0.6 mg/g of flavonoids. Complete analysis shows that except flavonoids all phytochemicals content was exceptionally high. Terpenoids analysis showed variation within the different hosts. Ganoderic acid, which is most active anticancerous molecule showed variation within different hosts. It can be concluded from the preliminary studies that there are variations in the chemical constituents of GL with change in host which makes it a "chemovariant"
Differential algorithms-assisted molecular modeling-based identification of mechanistic binding of ganoderic acids
(Springer, 2015) Gill, Balraj Singh; Kumar, Sanjeev
Ganoderma, in the recent years, has been comprehensively characterized and held invaluable for their miscellaneous pharmacological activities. Recently, attempts to explore and fathom the pathway of inhibition revealed GA-A and GA-H to impede the progression of breast cancer by inhibiting the signaling of AP-1 and NF-κB, although the mechanism has not yet been explored. NF-κB is a key transcription factor having irrefutable role in cell proliferation, apoptosis and cancer signaling and its subunits κB-IKKα, IKKβ and IKKγ (NEMO) are pivotal to the cancer signaling mechanism. The present study confirmed mechanistically the association between NF-κB and NEMO in regulating the signaling cascade of NF-κB. GA-A and GA-H were observed to participate in various non-covalent interactions, thus contributing largely to the stability of the ligand–macromolecules association as well as their role as anticancer agent in breast cancer. Amino acids, Lys90 and Asn732, were seen to be critically involved in the signaling cascade. Apart from this, residues Glu98 and Met94, Cys95 and Glu91 were involved in hydrogen bonding in GA-A and GA-H. The anticancer activity exhibited by GA-A and GA-H is attributed to certain docking poses and interaction that were found to be absent in the GA-F such as hydroxylation at 3 and 7 and/or 15 in the lanostane structure. This study is the first of its kind elucidating a possible mode of binding of ganoderic acid in NF-κB signaling pathway using molecular modeling studies, further evaluated by differential calculation-based algorithms.
Evaluating anti-oxidant potential of ganoderic acid A in STAT 3 pathway in prostate cancer
(Springer Netherlands, 2016) Gill, Balraj Singh; Kumar, Sanjeev; Navgeet
Evaluating anti-oxidant potential of Ganoderic acid A in STAT 3 pathway in Prostate cancer. Molecular docking and ADMET activities of different isoforms of ganoderic acid on STAT 3 pathway were performed by Maestro 9.6 (Schr�dinger Inc). The ganoderic acid A is best-docked among isoforms which analyses the expression level of antioxidant and STAT 3 pathway in PC-3 cells. The receptor-based molecular docking reveals the best binding interaction of SH2 domain of STAT3 and ganoderic acid A with GScore (?6.134), kcal/mol, Lipophilic EvdW (?1.83), Electro (?1.1), Glide emodel (?31.857), H bond (1.98), MM-GBSA (?69.555). The molecular docking QikProp analyzed the absorption, distribution, metabolism, excretion, and toxicity (ADME/T). The ganoderic acid A is best-docked among isoforms which downregulates the expression of STAT 3 in PC-3 cells. Moreover, ganoderic acid A inhibits proliferation, viability, ROS, DPPH, and analyzed the expression of SOD1, SOD2, and SOD3 by Real time PCR in a PC-3 cell in a dose-dependent manner. Molecular docking revealed the mechanistic binding of Ganoderic acid A in STAT3 signaling, which inhibits the proliferation, viability, and ROS in PC-3 cells. � 2016, Springer Science+Business Media Dordrecht.
Ganoderic Acid A Targeting ?-Catenin in Wnt Signaling Pathway: In Silico and In Vitro Study
(Springer Berlin Heidelberg, 2018) Gill, Balraj Singh; Kumar, Sanjeev; Navgeet
Wnt signaling pathways are the group of signaling transduction controlling the embryonic development, cell proliferation, cell migration, cell fate specification, and body axis pattern. Nuclear accumulation of ?-catenin in Wnt signaling is a widely recognized marker of poor cancer prognosis which regulates fat and glucose metabolism. Ganoderic acid is a triterpene isolated from fungus Ganoderma lucidum renowned for its pharmacological effects. The present study revealed the mechanistic study of ?-catenin with 50 isoforms of ganoderic acid by molecular docking using Maestro 9.6 (Schr?dinger Inc) in Wnt signaling pathway. Molecular docking reveals the binding interaction of ?-catenin and ganoderic acid A with GScore (?9.44), kcal/mol, lipophilic EvdW (?2.86), electro (?0.72), Glide emodel (?50.401), MM-GBSA (?87.441), H bond (?1.91) with Lys 180 and Asn 220 residues involved in hydrogen bonding. Qikprop analyzed the absorption, distribution, metabolism, excretion, and toxicity and confirmed that most of the isoforms satisfies Lipinski rule but needs little modifications in their structure. The ganoderic acid A is the best-docked isoforms which inhibits the proliferation, viability, and intracellular ROS of pancreatic cancer RIN-5F cells in a dose-dependent manner. ? 2016, International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg.
Ganoderic Acid A Targeting β-Catenin in Wnt Signaling Pathway: In Silico and In Vitro Study
(Springer, 2016) Gill, Balraj Singh; Kumar, Sanjeev; Navgeet
Wnt signaling pathways are the group of signaling transduction controlling the embryonic development, cell proliferation, cell migration, cell fate specification, and body axis pattern. Nuclear accumulation of β-catenin in Wnt signaling is a widely recognized marker of poor cancer prognosis which regulates fat and glucose metabolism. Ganoderic acid is a triterpene isolated from fungus Ganoderma lucidum renowned for its pharmacological effects. The present study revealed the mechanistic study of β-catenin with 50 isoforms of ganoderic acid by molecular docking using Maestro 9.6 (Schrödinger Inc) in Wnt signaling pathway. Molecular docking reveals the binding interaction of β-catenin and ganoderic acid A with GScore (−9.44), kcal/mol, lipophilic EvdW (−2.86), electro (−0.72), Glide emodel (−50.401), MM-GBSA (−87.441), H bond (−1.91) with Lys 180 and Asn 220 residues involved in hydrogen bonding. Qikprop analyzed the absorption, distribution, metabolism, excretion, and toxicity and confirmed that most of the isoforms satisfies Lipinski rule but needs little modifications in their structure. The ganoderic acid A is the best-docked isoforms which inhibits the proliferation, viability, and intracellular ROS of pancreatic cancer RIN-5F cells in a dose-dependent manner.
Ganoderic acid modulating TNF and its receptors: in silico and in vitro study
(Springer, 2017) Gill, Balraj Singh; Navgeet; Kumar, Sanjeev
Cancer is a multifactorial disease with a network of genes causing genetic alterations. The sophisticated techniques in molecular biology revealed different cancer pathway, but their mechanistic approach is still shrouded. Tumor necrosis factor and TNF-related apoptosis-inducing ligand receptors (DR5) emerged as potential target drug for the cancer therapy. Among natural products basidiomycete fungus, Ganoderma lucidum and its constituents endowed with a plethora of activities modulating signaling in cancer. Ganoderic acid, a triterpene with lanosteroidal skeleton play an inextricable role in modulating signaling cascades in various mitogenic pathways. In the present study, receptor-based molecular docking was performed to study the dynamic behavior of the docked complexes and the molecular interactions between ganoderic acid and its isoforms with tumor necrosis factor and its receptor (DR5). The top scoring compounds were compared with the already documented natural inhibitor of tumor necrosis factor, DR5-curcumin, catechin, bupropion, pentoxyphyllin for their binding affinity and other absorption, distribution, metabolism, excretion, and toxicity properties. Ganoderic acid A interact more promising as compared with other isoforms with GScore (−9.858 (kcal/mol), Lipophilic EvdW (−1.7), H Bond (−0.9), Glide emodel (−40.5) with the involvement of Tyr 151, Leu 120 and Gln 149 residues during binding with tumor necrosis factor. During docking of ganoderic acid with DR5, ganoderic acid A exhibits GScore (−8.7), HBond (−2.9), Glide emodel (−30.0) with the involvement of hydrogen bonding inMet99, Arg101, Pro97, Glu98 residues. Natural inhibitors already documented exhibit low-binding energy and other docking parameters, which have an edge of ganoderic acid A to tumor necrosis factor and DR5. Ganoderic acid A efficiently inhibits the proliferation, viability, and intracellular reactive oxygen
Ganoderic acid targeting multiple receptors in cancer: in silico and in vitro study
(Springer Netherlands, 2016) Gill, Balraj Singh; Navgeet; Kumar, Sanjeev; Gill, B.S.; Navgeet, Kumar, S.
Receptor tyrosine kinases (RTKs) are transmembrane high-affinity surface receptors responsible for cell migration, adhesion, apoptosis, metabolism, and cell proliferation activities in various cancers. Minute aberration in the RTK signaling modulates the downstream signaling pathways that results in cancer. Ganoderic acid is a triterpene isolated from Ganoderma lucidum, which is renowned for its therapeutics effect, especially in cancer. The present study discusses receptor-based molecular docking of insulin receptor (IR), insulin-like growth factor receptor 1 (IGFR-1), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), and estrogen receptor (ER) with 50 isoforms of ganoderic acid along with natural inhibitors. These receptors were assessed for toxicity (ADMET) by using Maestro 9.6 (Schr?dinger Inc). The calculated docking free energy yielded an excellent dock score for the ganoderic acid when docked with proteins IR, IGFR-1, VEGFR-1, VEGFR-2, and ER, suggesting its potential in combating cancer. Protein?ligand profile highlighted the binding interactions comprising lipophilic, hydrogen bonding, pi-pi stacking interactions, and noncovalent bonding which play a pivotal role in targeting cancer. In silico studies revealed structure of ganoderic acid A as best isoforms among 50 isoforms which exhibits biological activity in liver cancer cells. Ganoderic acids A significantly decrease the viability, proliferation, and oxidative stress in a dose-dependent manner in liver cancer cells. ? 2016, International Society of Oncology and BioMarkers (ISOBM).
Ganoderic acid targeting nuclear factor erythroid 2–related factor 2 in lung cancer
(Sage, 2017) Gill, Balraj Singh; Kumar, Sanjeev; Navgeet
Lung cancer causes huge mortality worldwide, and targeting new pathway may provide an alternative in modulating signaling in cancer. Nuclear factor erythroid 2–related factor 2 is the major regulator of endogenous and exogenous stress by activating numerous antioxidant genes critical in cancer, Alzheimer’s, Parkinson’s, and inflammatory bowel diseases. Ganoderic acid is a triterpene from basiodiomycetes fungus Ganoderma lucidum with numerous therapeutic effects. In this study, ganoderic acid and its 50 isomers and natural activators were docked by receptor-based molecular docking using Maestro 9.6 (Schrödinger Inc.) in the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2–related factor 2 signaling pathway. The receptor-based molecular docking reveals the best binding interaction of nuclear factor erythroid 2–related factor 2 and ganoderic acid A with GScore (−9.69) (kcal/mol), Lipophilic EvdW (−1.83), Electro (−0.72), Glide emodel (−73.369), H bond (−1.1), molecular mechanics/generalized Born surface area (−75.541) with Leu 718, Asp 800, Cys 797 residues involved in hydrogen bonding. The calculated docking energy highlights the lipophilic, hydrogen bonding, pi–pi stacking interactions, and non-covalent bonding. Analysis showed the involvement of cysteine and serine residues which were crucial in the activation and translocation from cytoplasm to the nucleus in the nuclear factor erythroid 2–related factor 2 signaling process. The molecular docking tool QikProp analyzed the absorption, distribution, metabolism, excretion, and toxicity but needs some modifications in their structure to satisfy Lipinski’s rule. Ganoderic acid A is a best docked isoform which inhibits the cell proliferation, viability, migration, and reactive oxygen species and messenger RNA expression of nuclear factor erythroid 2–related factor 2 in H460 cells.
Ganoderic acid, lanostanoid triterpene: a key player in apoptosis
(Springer New York LLC, 2018) Gill, Balraj Singh; Navgeet; Mehra, Richa; Kumar, Vicky; Kumar, Sanjeev
Cancer is a multifactorial disease, causing behavioral and metabolic alterations, leading to uncontrolled cell proliferation with collateral weakening of immune system. Crucial balance between cell proliferation and cell death determines the fate of a cell, which might progress towards survival or apoptosis. Apoptosis is a complex, programmed, and highly regulated process causing dramatic morphological and biochemical perturbations in the cellular machinery. Ganoderma lucidum is a basidiomycetes, polypore mushroom known for its pharmacological properties in cancer. The major bioconstituents in G. lucidum are terpenoids, polysaccharides, and proteins that target cancer-signaling factors like plasma membrane receptors proteins and adapter molecules. Of all constituents, the major terpenoid, i.e. Ganoderic acid is reported to interact with membrane receptors mainly, receptor tyrosine kinase (RTKs). Ganoderic acid interacts and modulates the signaling network in IR, IGFR-1, IGFR-2, VEGFR-1, VEFGR-2, and EGFR in cancer signaling pathways. It primarily targets NF-?B, RAS-MAPK, PI3K/Akt/mTOR, and cell cycle resulting in apoptosis. This review highlights the role of ganoderic acid in apoptosis and modulations of various signaling proteins in cancer. ? 2017, Springer Science+Business Media, LLC.
Ganoderma lucidum targeting lung cancer signaling: A review
(SAGE Publications Ltd, 2017) Gill, Balraj Singh; Navgeet; Kumar, Sanjeev; Gill, B.S.; Navgeet, Kumar, S.
Lung cancer causes huge mortality to population, and pharmaceutical companies require new drugs as an alternative either synthetic or natural targeting lung cancer. The conventional therapies cause side effects, and therefore, natural products are used as a therapeutic candidate in lung cancer. Chemical diversity among natural products highlights the impact of evolution and survival of fittest. One such neglected natural product is Ganoderma lucidum used for promoting health and longevity for a longer time. The major bioconstituents of G. lucidum are mainly terpenes, polysaccharides, and proteins, which were explored for various activities ranging from apoptosis to autophagy. The bioconstituents of G. lucidum activate plasma membrane receptors and initiate various downstream signaling leading to nuclear factor-?B, phosphoinositide 3-kinase, Akt, and mammalian target of rapamycin in cancer. The bioconstituents regulate the expression of various genes involved in cell cycle, immune response, apoptosis, and autophagy in lung cancer. This review highlights the inextricable role of G. lucidum and its bioconstituents in lung cancer signaling for the first time. ? The Author(s) 2017.
GANODERMA LUCIDUM, A POTENTIAL THERAPEUTIC MODULATOR IN CANCER SIGNALING: IN SILICO AND IN VITRO ANALYSIS
(Central University of Punjab, 2018) Gill, Balraj Singh; Kumar , Sanjeev and Kumar, Vinod
Misconstrued versatility of Ganoderma lucidum: a key player in multi-targeted cellular signaling
(Springer, 2016) Gill, Balraj Singh; Sharma, Prateek; Kumar, Raj; Kumar, Sanjeev
A Basidiomycetes fungus belonging to polypore family of mushrooms, Ganoderma lucidum (GL), has been known since a long time for their myriad therapeutic indications. Renowned as an invaluable resource of cardinal mycoconstituents they encompass numerous terpenoids polysaccharides and proteins. Possessing the therapeutically potent lanosteroidal skeleton, terpenoids are upheld for their invariable participation in therapeutically diverse bioactivities. Polysaccharides and proteins exhibiting distinguishable bioactivities provide this oriental mushroom with additional edges over immune function and anti-cancer potential. This review is a concerted effort to throw light upon the therapeutic versatility of the fungus, shadowed by various other natural products. An effort has been made towards conglomerating the mycoconstituents decisive for the many activities portrayed by this fungus. More importantly, this review seeks to fathom the inextricable role played by derivatives in modulating signaling cascades such as downregulation of various mitogenic pathways, inhibiting growth factors, or upregulating certain pathways enhancing cellular integrity.
Missing link between microRNA and prostate cancer
(Springer Netherlands, 2016) Gill, Balraj Singh; Alex, Jimi Marin; Navgeet; Kumar, Sanjeev; Gill, B.S.; Alex, J.M.; Navgeet, Kumar, S.
MicroRNAs are the non-coding RNAs which regulate endogenous gene expression in animal and plant cells. Alterations in the level of micro-ribonucleic acids (miRNAs) involving the deletions, overexpression, mutations, epigenetic silencing, or dysregulation of transcription factors that target specific miRNAs may culminate in various diseases including cancer. Recent findings demonstrate the role of miRNAs in prostate cancer. Numerous discoveries of miRNAs have marked the research and development surrounding prostate cancer management, diagnosis, and therapy which has made prediction easy, but the effective treatment strategy remains a mystery. This review seeks to draw a link between miRNA and prostate cancer through an understanding of the numerous signaling pathways that these miRNAs control, which may prove to be helpful in identifying therapeutically interesting molecular targets. ? 2016, International Society of Oncology and BioMarkers (ISOBM).
Triterpenes in cancer: significance and their influence
(Springer Netherlands, 2016) Gill, Balraj Singh; Kumar, Sanjeev; Navgeet
Natural products are enriched with numerous compounds with a broad spectrum of therapeutics indication suggesting the role of functional moieties as a core pharmacophore. This review highlights the role of triterpene in targeting signaling pathways in cancer. Advancement in cellular, biochemical, experimental, and computational approaches provides new insights into various pathways in cancer. In signaling network, triterpenes primarily target membrane receptors which control and modulates expression level of the biological responses. Triterpenes are immunomodulatory targeting nuclear factor kappa B, toll-like receptors, signal transducer and activator of transcription 3, and PI3K/Akt/mTOR. Triterpenes isolated from plants and fungus mainly focus on the process of apoptosis while other signaling areas in the cancer are still shrouded. Some of the triterpenes have already passed the clinical trial, whereas many more have been proven to yield effective results. This review would help the researchers to study the role of triterpenes in cancer, thus, helping them to discover and design efficacious therapeutics agents. ? 2016, Springer Science+Business Media Dordrecht.
Vitex negundo and its medicinal value
(Springer, 2018) Gill, Balraj Singh; Mehra, Richa; Navget; Kumar, Sanjeev
Natural products are rich in several potent bioactive compounds, targeting complex network of proteins involved in various diseases. Vitex negundo (VN), commonly known as “chaste tree”, is an ethnobotanically important plant with enormous medicinal properties. Different species of Vitex vary in chemical composition, thus producing different phytochemicals. Several bioactive compounds have been extracted from leaves, seeds, roots in form of volatile oils, flavonoids, lignans, iridoids, terpenes, and steroids. These bioactive compounds exhibit anti-inflammatory, antioxidant, antidiabetic, anticancer, antimicrobial. VN is typically known for its role in the modulation of cellular events like apoptosis, cell cycle, motility of sperms, polycystic ovary disease, and menstrual cycle. VN, reportedly, perturbs many cancer-signaling pathways involving p-p38, p-ERK1/2, and p-JNK in LPS-elicited cells, N-terminal kinase (JNK), COX-1 pathways, MAPK, NF-κB, tumor necrosis factor α (TNF-α), Akt, mTOR, vascular endothelial growth factor, hypoxia-inducible factor (HIF-1α). Several bioactive compounds obtained from VN have been commercialized and others are under investigation. This is the first review presenting up-to-date information about the VN, its bioactive constituents and their mode of action.