Identification of new anti-inflammatory agents based on nitrosporeusine natural products of marine origin

Philkhana, Satish Chandra; Verma, Abhishek Kumar; Jachak, Gorakhnath R.; Hazra, Bibhabasu; Basu, Anirban; Reddy, D. Srinivasa

doi:10.1016/j.ejmech.2017.04.015

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…These effects was confirmed by the reduction of pro-inflammatory enzymes such as COX-2 and iNOS, and by the modulation of expression of nuclear NF-κB and cytosolic IκB-α. It is well known that these factors play a key role in inflammatory process both in vitro ( Jang et al, 2017 ) and in vivo ( Philkhana et al, 2017 ), and their reduction supports our hypothesis that ketogal, such as ketorolac, has a significant anti-inflammatory effect. These very encouraging results demonstrate for the first time that ketogal could be a valid and novel therapeutic alternative to the ketorolac.…”

Section: Discussionsupporting

confidence: 87%

Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity

Russo

Avallone

et al. 2017

Front. Pharmacol.

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Ketorolac is a powerful non-steroidal anti-inflammatory drug (NSAID), with a great analgesic activity, present on the Italian market since 1991. Despite the excellent therapeutic activity, the chronic use of ketorolac has long been limited owing to the high incidence of gastrointestinal and kidney side events. In our previous study, we demonstrated that ketorolac–galactose conjugate (ketogal), synthesized and tested in a single-dose study, was able to reduce ulcerogenicity, while preserving the high pharmacological efficacy of its parent drug. In this paper, in order to verify the suitability of this compound, for repeated administration, ex vivo experiments on naïve mice were performed. Mice were treated for 5 or 7 days with the highest doses of two drugs (ketorolac 10 mg/kg and ketogal 16.3 mg/kg), and the expression of both gastric COX-1 and PGsyn was evaluated. Results showed that oral ketorolac treatment significantly reduced both enzymes; surprisingly, oral treatment with ketogal did not produce significant variation in the expression of the two constitutive enzymes. Moreover, histological experiments on stomach and kidneys clearly indicated that repeated administration of ketogal induced lower toxicity than ketorolac. At same time, in vivo results clearly showed that both ketorolac and ketogal had a similar therapeutic activity in a model of inflammation and in pain perception. These effects were accompanied by the reduction of enzyme expression such as COX-2 and iNOS, and by the modulation of levels of nuclear NF-κB and cytosolic IκB-α in the inflamed paws. These very encouraging results demonstrate for the first time that ketogal could represent a valid and novel therapeutic alternative to the ketorolac and might pave the way for clinical studies.

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Section: Discussionsupporting

confidence: 87%

Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity

Russo

Avallone

et al. 2017

Front. Pharmacol.

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“…Our data shows CNS leukocyte recruitment, and aggravated inflammatory response modulate host immune responses, which in excess may otherwise contribute to virus-induced damage and mortality. Nitrosporeusine is newly synthesised drug acts as an anti-inflammatory agent [ 20 ]. In our case, we have found that nitrosporeusine treatment in animal significantly increases animal survivability and decreases disease progression in BALB/c mouse ( Fig 1A & 1B ).…”

Section: Discussionmentioning

confidence: 99%

“…Nitrosporeusines A and B are two recently isolated marine natural products with a novel skeleton and exceptional biological profile. Our previous data suggest it as a potential candidate possessing anti-inflammatory property [ 20 ], so we planned and screened racemic as well as enantiopure forms. Preparation of several analogues followed the natural product synthesis, and all the synthesised compounds were evaluated for in vitro and in vivo anti-inflammatory potential.…”

Section: Methodsmentioning

confidence: 99%

Nitrosporeusine analogue ameliorates Chandipura virus induced inflammatory response in CNS via NFκb inactivation in microglia

et al. 2018

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Chandipura Virus (CHPV), a negative-stranded RNA virus belonging to the Rhabdoviridae family, has been previously reported to bring neuronal apoptosis by activating several factors leading to neurodegeneration. Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues gets activated and starts secreting chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the effect of CHPV on microglia and the activation of cellular signalling pathways leading to chemokine expression upon CHPV infection. Protein and mRNA expression profiles of chemokine genes revealed that CHPV infection strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. CHPV infection triggered the activation of signalling pathways mediated by mitogen-activated protein kinases, including p38, JNK 1 and 2, and nuclear factor κB (NF-kappaB). CHPV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-kappaB pathways. Considering the important role of inflammation in neurodegeneration, we have targeted NF-kappaB using a newly synthesised natural product nitrosporeusine analogue and showed incapability of microglial supernatant of inducing apoptosis in neurons after treatment.

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“…The research on lead compounds with novel structures, significant activities and clear mechanisms require multidisciplinary and systematic collaboration. The active ingredients of natural medicine have various skeleton structures and extensive biological activities (Winter et al, 2013;Mou et al, 2015;Lopez-Perez et al, 2017;Philkhana et al, 2017). Statistically, more than 1/3 of the new drugs on the market between 1981 and 2014 were directly or indirectly derived from natural products.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Transcriptome Profiling in Drug and Biomarker Discovery

et al. 2020

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The development of new drugs is multidisciplinary and systematic work. High-throughput techniques based on "-omics" have driven the discovery of biomarkers in diseases and therapeutic targets of drugs. A transcriptome is the complete set of all RNAs transcribed by certain tissues or cells at a specific stage of development or physiological condition. Transcriptome research can demonstrate gene functions and structures from the whole level and reveal the molecular mechanism of specific biological processes in diseases. Currently, gene expression microarray and high-throughput RNA-sequencing have been widely used in biological, medical, clinical, and drug research. The former has been applied in drug screening and biomarker detection of drugs due to its high throughput, fast detection speed, simple analysis, and relatively low price. With the further development of detection technology and the improvement of analytical methods, the detection flux of RNAseq is much higher but the price is lower, hence it has powerful advantages in detecting biomarkers and drug discovery. Compared with the traditional RNA-seq, scRNA-seq has higher accuracy and efficiency, especially the single-cell level of gene expression pattern analysis can provide more information for drug and biomarker discovery. Therefore, (sc) RNA-seq has broader application prospects, especially in the field of drug discovery. In this overview, we will review the application of these technologies in drug, especially in natural drug and biomarker discovery and development. Emerging applications of scRNA-seq and the third generation RNA-sequencing tools are also discussed.

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Identification of new anti-inflammatory agents based on nitrosporeusine natural products of marine origin

Cited by 16 publications

References 31 publications

Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity

Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity

Nitrosporeusine analogue ameliorates Chandipura virus induced inflammatory response in CNS via NFκb inactivation in microglia

High-Throughput Transcriptome Profiling in Drug and Biomarker Discovery

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