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Fulltext Standardized ethanol extract of Tinospora crispa upregulates pro-inflammatory mediators release in LPS-primed U937 human macrophages through stimulation of MAPK, NF-κB and PI3K-Akt signaling networks

Haque MA, Jantan I, Harikrishnan H, Ahmad W

BMC Complement Med Ther, 2020 Aug 06;20(1):245.
PMID: 32762741 DOI: 10.1186/s12906-020-03039-7

BACKGROUND: Immunomodulatory effects of Tinospora crispa have been investigated due to its traditional use to treat several inflammatory disorders associated to the immune system. The present study reports the underlying mechanisms involved in the stimulation of 80% ethanol extract of T. crispa stems on pro-inflammatory mediators release in lipopolysaccharide (LPS)-primed U937 human macrophages via MyD88-dependent pathways.
METHODS: Release of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and production of prostaglandin E2 (PGE2) were determined by using enzyme-linked immunosorbent assay (ELISA). Immunoblot technique was executed to determine the activation of MAPKs molecules, NF-κB, PI3K-Akt and cyclooxygenase-2 (COX-2) protein. Determination of pro-inflammatory cytokines and COX-2 relative gene expression levels was by performing the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). A reversed-phase HPLC method was developed and validated to standardize the T. crispa extract and chemical profiling of its secondary metabolites was performed by LC-MS/MS.
RESULTS: Qualitative and quantitative analyses of chromatographic data indicated that syringin and magnoflorine were found as the major components of the extract. T. crispa-treatment prompted activation of NF-κB by enhancing IKKα/β and NF-κB (p65) phosphorylation, and degradation of IκBα. The extract upregulated COX-2 protein expression, release of pro-inflammatory mediators and MAPKs (ERK, p38 and JNK) phosphorylation as well as Akt dose-dependently. T. crispa extract also upregulated the upstream signaling adaptor molecules, toll-like receptor 4 (TLR4) and MyD88. T. crispa-treatment also upregulated the pro-inflammatory markers mRNA expression.
CONCLUSION: The results suggested that T. crispa extract stimulated the MyD88-dependent signaling pathways by upregulating the various immune inflammatory related parameters.

Matched MeSH terms: Mitogen-Activated Protein Kinases/metabolism*
The synthetic curcuminoid BHMC restores endotoxin-stimulated HUVEC dysfunction:Specific disruption on enzymatic activity of p38 MAPK

Tham CL, Hazeera Harith H, Wai Lam K, Joong Chong Y, Singh Cheema M, Roslan Sulaiman M, et al.

Eur J Pharmacol, 2015 Feb 15;749:1-11.
PMID: 25560198 DOI: 10.1016/j.ejphar.2014.12.015

2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC) has been proven to selectively inhibit the synthesis of proinflammatory mediators in lipopolysaccharide-induced U937 monocytes through specific interruption of p38 Mitogen-Activated Protein Kinase enzymatic activity and improves the survival rate in a murine lethal sepsis model. The present study addressed the effects of BHMC upon lipopolysaccharide-induced endothelial dysfunction in human umbilical vein endothelial cells to determine the underlying mechanisms. The cytotoxicity effect of BHMC on HUVEC were determined by MTT assay. The effects of BHMC on endothelial dysfunction induced by lipopolysaccharide such as endothelial hyperpermeability, monocyte-endothelial adhesion, transendothelial migration, up-regulation of adhesion molecules and chemokines were evaluated. The effects of BHMC at transcriptional and post-translational levels were determined by Reverse Transcriptase-Polymerase Chain Reaction and Western Blots. The mode of action of BHMC was dissected by looking into the activation of Nuclear Factor-kappa B and Mitogen-Activated Protein Kinases. BHMC concentration-dependently reduced endothelial hyperpermeability, leukocyte-endothelial cell adhesion and monocyte transendothelial migration through inhibition of the protein expression of adhesion molecules (Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1) and secretion of chemokines (Monocyte Chemotactic Protein-1) at the transcriptional level. BHMC restored endothelial dysfunction via selective inhibition of p38 Mitogen-Activated Protein Kinase enzymatic activity which indirectly prevents the activation of Nuclear Factor-kappaB and Activator Protein-1 transcription factors. These findings further support earlier observations on the inhibition of BHMC on inflammatory events through specific disruption of p38 Mitogen-Activated Protein Kinase enzymatic activity and provide new insights into the inhibitory effects of BHMC on lipopolysaccharide-induced endothelial dysfunction.

Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/metabolism*
Plant Extracts and their Secondary Metabolites as Modulators of Kinases

Gill MSA, Saleem H, Ahemad N

Curr Top Med Chem, 2020;20(12):1093-1104.
PMID: 32091334 DOI: 10.2174/1568026620666200224100219

Natural Products (NP), specifically from medicinal plants or herbs, have been extensively utilized to analyze the fundamental mechanisms of ultimate natural sciences as well as therapeutics. Isolation of secondary metabolites from these sources and their respective biological properties, along with their lower toxicities and cost-effectiveness, make them a significant research focus for drug discovery. In recent times, there has been a considerable focus on isolating new chemical entities from natural flora to meet the immense demand for kinase modulators, and also to overcome major unmet medical challenges in relation to signal transduction pathways. The signal transduction systems are amongst the foremost pathways involved in the maintenance of life and protein kinases play an imperative part in these signaling pathways. It is important to find a kinase inhibitor, as it can be used not only to study cell biology but can also be used as a drug candidate for cancer and metabolic disorders. A number of plant extracts and their isolated secondary metabolites such as flavonoids, phenolics, terpenoids, and alkaloids have exhibited activities against various kinases. In the current review, we have presented a brief overview of some important classes of plant secondary metabolites as kinase modulators. Moreover, a number of phytocompounds with kinase inhibition potential, isolated from different plant species, are also discussed.

Matched MeSH terms: Protein Kinases/metabolism*
Fulltext Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

Agarwal R, Agarwal P

Exp Biol Med (Maywood), 2017 Feb;242(4):374-383.
PMID: 27798117 DOI: 10.1177/1535370216675065

Disturbances of extracellular matrix homeostasis are associated with a number of pathological conditions. The ability of extracellular matrix to provide contextual information and hence control the individual or collective cellular behavior is increasingly being recognized. Hence, newer therapeutic approaches targeting extracellular matrix remodeling are widely investigated. We reviewed the current literature showing the effects of resveratrol on various aspects of extracellular matrix remodeling. This review presents a summary of the effects of resveratrol on extracellular matrix deposition and breakdown. Mechanisms of action of resveratrol in extracellular matrix deposition involving growth factors and their signaling pathways are discussed. Involvement of phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways and role of transcription factors and sirtuins on the effects of resveratrol on extracellular matrix homeostasis are summarized. It is evident from the literature presented in this review that resveratrol has significant effects on both the synthesis and breakdown of extracellular matrix. The major molecular targets of the action of resveratrol are growth factors and their signaling pathways, phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways, transcription factors, and SIRT-1. The effects of resveratrol on extracellular matrix and the molecular targets appear to be related to experimental models, experimental environment as well as the doses.

Matched MeSH terms: Mitogen-Activated Protein Kinases/metabolism*
Fulltext Inactivation of the catalytic subunit of cAMP-dependent protein kinase A causes delayed appressorium formation and reduced pathogenicity of Colletotrichum gloeosporioides

Priyatno TP, Abu Bakar FD, Kamaruddin N, Mahadi NM, Abdul Murad AM

ScientificWorldJournal, 2012;2012:545784.
PMID: 22666136 DOI: 10.1100/2012/545784

The cyclic AMP- (cAMP-) dependent protein kinase A signaling pathway is one of the major signaling pathways responsible for regulation of the morphogenesis and pathogenesis of several pathogenic fungi. To evaluate the role of this pathway in the plant pathogenic fungus, Colletotrichum gloeosporioides, the gene encoding the catalytic subunit of cAMP-dependent protein kinase A, CgPKAC, was cloned, inactivated, and the mutant was analyzed. Analysis of the Cgpkac mutant generated via gene replacement showed that the mutants were able to form appressoria; however, their formation was delayed compared to the wild type. In addition, the mutant conidia underwent bipolar germination after appressoria formation, but no appressoria were generated from the second germ tube. The mutants also showed reduced ability to adhere to a hydrophobic surface and to degrade lipids localized in the appressoria. Based on the number of lesions produced during a pathogenicity test, the mutant's ability to cause disease in healthy mango fruits was reduced, which may be due to failure to penetrate into the fruit. These findings indicate that cAMP-dependent protein kinase A has an important role in regulating morphogenesis and is required for pathogenicity of C. gloeosporioides.

Matched MeSH terms: Cyclic AMP-Dependent Protein Kinases/metabolism