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Fulltext The triumvirate of NF-κB, inflammation and cytokine storm in COVID-19

Attiq A, Yao LJ, Afzal S, Khan MA

Int Immunopharmacol, 2021 Dec;101(Pt B):108255.
PMID: 34688149 DOI: 10.1016/j.intimp.2021.108255

The coronavirus disease (COVID-19) has once again reminded us of the significance of host immune response and consequential havocs of the immune dysregulation. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inflicts severe complications to the infected host, including cough, dyspnoea, fever, septic shock, acute respiratory distress syndrome (ARDs), and multiple organ failure. These manifestations are the consequence of the dysregulated immune system, which gives rise to excessive and unattended production of pro-inflammatory mediators. Elevated circulatory cytokine and chemokine levels are accompanied by spontaneous haemorrhage, thrombocytopenia and systemic inflammation, which are the cardinal features of life-threatening cytokine storm syndrome in advanced COVID-19 diseases. Coronavirus hijacked NF-kappa B (NF-κB) is responsible for upregulating the expressions of inflammatory cytokine, chemokine, alarmins and inducible enzymes, which paves the pathway for cytokine storm. Given the scenario, the systemic approach of simultaneous inhibition of NF-κB offers an attractive therapeutic intervention. Targeted therapies with proteasome inhibitor (VL-01, bortezomib, carfilzomib and ixazomib), bruton tyrosine kinase inhibitor (acalabrutinib), nucleotide analogue (remdesivir), TNF-α monoclonal antibodies (infliximab and adalimumab), N-acetylcysteine and corticosteroids (dexamethasone), focusing the NF-κB inhibition have demonstrated effectiveness in terms of the significant decrease in morbidity and mortality in severe COVID-19 patients. Hence, this review highlights the activation, signal transduction and cross-talk of NF-κB with regard to cytokine storm in COVID-19. Moreover, the development of therapeutic strategies based on NF-κB inhibition are also discussed herein.
Modulation of inflammatory pathways, medicinal uses and toxicities of Uvaria species: potential role in the prevention and treatment of inflammation

Jalil J, Attiq A, Hui CC, Yao LJ, Zakaria NA

Inflammopharmacology, 2020 Oct;28(5):1195-1218.
PMID: 32617790 DOI: 10.1007/s10787-020-00734-2

The therapeutic efficacy of the contemporary anti-inflammatory drugs are well established; however, prolonged use of such can often lead to serious and life-threatening side effects. Natural product-based anti-inflammatory compounds with superior efficacy and minimum toxicity can serve as possible therapeutic alternatives in this scenario. Genus Uvaria is a part of Annonaceae family, while the majority of its species are widely distributed in tropical rain forest regions of South East Asia. Uvaria species have been used extensively used as traditional medicine for treating all sorts of inflammatory diseases including catarrhal inflammation, rheumatism, acute allergic reactions, hemorrhoids, inflammatory liver disease and inflamed joints. Phytochemical analysis of Uvaria species has revealed flavones, flavonoids, tannins, saponins, polyoxygenated cyclohexene and phenolic compounds as major phyto-constituents. This review is an attempt to highlight the anti-inflammatory activity of Uvaria species by conducting a critical appraisal of the published literature. The ethnopharmacological relevance of Uvaria species in the light of toxicological studies is also discussed herein. An extensive and relevant literature on anti-inflammatory activity of Uvaria species was collected from available books, journals and electronic databases including PubMed, ScienceDirect, Scopus, Proquest and Ovid. Extracts and isolates of Uvaria species exhibited significant anti-inflammatory activity through various mechanisms of action. 6,7-di-O-Methyl-baicalein, flexuvarol B, chrysin, (-)-zeylenol, 6-hydroxy-5,7-dimethoxy-flavone, and pinocembrin were the most potent anti-inflammatory compounds with comparable IC50 with positive controls. Therefore, it is suggested that further research should be carried out to determine the pharmacokinetics, pharmacodynamics and toxicity of these therapeutically significant compounds, to convert the pre-clinical results into clinical data for drug development and design.
The Medicinal Uses, Toxicities and Anti-inflammatory Activity of Polyalthia Species (Annonaceae)

Yao LJ, Jalil J, Attiq A, Hui CC, Zakaria NA

J Ethnopharmacol, 2018 Oct 11.
PMID: 30316887 DOI: 10.1016/j.jep.2018.10.001

ETHNOPHARMACOLOGICAL RELEVANCE: Polyalthia is one of the largest and notable genera in Annonaceae family. Polyalthia species have been widely used in folklore medicine for the treatment of rheumatic fever, gastrointestinal ulcer and generalized body pain. Numerous in vitro and in vivo studies on Polyalthia Species have also corroborated the significant anti-inflammatory potential of its extracts and secondary metabolites.
AIM OF THE STUDY: This review is an attempt to assess the anti-inflammatory activity of Polyalthia species by giving critical appraisal and establishing evidences of their traditional uses. Moreover this review will highlight the lead compounds for future drug development that can serve as a potential anti-inflammatory drug with comparative efficacy and minimum side effects.
MATERIALS AND METHODS: An extensive literature review, focusing the anti-inflammatory potential of Polyalthia species was conducted using the following databases: PubMed, ScienceDirect, SpringerLink, Ovid, Scopus and ProQuest, as well as the locally available books, journals and relevant documents. The reference lists of retrieved papers were also searched for additional studies.
RESULTS: The Polyalthia species have shown significant anti-inflammatory activity through various mechanism of action. The most significant anti-inflammatory mechanism includes the inhibition of nuclear factor kappa B (NF-κB), prostaglandins (PGs), pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS). The data suggests that hydroxycleroda-3,13-dien-15,16-olide and 16-oxocleroda-3,13-dien-15-oic acid, quercetin, rutin, spinasterol, α-spinasterol, goniothalamin and (-)-5-hydroxygoniothalamin are the most potent anti-inflammatory compounds from Polyalthia species with comparable IC50 with positive controls.
CONCLUSIONS: Numerous pharmacological studies have supported the use of Polyalthia species against pain, rheumatic fever, haemorrhages and inflammation in traditional medicine. Flavonoids, diterpenoids, sterols and styrylpyrones from genus Polyalthia are the most significant class of compounds with potent anti-inflammatory activity. Secondary metabolites from these classes should be brought into further research to fill the gaps of knowledge in pharmacokinetics, pharmacodynamics, bioavailability, and toxicity in order to convert the pre-clinical results into clinical data for further investigation.

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