SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade

Accumulating evidence indicates a potential role for bacterial lipopolysaccharide (LPS) in the overactivation of the immune response during SARS-CoV-2 infection. LPS is recognised by Toll-like receptor 4 (TLR4) in innate immunity. Here, we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the SARS-CoV-2 spike (S) protein. LPS binds to the S2 pocket with a lower affinity compared to S1, suggesting its possible role as an intermediate in the TLR4 cascade. Congruently, nuclear factor-kappa B (NF-κB) activation in vitro is strongly boosted by S2. In vivo, however, a boosting effect is observed for both S1 and S2, with the former potentially facilitated by proteolysis. Collectively, our study suggests the S protein may act as a delivery system for LPS in host innate immune pathways. The LPS binding pockets are highly conserved across different SARS-CoV-2 variants and therefore represent potential therapeutic targets.

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Exploring the LPS/TLR4 signal pathway with small molecules

Biochemical Society Transactions ◽

10.1042/bst0381390 ◽

2010 ◽

Vol 38 (5) ◽

pp. 1390-1395 ◽

Cited By ~ 64

Author(s):

Francesco Peri ◽

Matteo Piazza ◽

Valentina Calabrese ◽

Gaetana Damore ◽

Roberto Cighetti

Keyword(s):

Innate Immunity ◽

Small Molecules ◽

Innate Immune ◽

Toll Like Receptor 4 ◽

Innate Immunity Cells ◽

Specific Receptors ◽

Extracellular Side ◽

Tlr4 Activation ◽

Lps Binding

The identification of the bacterial endotoxin receptors for innate immunity, most notably TLR4 (Toll-like receptor 4), has sparked great interest in therapeutic manipulation of the innate immune system. In the present mini-review, several natural and synthetic molecules that modulate the TLR4-mediated LPS (lipopolysaccharide) signalling in animals and humans are considered, and their mechanisms of action are discussed. The process of LPS sensing and signal amplification in humans is based on the sequential action of specific receptors situated in the extracellular side of the innate immunity cells, which bind and transfer LPS to TLR4: LBP (LPS-binding protein), CD14, MD-2 (myeloid differentiation protein 2). We classified the compounds active on TLR4 pathway depending on the specific molecular targets (LPS, LBP, CD14, MD-2 or TLR4). Small molecules developed by our group are described that inhibit LPS-stimulated TLR4 activation by selectively targeting the LPS–CD14 interaction. These compounds have an interesting antiseptic shock, anti-inflammatory and anti-neuropathic pain activity in vivo.

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194 A Non-Gluten Component of Wheat is a Strong Stimulator of Innate Immune Responses In Vitro and In Vivo and Acts via Toll Like Receptor 4

Gastroenterology ◽

10.1016/s0016-5085(10)60165-5 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-36

Author(s):

Yvonne Junker ◽

Donatella Barisani ◽

Daniel A. Leffler ◽

Towia Libermann ◽

Simon T. Dillon ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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A Novel Intravaginal Delivery System for Itraconazole: In Vitro and In Vivo Evaluation

Current Drug Delivery ◽

10.2174/156720109787846289 ◽

2009 ◽

Vol 6 (2) ◽

pp. 151-158 ◽

Cited By ~ 2

Author(s):

N. Dobaria ◽

R. Mashru ◽

A. Badhan ◽

A. Thakkar

Keyword(s):

Delivery System ◽

In Vivo Evaluation ◽

Intravaginal Delivery

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Conifers Phytochemicals: A Valuable Forest with Therapeutic Potential

Molecules ◽

10.3390/molecules26103005 ◽

2021 ◽

Vol 26 (10) ◽

pp. 3005

Author(s):

Kanchan Bhardwaj ◽

Ana Sanches Silva ◽

Maria Atanassova ◽

Rohit Sharma ◽

Eugenie Nepovimova ◽

...

Keyword(s):

Experimental Data ◽

Potential Role ◽

Therapeutic Potential ◽

Fungal Infections ◽

Cell Damage ◽

Cancer Growth ◽

Naturally Occurring ◽

Antioxidant Effects

Conifers have long been recognized for their therapeutic potential in different disorders. Alkaloids, terpenes and polyphenols are the most abundant naturally occurring phytochemicals in these plants. Here, we provide an overview of the phytochemistry and related commercial products obtained from conifers. The pharmacological actions of different phytochemicals present in conifers against bacterial and fungal infections, cancer, diabetes and cardiovascular diseases are also reviewed. Data obtained from experimental and clinical studies performed to date clearly underline that such compounds exert promising antioxidant effects, being able to inhibit cell damage, cancer growth, inflammation and the onset of neurodegenerative diseases. Therefore, an attempt has been made with the intent to highlight the importance of conifer-derived extracts for pharmacological purposes, with the support of relevant in vitro and in vivo experimental data. In short, this review comprehends the information published to date related to conifers’ phytochemicals and illustrates their potential role as drugs.

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Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Cancers ◽

10.3390/cancers13112545 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2545

Author(s):

Ya-Hui Chen ◽

Po-Hui Wang ◽

Pei-Ni Chen ◽

Shun-Fa Yang ◽

Yi-Hsuan Hsiao

Keyword(s):

Cervical Cancer ◽

Potential Role ◽

Treatment Options ◽

Cellular Mechanisms ◽

Anticancer Effects ◽

Clinical Benefits ◽

Underlying Mechanisms

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

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Development of Triamcinolone Acetonide-Loaded Microemulsion as a Prospective Ophthalmic Delivery System for Treatment of Uveitis: In Vitro and In Vivo Evaluation

Pharmaceutics ◽

10.3390/pharmaceutics13040444 ◽

2021 ◽

Vol 13 (4) ◽

pp. 444

Author(s):

Alaa Mahran ◽

Sayed Ismail ◽

Ayat A. Allam

Keyword(s):

Triamcinolone Acetonide ◽

Delivery System ◽

Histopathological Examination ◽

Rabbit Model ◽

Subconjunctival Injection ◽

In Vivo Evaluation ◽

Ternary Phase Diagrams ◽

Ophthalmic Delivery

Treatment of uveitis (i.e., inflammation of the uvea) is challenging due to lack of convenient ophthalmic dosage forms. This work is aimed to determine the efficiency of triamcinolone acetonide (TA)-loaded microemulsion as an ophthalmic delivery system for the treatment of uveitis. Water titration method was used to construct different pseudo-ternary phase diagrams. Twelve microemulsion formulations were prepared using oleic acid, Cremophor EL, and propylene glycol. Among all tested formulations, Formulation F3, composed of oil: surfactant-co-surfactant (1:1): water (15:35:50% w/w, respectively), was found to be stable and showed acceptable pH, viscosity, conductivity, droplet size (211 ± 1.4 nm), and zeta potential (−25 ± 1.7 mV) and almost complete in vitro drug release within 24 h. The in vivo performance of the optimized formulation was evaluated in experimentally uveitis-induced rabbit model and compared with a commercial TA suspension (i.e., Kenacort®-A) either topically or by subconjunctival injection. Ocular inflammation was evaluated by clinical examination, white blood cell count, protein content measurement, and histopathological examination. The developed TA-loaded microemulsion showed superior therapeutic efficiency in the treatment of uveitis with high patient compliance compared to commercial suspension. Hence, it could be considered as a potential ocular treatment option in controlling of uveitis.

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Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

Biomedicines ◽

10.3390/biomedicines9060599 ◽

2021 ◽

Vol 9 (6) ◽

pp. 599

Author(s):

Víctor Farré-Alins ◽

Alejandra Palomino-Antolín ◽

Paloma Narros-Fernández ◽

Ana Belen Lopez-Rodriguez ◽

Céline Decouty-Perez ◽

...

Keyword(s):

Injury Severity ◽

White Blood Cells ◽

Serum Amyloid ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Important Link ◽

Tlr4 Mrna ◽

Serum Amyloid A1

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.

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