Shikonin alleviates the biotoxicity produced by pneumococcal pneumolysin

Zhao, Xiaoru; Zhou, Yonglin; Wang, Laiying; Li, Meng; Shi, Dan; Li, Dan; Wang, Jianfeng

doi:10.1016/j.lfs.2017.04.002

Cited by 25 publications

(19 citation statements)

References 41 publications

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“…Also, in silico inhibitors of PgdA have been described ( Bui et al, 2011 ). Multiple studies have shown that inhibition of pneumolysin, a virulence factors known to be essential for bacterial survival in the respiratory tract, reduces mortality in in vivo models ( Kadioglu et al, 2008 ; Arzanlou et al, 2011 ; Li et al, 2015 ; Zhao et al, 2016 , 2017 ; Song et al, 2017a , b ). Apart from direct inhibition, also sequestration of pneumolysin in liposomes has been shown beneficial on infection outcome in animal models ( Henry et al, 2015 ; Baumgartner et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

et al. 2020

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Pneumonia, of which Streptococcus pneumoniae is the most common causative agent, is considered one of the three top leading causes of death worldwide. As seen in other bacterial species, antimicrobial resistance is on the rise for this pathogen. Therefore, there is a pressing need for novel antimicrobial strategies to combat these infections. Recently, uridine diphosphate glucose pyrophosphorylase (UDPG:PP) has been put forward as a potential drug target worth investigating. Moreover, earlier research demonstrated that streptococci lacking a functional galU gene (encoding for UDPG:PP) were characterized by significantly reduced in vitro and in vivo virulence. Therefore, in this study we evaluated the anti-virulence activity of potential UDPG:PP inhibitors. They were selected in silico using a tailor-made streptococcal homology model, based on earlier listerial research. While the compounds didn't affect bacterial growth, nor affected in vitro adhesion to and phagocytosis in macrophages, the amount of polysaccharide capsule was significantly reduced after co-incubation with these inhibitors. Moreover, co-incubation proved to have a positive effect on survival in an in vivo Galleria mellonella larval infection model. Therefore, rather than targeting bacterial survival directly, these compounds proved to have an effect on streptococcal virulence by lowering the amount of polysaccharide and thereby probably boosting recognition of this pathogen by the innate immune system. While the compounds need adaptation to broaden their activity to more streptococcal strains rather than being strain-specific, this study consolidates UDPG:PP as a potential novel drug target.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

et al. 2020

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“…The various PLY antagonists identified, none of which was found to possess antimicrobial activity, effectively attenuated the hemolytic activity of PLY, as well as the injurious effects of the toxin on an alveolar epithelial cell line in vitro [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. In addition, subcutaneous administration of these various natural antagonists of PLY resulted in significantly improved survival in a murine model of intranasal pneumococcal lung infection [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. The various members of each category of natural antagonists of PLY are summarized as follows: phytosterols : β-sitosterol was initially identified as a cholesterol-mimic, interacting with the conserved cholesterol-binding site located on domain 4 of PLY, with potency comparable with that of cholesterol [ 99 ].…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

“…All three agents were found to cause inhibition of the hemolytic activity of PLY at concentrations of around 16 µg/mL by apparent interference with the oligomerization of toxin monomers [ 103 , 104 , 105 ] naphthoquinones: two members of this class of chemical agent viz. shikonin {also known as alkanin: 5,8-dihydroxy-2-[(1 S )-1-hydroxy-4-methylpent-3-en-1 yl]naphthalene-1,4-dione} [ 106 ] and juglone (5-hydroxy-1,4-naphthalenedione) [ 107 ] have also been reported to inhibit the pore-forming activity of PLY via interference with toxin oligomerization. Shikonin demonstrated superior activity, causing almost complete inhibition of the hemolytic activity of PLY at concentrations ≥1 µg/mL [ 106 ].…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

“…shikonin {also known as alkanin: 5,8-dihydroxy-2-[(1 S )-1-hydroxy-4-methylpent-3-en-1 yl]naphthalene-1,4-dione} [ 106 ] and juglone (5-hydroxy-1,4-naphthalenedione) [ 107 ] have also been reported to inhibit the pore-forming activity of PLY via interference with toxin oligomerization. Shikonin demonstrated superior activity, causing almost complete inhibition of the hemolytic activity of PLY at concentrations ≥1 µg/mL [ 106 ]. Although not addressed in these studies [ 106 , 107 ], it is noteworthy that 1,4-naphthoquinones possess pro-oxidative properties that may promote oxidative inactivation of membrane pore formation mediated by PLY and other CDCs via oxidative inactivation of the essential cysteine residue located in the undecapeptide membrane insertion region of the toxin [ 51 ].…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

“…Shikonin demonstrated superior activity, causing almost complete inhibition of the hemolytic activity of PLY at concentrations ≥1 µg/mL [ 106 ]. Although not addressed in these studies [ 106 , 107 ], it is noteworthy that 1,4-naphthoquinones possess pro-oxidative properties that may promote oxidative inactivation of membrane pore formation mediated by PLY and other CDCs via oxidative inactivation of the essential cysteine residue located in the undecapeptide membrane insertion region of the toxin [ 51 ].…”

Section: Update On Pneumolysin-targeted Therapeutic Strategiesmentioning

confidence: 99%

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Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

Anderson

Nel

Feldman

2018

IJMS

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Pneumolysin (PLY), a member of the family of Gram-positive bacterial, cholesterol-dependent, β-barrel pore-forming cytolysins, is the major protein virulence factor of the dangerous respiratory pathogen, Streptococcus pneumoniae (pneumococcus). PLY plays a major role in the pathogenesis of community-acquired pneumonia (CAP), promoting colonization and invasion of the upper and lower respiratory tracts respectively, as well as extra-pulmonary dissemination of the pneumococcus. Notwithstanding its role in causing acute lung injury in severe CAP, PLY has also been implicated in the development of potentially fatal acute and delayed-onset cardiovascular events, which are now recognized as being fairly common complications of this condition. This review is focused firstly on updating mechanisms involved in the immunopathogenesis of PLY-mediated myocardial damage, specifically the direct cardiotoxic and immunosuppressive activities, as well as the indirect pro-inflammatory/pro-thrombotic activities of the toxin. Secondly, on PLY-targeted therapeutic strategies including, among others, macrolide antibiotics, natural product antagonists, cholesterol-containing liposomes, and fully humanized monoclonal antibodies, as well as on vaccine-based preventive strategies. These sections are preceded by overviews of CAP in general, the role of the pneumococcus as the causative pathogen, the occurrence and types of CAP-associated cardiac complication, and the structure and biological activities of PLY.

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Bioavailability and Pharmacological Properties of Shikonin‐ A Phytocompound from Lithospermum Erythrorhizon

Biswal,

Biswal

2024

ChemistrySelect

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Lithospermum erythrorhizon, commonly known as gromwell, is a valuable medicinal plant with a wide range of pharmacological activities. Its roots are rich in bioactive compounds such as phenolic acids, flavonoids, naphthoquinones, alkaloids, and other phytochemicals. Among these, shikonin, a naphthoquinone, stands out due to its remarkable pharmacological properties, including anti‐inflammatory, antimicrobial, and anticancer activities. This review provides an overview of the plant's morphology, distribution, ethnomedical applications, and phytochemistry, with a particular focus on shikonin. Online databases like PubMed, Google Scholar, Web of Science, and Scopus were used to gather information using keywords such as Lithospermum erythrorhizon, shikonin, phytochemistry, and pharmacological activities. Findings highlight that shikonin demonstrates significant pharmacodynamic effects, particularly in cancer therapy. However, its hydrophobic nature limits its bioavailability. To address this, encapsulating shikonin in advanced drug delivery systems, such as micelles, can enhance its solubility, stability, and therapeutic efficacy. This review underscores the potential of shikonin as a novel drug for treating various diseases, especially cancer, and emphasizes the importance of innovative delivery strategies to maximize its clinical applications.

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Shikonin alleviates the biotoxicity produced by pneumococcal pneumolysin

Cited by 25 publications

References 41 publications

In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

Bioavailability and Pharmacological Properties of Shikonin‐ A Phytocompound from Lithospermum Erythrorhizon

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