Liming Zhang

Jellyfish stings are the most common type of marine life injuries. However, at present, the treatment measures against jellyfish stings are mostly empirical and supportive, with uncertain therapeutic outcomes, and there is a lack of specific antidotes based on the toxic mechanism of jellyfish venom in clinical practice. In our previous study, polyphenol epigallocatechin-3-gallate (EGCG) was found to neutralize the toxicity of jellyfish Nemopilema nomurai venom (NnV) in vivo and in vitro. Herein we further demonstrated that EGCG exerted its antagonistic effect against NnV through inhibiting the oxidative stress, pro-apoptotic proteins, and systemic inflammatory responses. Subsequently, we constructed a polyethylene glycol (PEG)-EGCG/tetracycline hydrochloride (HTC) co-loaded micellar nanocomplex in order to enhance the stability and bioavailability of EGCG in vivo, which successfully integrated the membrane-repair function of PEG, the enzyme inhibitory effect of HTC and the antioxidant properties of EGCG. Notably, this micellar nanocomplex demonstrated significant protective effects against both functional damage and pathological alterations in a non-lethal NnV-envenomed mouse model. When administered 1 h after NnV envenomation, EGCG (40 mg/kg), HTC and PEG-EGCG (containing 40 mg/kg EGCG) only partially improved abnormal blood biochemical indicators and moderately alleviated histopathologic damage, and PEG-EGCG/HTC containing merely 8 mg/kg EGCG completely mitigated the toxic reactions in envenomed mice. In the preventive regimen, the administration of EGCG, HTC or PEG-EGCG 30 min before exposure showed no significant improvement in abnormal blood biochemical indicators and histopathologic damage, while PEG-EGCG/HTC could still significantly improve the functional impairments and histopathologic damage of the heart and liver in NnV-envenomed mice. These findings suggest the clinical translational potential of PEG-EGCG/HTC against jellyfish envenomation.

Excessive ultraviolet B (UVB) exposure is the leading environmental contributor to the development of skin aging, also referred to as photoaging. We previously obtained a group of modified antioxidant peptides (WP5, LW5 and YY6), which were derived from marine organisms, through a single amino acid substitution, and demonstrated that the antioxidant peptides exhibited apparent protective effects against UVB-induced oxidative damage in human keratinocyte cells. Nonetheless, it remains uncertain whether they can alleviate skin photoaging caused by UVB. This research aims to investigate the anti-photoaging effects of the antioxidant peptides in vitro and in vivo and the underlying molecular mechanisms. We found that the antioxidant peptides significantly alleviated the senescence of HDF-a cells induced by UVB and suppressed the expression of matrix metalloproteinases (MMPs) and the degradation of collagen I, and the mitogen-activated protein kinase (MAPK) pathways, particularly the p38 MAPK pathway, might involve in anti-photoaging effects of the antioxidant peptides in HDF-a cells. Furthermore, an emulsion containing antioxidant peptides was prepared, and it was also found to inhibit the expression of MMPs and inflammation factors IL-6 and IL-1β in the mice exposed to UVB. Our results suggest that these antioxidant peptides might be applied as effective components in cosmetics for retarding skin photoaging in the future.

Nemopilema nomurai is a species of common large toxic jellyfish in China seas, and its tentacle tissues contain various types of nematocysts. However, the correlation between the morphology and function of nematocysts still remains unclear. In this study, we first obtained two monomorphic nematocysts with high-purity from N. nomurai, namely Anisorhizas and O-isorhizas, by density gradient centrifugation: the Anisorhizas is small and rod-shaped and the O-isorhizas is larger and spherical. Upon deionized water stimulation, O-isorhizas exhibited a stronger discharge capability than Anisorhizas. The nematocyst contents of Anisorhizas (AnC) and O-isorhizas (OnC) were extracted separately, and their composition and bioactivities were analyzed simultaneously. The protein bands by SDS-PAGE revealed similar distributions in AnC and OnC, except that the protein band distribution in OnC was more extensive. OnC showed stronger cytotoxicity, hemolytic activity, metalloprotease activity, and serine protease activity than AnC. In contrast, AnC exhibited a higher antioxidant activity and significant proinflammatory activity. Both AnC and OnC exhibited antimicrobial activities against certain marine pathogenic Vibrios. These results suggest that O-isorhizas, with the larger capsule capability, stronger discharge ability and toxicity, likely plays a major role in inducing toxic effects and tissue damage, while Anisorhizas, being smaller and less toxic, may undertake preferentially other functions, such as synergistic predation, environmental stress adaptation, and energy balance maintenance. This study provides insights into the morpho-functional relationship between various types of nematocysts, and also lays a foundation for further exploration of the functional diversity of nematocysts and the mechanisms underlying jellyfish envenomation.

Nemopilema nomurai is a species of common large toxic jellyfish in China seas, and its tentacle tissues contain various types of nematocysts. However, the correlation between the morphology and function of nematocysts still remains unclear. In this study, we first obtained two monomorphic nematocysts with high-purity from N. nomurai, namely Anisorhizas and O-isorhizas, by density gradient centrifugation: the Anisorhizas is small and rod-shaped and the O-isorhizas is larger and spherical. Upon deionized water stimulation, O-isorhizas exhibited a stronger discharge capability than Anisorhizas. The nematocyst contents of Anisorhizas (AnC) and O-isorhizas (OnC) were extracted separately, and their composition and bioactivities were analyzed simultaneously. The protein bands by SDS-PAGE revealed similar distributions in AnC and OnC, except that the protein band distribution in OnC was more extensive. OnC showed stronger cytotoxicity, hemolytic activity, metalloprotease activity, and serine protease activity than AnC. In contrast, AnC exhibited a higher antioxidant activity and significant proinflammatory activity. Both AnC and OnC exhibited antimicrobial activities against certain marine pathogenic Vibrios. These results suggest that O-isorhizas, with the larger capsule capability, stronger discharge ability and toxicity, likely plays a major role in inducing toxic effects and tissue damage, while Anisorhizas, being smaller and less toxic, may undertake preferentially other functions, such as synergistic predation, environmental stress adaptation, and energy balance maintenance. This study provides insights into the morpho-functional relationship between various types of nematocysts, and also lays a foundation for further exploration of the functional diversity of nematocysts and the mechanisms underlying jellyfish envenomation.

Superoxide dismutase (SOD) plays important roles in the balance of oxidation and antioxidation in body mostly by scavenging superoxide anion free radicals (O₂^.−). Previously, we reported a novel Cu/Zn SOD from jellyfish Cyanea capillata, named CcSOD1, which exhibited excellent SOD activity and high stability. TAT peptide is a common type of cell penetrating peptides (CPPs) that efficiently deliver extracellular biomacromolecules into cytoplasm. In this study, we constructed a recombinant expression vector that combined the coding sequences of TAT peptide and CcSOD1, and then obtained sufficient and high-purity TAT-CcSOD1 fusion protein. Compared with some reported SODs/CPP-SODs, TAT-CcSOD1 possessed stronger tolerance to heat and acid–base environment. TAT-CcSOD1 efficiently penetrated cell membrane and significantly enhanced the O₂^.− scavenging ability in cells, and attenuated H₂O₂-induced cytotoxicity and NO generation in HaCaT cells. This study serves as a critical step forward for the application of TAT-CcSOD1 as a potential protective/therapeutic agent against oxidative stress-related conditions in the future.

Background: Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed. Methods: We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood–brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed. Results: The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality. Conclusion: The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders. Graphical

Tetrodotoxin (TTX) is a highly fatal marine biotoxin. Constantly increasing intoxications and the lack of specific antitoxic drugs in clinical applications highlight the need for further research into the toxic effects of TTX. Current reports on poisoning cases and the TTX toxicity mechanism suggest that the blocking of voltage-gated sodium channels (VGSCs) by TTX is probably reversible, but direct evidence of this is lacking, as far as we are aware. This study explored the acute toxic effects of TTX at sub-lethal doses via different routes, analyzing variations in muscle strength and TTX concentration in the blood in mice. We found that the loss of muscle strength in mice caused by TTX was dose-dependent and reversible, and the death time and muscle strength variations after oral gavage with TTX appeared to occur later and were more variable than those after intramuscular injection. In conclusion, we systematically compared the acute toxic effects of TTX for two different administration routes at sub-lethal doses, directly verifying the reversible reaction of TTX blocking VGSCs and speculating that averting a complete block of VGSCs by TTX could be an effective strategy for preventing death from TTX poisoning. This work may provide data for the diagnosis and treatment of TTX poisoning.

Thioredoxin (Trx) plays a critical role in maintaining redox balance in various cells and exhibits anti-oxidative, anti-apoptotic, and anti-inflammatory effects. However, whether exogenous Trx can inhibit intracellular oxidative damage has not been investigated. In previous study, we have identified a novel Trx from the jellyfish Cyanea capillata, named CcTrx1, and confirmed its antioxidant activities in vitro. Here, we obtained a recombinant protein, PTD-CcTrx1, which is a fusion of CcTrx1 and protein transduction domain (PTD) of HIV TAT protein. The transmembrane ability and antioxidant activities of PTD-CcTrx1, and its protective effects against H₂O₂-induced oxidative damage in HaCaT cells were also detected. Our results revealed that PTD-CcTrx1 exhibited specific transmembrane ability and antioxidant activities, and it could significantly attenuate the intracellular oxidative stress, inhibit H₂O₂-induced apoptosis, and protect HaCaT cells from oxidative damage. The present study provides critical evidence for application of PTD-CcTrx1 as a novel antioxidant to treat skin oxidative damage in the future.

Jellyfish stings are the most common marine animal injuries worldwide, with approximately 150 million envenomation cases annually, and the victims may suffer from severe pain, itching, swelling, inflammation, arrhythmias, cardiac failure, or even death. Consequently, identification of effective first aid reagents for jellyfish envenoming is urgently needed. Here, we found that the polyphenol epigallocatechin-3-gallate (EGCG) markedly antagonized the hemolytic toxicity, proteolytic activity, and cardiomyocyte toxicity of the jellyfish Nemopilema nomurai venom in vitro and could prevent and treat systemic envenoming caused by N. nomurai venom in vivo. Moreover, EGCG is a natural plant active ingredient and widely used as a food additive without toxic side effects. Hence, we suppose that EGCG might be an effective antagonist against systemic envenoming induced by jellyfish venom.