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Bee venom is a natural toxin produced by honeybees and plays an important role in defending bee colonies. Bee venom has several kinds of peptides, including melittin, apamin, adolapamine, and mast cell degranulation peptides. Apamin accounts for about 2%–3% dry weight of bee venom and is a peptide neurotoxin that contains 18 amino acid residues that are tightly crosslinked by two disulfide bonds. It is well known for its pharmacological functions, which irreversibly block Ca2+-activated K+ (SK) channels. Apamin regulates gene expression in various signal transduction pathways involved in cell development. The aim of this study was to review the current understanding of apamin in the treatment of apoptosis, fibrosis, and central nervous system diseases, which are the pathological processes of various diseases. Apamin’s potential therapeutic and pharmacological applications are also discussed.

Small-conductance calcium-activated potassium channel 2 (SK2) serves a variety of biological functions by coupling intracellular calcium dynamics with membrane potential. SK2 modulators are in development for the treatment of neurological and cardiovascular diseases, though the mechanisms of pharmacological modulation remain incompletely understood. We determined structures of an SK2-4 chimeric channel in Ca -bound and Ca -free conformations and in complex with the bee toxin apamin, a small molecule inhibitor, and a small molecule activator. The structures revealed that the S3-S4 linker forms a hydrophobic constriction at the extracellular opening of the pore. Apamin binds to this extracellular constriction and blocks the exit of potassium ions. Furthermore, we identified a structurally related SK2 inhibitor and activator that bind to the transmembrane domains. The compounds exert opposing effects on gating by differentially modulating the conformation of the S6 helices. These results provide important mechanistic insights to facilitate the development of targeted SK2 channel therapeutics.

Parkinson’s disease (PD), a neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons. The pathogenesis of PD is associated with several factors including oxidative stress, inflammation, and mitochondrial dysfunction. Ca2+ signaling plays a vital role in neuronal signaling and altered Ca2+ homeostasis has been implicated in many neuronal diseases including PD. Recently, we reported that apamin (APM), a selective antagonist of the small-conductivity Ca2+-activated K+ (SK) channel, suppresses neuroinflammatory response. However, the mechanism(s) underlying the vulnerability of DA neurons were not fully understood. In this study, we investigated whether APM affected 1-methyl-4-phenyl pyridinium (MPP+)-mediated neurotoxicity in SH-SY5Y cells and rat embryo primary mesencephalic neurons. We found that APM decreased Ca2+ overload arising from MPP+-induced neurotoxicity response through downregulating the level of CaMKII, phosphorylation of ERK, and translocation of nuclear factor NFκB/signal transducer and activator of transcription (STAT)3. Furthermore, we showed that the correlation of MPP+-mediated Ca2+ overload and ERK/NFκB/STAT3 in the neurotoxicity responses, and dopaminergic neuronal cells loss, was verified through inhibitors. Our findings showed that APM might prevent loss of DA neurons via inhibition of Ca2+-overload-mediated signaling pathway and provide insights regarding the potential use of APM in treating neurodegenerative diseases.

The small-conductance calcium-activated potassium (SK1-3 or K 2) channels regulate the intrinsic excitability and firing frequency of excitable cells. SK channels are modulated by a variety of distinct modulators; however, the underlying mechanisms remain elusive. Here, we present four cryoelectron microscopy structures of the human SK2-calmodulin complex bound with apamin, UCL1684, AP30663, and CAD-1883, elucidating their distinct binding sites and regulatory mechanisms. Apamin and UCL1684 compete for a similar binding site above the selectivity filter, which is formed by the distinct S3-S4 linker of SK2. CAD-1883 glues the N-lobe of calmodulin and the S4-S5 linker of SK2, reinforcing the open state. In contrast, AP30663 resides in the central cavity of SK2, blocking ion conductance. This study reveals multiple modulation sites in SK2 and the molecular mechanisms for the inhibition and potentiation of SK channels, which could advance rational drug design targeting SK2 channel for the treatment of cardiovascular and neurological disorders.

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

Neuroinflammation plays a vital role in neurodegenerative conditions. Microglia are a key component of the neuroinflammatory response. There is a growing interest in developing drugs to target microglia and thereby control neuroinflammatory processes. Apamin (APM) is a specifically selective antagonist of small conductance calcium-activated potassium (SK) channels. However, its effect on neuroinflammation is largely unknown. We examine the effects of APM on lipopolysaccharide (LPS)-stimulated BV2 and rat primary microglial cells. Regarding the molecular mechanism by which APM significantly inhibits proinflammatory cytokine production and microglial cell activation, we found that APM does so by reducing the expression of phosphorylated CaMKII and toll-like receptor (TLR4). In particular, APM potently suppressed the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription (STAT)3 and phosphorylated mitogen-activated protein kinases (MAPK)-extracellular signal-regulated kinase (ERK). In addition, the correlation of NF-κB/STAT3 and MAPK-ERK in the neuroinflammatory response was verified through inhibitors. The literature and our findings suggest that APM is a promising candidate for an anti-neuroinflammatory agent and can potentially be used for the prevention and treatment of various neurological disorders.

Renal fibrosis is a progressive and chronic process that influences kidneys with chronic kidney disease (CKD), irrespective of cause, leading to irreversible failure of renal function and end-stage kidney disease. Among the signaling related to renal fibrosis, transforming growth factor-β1 (TGF-β1) signaling is a major pathway that induces the activation of myofibroblasts and the production of extracellular matrix (ECM) molecules. Apamin, a component of bee venom (BV), has been studied in relation to various diseases. However, the effect of apamin on renal interstitial fibrosis has not been investigated. The aim of this study was to estimate the beneficial effect of apamin in unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-β1-induced renal fibroblast activation. This study revealed that obstructive kidney injury induced an inflammatory response, tubular atrophy, and ECM accumulation. However, apamin treatment suppressed the increased expression of fibrotic-related genes, including α-SMA, vimentin, and fibronectin. Administration of apamin also attenuated the renal tubular cells injury and tubular atrophy. In addition, apamin attenuated fibroblast activation, ECM synthesis, and inflammatory cytokines such as TNF-α, IL-1β, and IL-6 by suppressing the TGF-β1-canonical and non-canonical signaling pathways. This study showed that apamin inhibits UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibroblasts activation in vitro. Apamin inhibited the inflammatory response, tubular atrophy, ECM accumulation, fibroblast activation, and renal interstitial fibrosis through suppression of TGF-β1/Smad2/3 and STAT3 signaling pathways. These results suggest that apamin might be a potential therapeutic agent for renal fibrosis.Key messagesUUO injury can induce renal dysfunction; however, apamin administration prevents renal failure in UUO mice.Apamin inhibited renal inflammatory response and ECM deposition in UUO-injured mice.Apamin suppressed the activation of myofibroblasts in vivo and in vitro.Apamin has the anti-fibrotic effect on renal fibrosis via regulation of TGF-β1 canonical and non-canonical signaling.

Bee venom (BV) is a rich source of secondary metabolites from honeybees (Apis mellifera L.). It contains a variety of bioactive ingredients including peptides, proteins, enzymes, and volatile metabolites. The compounds contribute to the venom’s observed biological functions as per its anti-inflammatory and anticancer effects. The antimicrobial action of BV has been shown in vitro and in vivo experiments against bacteria, viruses, and fungi. The synergistic therapeutic interactions of BV with antibiotics has been reported. The synergistic effect contributes to a decrease in the loading and maintenance dosage, a decrease in the side effects of chemotherapy, and a decrease in drug resistance. To our knowledge, there have been no reviews on the impact of BV and its antimicrobial constituents thus far. The purpose of this review is to address the antimicrobial properties of BV and its compounds.

Background/Aim We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP. Methods AP was induced via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 μg/kg) every hour for 6 times. In the apamin treatment group, apamin was administered subcutaneously (10, 50, or 100 μg/kg) at both 18 and 1 h before the first cerulein injection. The mice were sacrificed at 6 h after the final cerulein injection. Blood samples were obtained to determine serum amylase and lipase levels, as well as cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examination, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction. Furthermore, we isolated the pancreatic acinar cells to specify the role of apamin in AP. Results Pre-treatment with apamin inhibited histological damage, pancreatic weight/body weight ratio, serum level of amylase and lipase, MPO activity, and cytokine production. In addition, apamin treatment significantly inhibited cerulein-induced pancreatic acinar cell death. Furthermore, apamin treatment inhibited the cerulein-induced activation of c-Jun NH 2 -terminal kinases (JNK). Conclusions These results could suggest that apamin could protect against AP by inhibition of JNK activation.

Neural activity decreases with age and therefore may be causative in age-related decrements in cognition. A major negative controller of neural activity is calcium-activated small conductance potassium channels. These ion channels are blocked by the apamin molecule, which is a component of bee venom. We show that the treatment of aged mice with apamin increases some cognitive behaviors, but not all.