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Cantharidin (CTD) is a compound of mylabris with antitumor activity, and CTD can potentially cause toxicity, especially hepatotoxicity. The classical Traditional Chinese Medicine prescription Shuganning injection (SGNI) exerts notable anti-inflammatory and hepatoprotective effects. However, the protective property and mechanism of SGNI against CTD-induced liver injury (CTD-DILI) have not yet been elucidated. To investigate the effective compounds, potential targets, and molecular mechanism of SGNI against CTD-DILI, network pharmacology combined with experiments were performed. This study found that SGNI could act with 62 core therapeutic targets, regulate multiple biological processes such as apoptosis, and oxidative stress, and influence apoptotic and p53 signaling pathways to treat CTD-DILI. Subsequently, HepaRG cell experiments demonstrated that SGNI pretreatment significantly increased the levels of GSH-Px and SOD, inhibiting the apoptosis induced by CTD. In vivo, according to H&E staining, SGNI can reduce the degeneration of hepatocytes and cytoplasmic vacuolation in mice exposed to CTD. Western blot analysis results indicated that SGNI pretreatment significantly suppressed the expressions of Caspase-3 and Bax while increasing the expression of Bcl-2. In conclusion, SGNI acted as a protective agent against CTD-DILI by inhibiting apoptosis.

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Recent advances in digitalization and increasing integration of international markets are paving the way for a new generation of firms to use non-traditional entry modes that are largely marginalized in previous entry mode studies. While extant research revolves around the level of resource commitment and control in foreign activities, non-traditional modes are encapsulated by the extent of embeddedness required for exploring new and/or exploiting existing resources. In particular, we draw attention to four such categories of non-traditional entry modes the literature has touched on, i.e., capital access, innovation outposts, virtual presence, and the managed ecosystem. We explore the key attributes, antecedents, and strategic implications of these modes. Our paper highlights the need for enriching current entry mode research by considering a broader range of entry mode activities available to firms as well as employing new theoretical perspectives to understand the complex phenomena of internationalization.

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Gut-associated microbes can influence insect health and fitness. Understanding the structure of bacterial communities provides valuable insights on how different species may be selected and their functional characteristics in their hosts. The neutral model is powerful in predicting the structure of microbial communities, but its application in insects remains rare. Here, we examined the contribution of neutral processes to the gut-associated bacterial communities in Helicoverpa armigera caterpillars collected from different maize varieties at four locations. The gut-associated bacteria can be assigned to 37 Phyla, 119 orders, and 515 genera, with each individual gut containing 17-75% of the OTUs and 19-79% of the genera in the pooled samples of each population. The distribution patterns of most (75.59-83.74%) bacterial taxa were in good agreement with the neutral expectations. Of the remaining OTUs, some were detected in more individual hosts than would be predicted by the neutral model (i.e., above-partition), and others were detected in fewer individual hosts than predicted by the neutral model (i.e., below-partition). The bacterial taxa in the above-partitions were potentially selected by the caterpillar hosts, while the bacteria in the below-partitions may be preferentially eliminated by the hosts. Moreover, the gut-associated microbiota seemed to vary between maize varieties and locations, so ecological parameters outside hosts can affect the bacterial communities. Therefore, the structure of gut microbiota in the H. armigera caterpillar was mainly determined by stochastic processes, and the bacteria in the above-partition warrant further investigation for their potential roles in the caterpillar host.

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The multicolored Asian lady beetle, Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), is an important natural enemy in agricultural ecosystems. In spite of being a carnivore consuming protein-rich preys, the lady beetles often consume carbohydrate-rich food like nectar or honeydew. However, most studies on nutrition regulation of carnivores mainly focus on protein and lipid, two major macronutrients in preys. In this study, nutrition regulation of protein and carbohydrate has been investigated in the 4th instar larvae of H. axyridis using Geometric Framework. We provided the insects two pairs of foods, one a protein-biased one and the second carbohydrate-biased, to determine the intake target. We then confined them to nutritionally imbalanced foods to examine how they regulated food intake to achieve maximal performance. The larvae performed well on the 2 foods that containing the closest P : C ratios to the intake target, but, surprisingly, the lipid content was much lower than that in the choice experiment. The lady beetles seemed to maintain the optimal lipid content by consuming carbohydrate-rich food. Moreover, consuming the carbohydrate-rich food was less metabolically expensive than the protein-rich food. Therefore, switching behavior between plant and animal foods actually reflects their nutritive needs. These findings extended our understanding of predator forage behavior and its influence on food web in ecosystems, and shed light on the role of agri-environment schemes in meeting the nutritional need of predators in field.

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Sterols serve structural and physiological roles in insects. However, insects and other arthropods have lost many genes in the sterol biosynthesis pathway, so they must acquire sterols from their food. Sterols occur naturally as free (unconjugated) molecules, and as conjugated ones (mostly steryl esters). Once sterols are ingested and make their way into the gut, steryl esters can be converted into free sterols by Magro protein, a lipase excreted by enterocytes. Sterols in the free form enter midgut enterocytes through NPC1b and are then transported to the smooth endoplasmic reticulum membrane for possible metabolism. For most insect herbivores, phytosterol dealkylation converts plant sterols into cholesterol. Some ingested sterols may also be consumed by microbiota dwelling inside the insect gut lumen; bacteria use sterols as a source of carbon and energy. Further studies will reveal interesting and exciting discoveries regarding the pathways for the dietary sterols entering the insect alimentary canal.

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BACKGROUND: Insects cannot synthesize sterols and must acquire them from food. The mechanisms underlying how insects uptake dietary sterols are largely unknown except that NPC1b, an integral membrane protein, has been shown to be responsible for dietary cholesterol uptake in Drosophila melanogaster. However, whether NPC1b orthologs in other insect species, particularly the economically important pests, function similarly remains to be determined. RESULTS: In this study, we characterized the function of NPC1b in Helicoverpa armigera, a global pest that causes severe yield losses to many important crops. Limiting dietary cholesterol uptake to insects significantly inhibited food ingestion and weight gain. Compared to the wild-type H. armigera, the CRISPR/Cas9-edited NPC1b mutant larvae were incapable of getting adequate cholesterol and died in their early life stage. Gene expression profile and in situ hybridization analyses indicated that NPC1b was mainly expressed in the midgut where dietary cholesterol was absorbed. Expression of NPC1b was also correlated with the feeding life stages and was especially upregulated during early larval instars. Protein-ligand docking and sequence similarity analyses further demonstrated that NPC1b proteins of lepidopteran insects shared a relatively conserved cholesterol binding region, NPC1b_NTD, which, however, was highly divergent from bees-derived sequences. CONCLUSION: NPC1b was crucial for dietary cholesterol uptake and growth of H. armigera, and therefore could serve as an insecticide target for the development of a novel pest-management approach to control this economically significant insect pest with little off-target effect on bees and sterol-autotrophic animals. © 2020 Society of Chemical Industry.

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Haemophilus parasuis (H. parasuis) is the causative agent of Glässer's disease, a severe membrane inflammation disorder. Previously we showed that Baicalin (BA) possesses anti-inflammatory effects via the NLRP3 inflammatory pathway in an LPS-challenged piglet model. However, whether BA has anti-inflammatory effects upon H. parasuis infection is still unclear. This study investigated the anti-inflammatory effects and mechanisms of BA on H. parasuis-induced inflammatory responses via the NF-κB and NLRP3 inflammasome pathway in piglet mononuclear phagocytes (PMNP). Our data demonstrate that PMNP, when infected with H. parasuis, induced ROS (reactive oxygen species) production, promoted apoptosis, and initiated transcription expression of IL-6, IL-8, IL-10, PGE2, COX-2 and TNF-α via the NF-κB signaling pathway, and IL-1ß and IL-18 via the NLRP3 inflammasome signaling pathway. Moreover, when BA was administrated, we observed a reduction in ROS production, suppression of apoptosis, and inhibition of the activation of NF-κB and NLRP3 inflammasome signaling pathway in PMNP treated with H. parasuis. To our best knowledge, this is the first example that uses piglet primary immune cells for an H. parasuis infection study. Our data strongly suggest that BA can reverse the inflammatory effect initiated by H. parasuis and possesses significant immunosuppression activity, which represents a promising therapeutic agent in the treatment of H. parasuis infection.

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In this study, the anti-inflammatory effects and mechanisms of baicalin on LPS-induced NLRP3 inflammatory pathway were investigated in piglet mononuclear phagocytes (control, LPS stimulation, LPS stimulation + 12.5 µg/ml baicalin, LPS stimulation + 25 µg/ml baicalin, LPS stimulation + 50 µg/ml baicalin and LPS stimulation + 100 µg/ml baicalin). The levels of reactive oxygen species (ROS), the secretion levels of IL-1ß, IL-18 and TNF-α, mRNA expression levels of IL-1ß, IL-18, TNF-α and NLRP3, as well as the protein levels of cleaved caspase-1 p20 were significantly increased after LPS-challengein vitro However, LPS stimulation did not influence apoptosis-associated speck-like protein and caspase-1 mRNA levels, which are also components of the NLRP3 inflammasome. Baicalin at 50 µg/ml and 100 µg/ml could inhibit the production of ROS, TNF-α, IL-1ß and IL-18, and down-regulate mRNA expression of IL-1ß, IL-18, TNF-α and NLRP3, as well as expression of cleaved caspase-1 p20. These results showed that the anti-inflammatory effects of baicalin occurred via the regulation of the release of ROS and mRNA expression of NLRP3. The anti-inflammatory activity of baicalin could be related to the suppression of NLRP3 inflammasome pathway under LPS stimulation.

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Acetaminophen (AAP) and N-acetylcysteine (NAC) have been found to have anti-inflammatory effects via the TLR-NF-κB pathway in LPS-challenged piglets. However, the action mechanisms employed by AAP and NAC have yet to be completely understood. This study investigated the anti-inflammatory effects and mechanisms of AAP and NAC on LPS-induced inflammatory responses via the NLRP3 inflammasome pathway in piglet mononuclear phagocytes. The results show that mRNA expression levels of IL-1ß, IL-18 and NLRP3, as well as the protein level of cleaved caspase-1, are significantly increased after LPS challenge in vitro. LPS stimulation did not change ASC and caspase-1 mRNA levels, which were components of NLRP3 inflammasome complex. AAP (0.5-1.0 mM) and NAC (0.5-1.0 mM) used individually or in combination could down-regulate protein expression of cleaved caspase-1 and mRNA expression of IL-1ß, IL-18 and NLRP3. NAC could significantly enhance the above inhibition actions of AAP. The combined use of AAP plus NAC had better inhibition action on the NLRP3 inflammasome pathway. These results indicate that the anti-inflammatory effects of AAP and NAC occur via the regulation on mRNA expression of NLRP3 and activation of caspase-1. The anti-inflammatory activity of AAP and NAC could be related to the suppression of NLRP3 inflammasome pathway under LPS stimulation.

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