Fentanyl and its derivatives: Pain-killers or man-killers?

Fentanyl is a synthetic µ-opioid receptor agonist approved to treat severe to moderate pain with faster onset of action and about 100 times more potent than morphine. Over last two decades, abuse of fentanyl and its derivatives has an increased trend, globally. Currently, the United States (US) faces the most serious situation related to fentanyl overdose, commonly referred to as the opioid epidemic. Nowadays, fentanyl is considered as the number one cause of death for adults aged 18-45 in the US. Synthesis and derivatization of fentanyl is inexpensive to manufacture and easily achievable. Indeed, more than 1400 fentanyl derivatives have been described in the scientific literature and patents. In addition, accessibility and efficacy of fentanyl and its derivatives can play a potential role in misuse of these compounds as a chemical weapon. In this review, the properties, general pharmacology, and overdose death cases associated with fentanyl and selected derivatives are presented. Moreover, current opioid epidemic in the US, Moscow theatre hostage crisis, and potential misuse of fentanyl and its derivatives as a chemical weapon are disclosed.

New insight into mycotoxins and bacterial toxins: Toxicity assessment, molecular mechanism and food safety (preface to the special issue of food and chemical toxicology on the outcomes of Myco & bacterial toxin).

The special issue "New Insight into Mycotoxins and Bacterial Toxins: Toxicity Assessment, Molecular Mechanism and Food Safety" in Food and Chemical Toxicology contains 19 articles on current hot topics in mycotoxins and bacterial toxins. Dietary exposure to mycotoxins and risk assessments are reported in this issue. Molecular mechanisms of multiple mycotoxins and emerging mechanisms of toxicity are especially concerned by researchers. Moreover, mycotoxin-detoxifying substances and antimicrobial agents are also fully investigated in the context. This special issue will help to further understand the mycotoxins and bacterial toxins, casting new light for the control of food safety.

Characterization and interactions of spoilage of Pseudomonas fragi C6 and Brochothrix thermosphacta S5 in chilled pork based on LC-MS/MS and screening of potential spoilage biomarkers.

Pseudomonas and Brochothrix are the main spoilage organisms in pork, and each of these plays an essential role in the spoilage process. However, the effect of co-contamination of these two organisms in pork has not been elucidated. The changing bacterial communities during spontaneous spoilage of pork at 4 °C were evaluated using high-throughput sequencing. The dominant spoilage bacteria were isolated and these were identified as Pseudomonas fragi C6 and Brochothrix thermosphacta S5. Chilled pork was then experimentally contaminated with these strains, individually and in combination, and the progression of spoilage was assessed by analyzing various physicochemical indicators. These included total viable counts (TVC), pH, color, total volatile basic nitrogen (TVB-N), and detection of microbial metabolites. After 7 days of chilled storage, co-contaminated pork produced higher TVC and TVB-N values than mono-contaminated samples. Metabolomic analysis identified a total of 8,084 metabolites in all three groups combined. Differential metabolites were identified, which were involved in 38 metabolic pathways. Among these pathways, the biosynthesis of alkaloids derived from purine and histidine was identified as an important pathway related to spoilage. Specifically, histidine, histamine, AMP, IMP, GMP, succinic acid, and oxoglutaric acid were identified as potential spoilage biomarkers. The study showed that the combined presence of P. fragi C6 and B. thermosphacta S5 bacteria makes chilled pork more prone to spoilage, compared to their individual presence. This study provides insights that can assist in applying appropriate techniques to maintain quality and safety changes in meat during storage and further the assessment of freshness.

Stability mechanism and countermeasure of the solid coal rib in deep gob-side entry retaining: Insights from theoretical analysis numerical simulation.

The stability and integrity of the solid coal rib in deep gob-side entry retaining (GER) can be compromised due to the cyclic loading and unloading caused by mining-induced stress. This can lead to failure of the deep GER during depressurized mining operations. In this study, we focus on a specific case at the 94103 working face in Qishan Coal Mine of Xuzhou Mining Bureau. We establish an engineering model that describes the interaction between the solid coal rib and the main roof in GER, aiming to elucidate the characteristics of main roof failure and instability throughout the entire GER process. this model particularly emphasizes the mechanical properties of the solid coal rib as a contributing factor. Additionally, developed a limit stress state model for evaluating bolt-supported plastic solid coal ribs, which helps determine appropriate support resistance levels to prevent two common forms of failure in these ribs. Furthermore, created a numerical calculation model to investigate different bolt conditions' impact on solid coal rib failure mechanisms. Finally, based on field monitoring data validation, we propose control measures for reinforcing solid coal ribs along with suggestions for roof support design and filling body construction schemes under similar geological conditions. These research findings offer valuable guidance for developing effective reinforcement strategies for filling bodies.

Pralidoxime-like reactivator with increased lipophilicity - Molecular modeling and in vitro study.

Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore AChE function when it has been covalently inhibited by an OP compound. Currently available commercial reactivators exhibit limited ability to penetrate the blood-brain barrier, where reactivation of inhibited AChE is crucial. Consequently, there have been numerous efforts to discover more brain-penetrating AChE reactivators. In this study, we examined a derivative of 2-PAM designed to possess increased lipophilicity. This enhanced lipophilicity was achieved through the incorporation of a benzyl group into its molecular structure. Initially, a molecular modeling study was conducted, followed by a comparison of its reactivation efficacy with that of 2-PAM against 10 different AChE inhibitors in vitro. Unfortunately, this relatively significant structural modification of 2-PAM resulted in a decrease in its reactivation potency. Consequently, this derivative cannot be considered as a broad-spectrum AChE reactivator.

The modulatory effects on enterohepatic cholesterol metabolism of novel cholesterol-lowering peptides from gastrointestinal digestion of Xuanwei ham.

The aim of this study was to investigate the effects and mechanism of in vitro protein digestive products of Xuanwei ham with different ripening periods on cholesterol metabolism and hypercholesterolemia. The results showed that compared with other gastrointestinal digestion (GID) groups, the GID group of Xuanwei ham with 3-year ripening period (XWH3-GID) inhibited the expression of Niemann-Pick C1-like 1 (NPC1L1) and acetyl-CoA acetyltransferase 2 (ACAT2) through hepatocyte nuclear factor 1-alpha (HNF-1α), which in turn effectively inhibited cholesterol absorption in Caco-2 cell monolayers. Following absorption by Caco-2 cell monolayers, the XWH3-GID group suppressed the expression and secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) via HNF-1α, which enhanced the protein expression and fluorescence intensity of low density lipoprotein receptor (LDLR) on the HepG2 cell membrane, and thus promoted the uptake of low density lipoprotein (LDL). Importantly, three novel peptides (LFP, PKF and VPFP) derived from titin were identified after intestinal epithelial transport in the XWH3-GID group, which could exert cholesterol-lowering effects through inhibiting intestinal cholesterol absorption and promoting peripheral hepatic LDL uptake, and effectively ameliorate western diet-induced hypercholesterolemia in ApoE-/- mice. These results suggest that Xuanwei ham with 3-year ripening period can be used as a source of cholesterol-lowering peptides and has potential to intervene in hypercholesterolemia.

Deoxynivalenol upregulates hypoxia-inducible factor-1α to promote an "immune evasion" process by activating STAT3 signaling.

Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-ß, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.

Deoxynivalenol: Emerging Toxic Mechanisms and Control Strategies, Current and Future Perspectives.

Deoxynivalenol (DON) is the most frequently present mycotoxin contaminant in food and feed, causing a variety of toxic effects in humans and animals. Currently, a series of mechanisms involved in DON toxicity have been identified. In addition to the activation of oxidative stress and the MAPK signaling pathway, DON can activate hypoxia-inducible factor-1α, which further regulates reactive oxygen species production and cancer cell apoptosis. Noncoding RNA and signaling pathways including Wnt/ß-catenin, FOXO, and TLR4/NF-κB also participate in DON toxicity. The intestinal microbiota and the brain-gut axis play a crucial role in DON-induced growth inhibition. In view of the synergistic toxic effect of DON and other mycotoxins, strategies to detect DON and control it biologically and the development of enzymes for the biodegradation of various mycotoxins and their introduction in the market are the current and future research hotspots.

Emesis to trichothecene deoxynivalenol and its congeners correspond to secretion of peptide YY and 5-HT.

The type B trichothecenes pollute food crops and have been associated to alimentary toxicosis resulted in emetic reaction in human and animal. This group of mycotoxins consists deoxynivalenol (DON) and four structurally related congeners: 3-acetyl-deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), nivalenol (NIV) and 4-acetyl-nivalenol (fusarenon X, FX). While emesis induced by intraperitoneally dosed to DON in the mink has been related to plasma up-grading of 5-hydroxytryptamine (5-HT) and neurotransmitters peptide YY (PYY), the impact of oral dosing with DON or its four congeners on secretion of these chemical substances have not been established. The aim of this work was to contraste emetic influence to type B trichothecene mycotoxins by orally dosing and involve these influence to PYY and 5-HT. All five toxins attracted marked emetic reaction that are relevant to elevated PYY and 5-HT. The reduction in vomiting induced by the five toxins and PYY was due to blocking of the neuropeptide Y2 receptor. The inhibition of the induced vomiting response by 5-HT and all five toxins is regulated by the 5-HT3 receptor inhibitor granisetron. In a word, our results indicate that PYY and 5-HT take a key role in the emetic reaction evoked by type B trichothecenes.

Research update on aflatoxins toxicity, metabolism, distribution, and detection: A concise overview.

Serious health risks associated with the consumption of food products contaminated with aflatoxins (AFs) are worldwide recognized and depend predominantly on consumed AF concentration by diet. A low concentration of aflatoxins in cereals and related food commodities is unavoidable, especially in subtropic and tropic regions. Accordingly, risk assessment guidelines established by regulatory bodies in different countries help in the prevention of aflatoxin intoxication and the protection of public health. By assessing the maximal levels of aflatoxins in food products which are a potential risk to human health, it's possible to establish appropriate risk management strategies. Regarding, a few factors are crucial for making a rational risk management decision, such as toxicological profile, adequate information concerning the exposure duration, availability of routine and some novel analytical techniques, socioeconomic factors, food intake patterns, and maximal allowed levels of each aflatoxin in different food products which may be varied between countries.

CircZBTB44 promotes renal carcinoma progression by stabilizing HK3 mRNA structure.

CircZBTB44 (hsa_circ_0002484) has been identified to be upregulated in renal cell carcinoma (RCC) tissues, while its role and contribution in RCC remain elusive. We confirmed the overexpression of circZBTB44 in RCC cells compared to normal kidney cell HK-2. CircZBTB44 knockdown suppressed the viability, proliferation, and migration of RCC cells and inhibited tumorigenesis in xenograft mouse models. Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) and Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) are two RNA binding proteins of circZBTB44. HNRNPC facilitated the translocation of circZBTB44 from nuclei to cytoplasm via m6A modification, facilitating the interaction of IGF2BP3 and circZBTB44 in the cytoplasm of RCC cells. Furthermore, circZBTB44 upregulated Hexokinase 3 (HK3) expression by binding to IGF2BP3 in RCC cells. HK3 exerted oncogenic effects on RCC cell malignant behaviors and tumor growth. In the co-culture of RCC cells with macrophages, circZBTB44 promoted M2 polarization of macrophages by up-regulating HK3. In summary, HNRNPC mediated circZBTB44 interaction with IGF2BP3 to up-regulate HK3, promoting the proliferation and migration of RCC cells in vitro and tumorigenesis in vivo. The results of the study shed new light on the targeted therapy of RCC.

Mycotoxins: Emerging toxic mechanisms, and unanswered research questions.

Recently, a series of toxic mechanisms have been explored in mycotoxins. Emerging evidence show that mycotoxins may induce human neurodegenerative diseases (ND); however, this idea is still unproven. Besides to identify this hypothesis, some questions, for example, how the mycotoxins induce this disease and what the molecular mechanism is, as well as whether the brain-gut axis is involved in this context, should be answered. Very recent studies further reported an "immune evasion" mechanism in trichothecenes; moreover, hypoxia seems to play important function in this process; nevertheless, whether this "immune evasion" process is present in other mycotoxins, especially in aflatoxins, should be tested. In this work, we mainly discussed some key scientific questions that need to be answered in the toxic mechanisms of mycotoxins. We especially focused on the research questions in the key signaling pathways, balance mechanism of immunostimulatory and immunosuppressive effects, and the relationship between autophagy and apoptosis. Interesting topics such as mycotoxins and aging, cytoskeleton and immunotoxicity are also discussed. More importantly, we compile a special issue: "New insight into mycotoxins and bacterial toxins: toxicity assessment, molecular mechanism and food safety" for Food and Chemical Toxicology. Researchers are encouraged to submit their newest work to this special issue.

T-2 toxin-induced intestinal damage with dysregulation of metabolism, redox homeostasis, inflammation, and apoptosis in chicks.

T-2 toxin is a worldwide problem for feed and food safety, leading to livestock and human health risks. The objective of this study was to explore the mechanism of T-2 toxin-induced small intestine injury in broilers by integrating the advanced microbiomic, metabolomic and transcriptomic technologies. Four groups of 1-day-old male broilers (n = 4 cages/group, 6 birds/cage) were fed a control diet and control diet supplemented with T-2 toxin at 1.0, 3.0, and 6.0 mg/kg, respectively, for 2 weeks. Compared with the control, dietary T-2 toxin reduced feed intake, body weight gain, feed conversion ratio, and the apparent metabolic rates and induced histopathological lesions in the small intestine to varying degrees by different doses. Furthermore, the T-2 toxin decreased the activities of glutathione peroxidase, thioredoxin reductase and total antioxidant capacity but increased the concentrations of protein carbonyl and malondialdehyde in the duodenum in a dose-dependent manner. Moreover, the integrated microbiomic, metabolomic and transcriptomic analysis results revealed that the microbes, metabolites, and transcripts were primarily involved in the regulation of nucleotide and glycerophospholipid metabolism, redox homeostasis, inflammation, and apoptosis were related to the T-2 toxin-induced intestinal damage. In summary, the present study systematically elucidated the intestinal toxic mechanisms of T-2 toxin, which provides novel ideas to develop a detoxification strategy for T-2 toxin in animals.

A Highly Stable, Capacity Dense Carboxylate Viologen Anolyte towards Long-Duration Energy Storage.

Aqueous organic redox flow batteries (AORFBs) have received increasing attention as an emergent battery technology for grid-scale renewable energy storage. However, physicochemical properties of redox-active organic electrolytes remain fine refinement to maximize their performance in RFBs. Herein, we report a carboxylate functionalized viologen derivative, N,N'-dibutyrate-4,4'-bipyridinium, (CBu)2 V, as a highly stable, high capacity anolyte material under near pH neutral conditions. (CBu)2 V can achieve solubility of 2.1 M and display a reversible, kinetically fast reduction at -0.43 V vs NHE at pH 9. DFT studies revealed that the high solubility of (CBu)2 V is attributed to its high molecular polarity while its negative reduction potential is benefitted from electron-donating carboxylate groups. A 0.89 V (CBu)2 V/(NH)4 Fe(CN)6 AORFB demonstrated exceptional energy storage performance, specifically, 100 % capacity retention with a discharge energy density of 9.5 Wh L-1 for 1000 cycles, power densities of up to 85 mW cm-2 , and an energy efficiency of 70 % at 60 mA cm-2 . (CBu)2 V not only represents the most capacity dense viologen with pendant ionic groups and also exhibits the longest (1200 hours or 50 days) and the most stable flow battery performance to date.

Bacillus amyloliquefaciens B10 Alleviates the Immunosuppressive Effects of Deoxynivalenol and Porcine Circovirus Type 2 Infection.

As one of the most common mycotoxins, deoxynivalenol (DON) can contaminate a wide range of crops and foods. Porcine circovirus 2 (PCV2) is a kind of immunosuppressive virus, which can cause porcine circovirus associated disease (PCVD) in pig farms infected with PCV2. Pigs are extremely sensitive to DON, and PCV2-infected pig farms are often contaminated with DON. Our previous studies indicated that Bacillus amyloliquefaciens B10 (B10) has the potential to alleviate the toxicity of mycotoxins. The research was aimed at investigating the effects of Bacillus amyloliquefaciens B10 on the immunosuppressive effects caused by both DON and PCV2 infection. The results indicated that the expression of the PCV2 capsid protein CAP was significantly decreased after pretreatment with Bacillus amyloliquefaciens B10. Then, the effects of the Bacillus amyloliquefaciens B10 pretreatment on the type I interferon, antiviral protein and the antiviral signal pathway cGAS-STING was further investigated. The findings displayed that the expression of the type I interferon and antiviral protein were increased, while the IL-10 were decreased after pretreatment with Bacillus amyloliquefaciens B10. The inhibition of DON on the cGAS-STING signal pathway was relieved. Furthermore, it was found that this intervention effect was produced by inhibiting autophagy. In summary, Bacillus amyloliquefaciens B10 can mitigate the immunosuppressive effects of PCV2 and DON by inhibiting the production of autophagy.

Hypertension related toxicity of chloroquine explains its failure against COVID-19: Based on rat model.

Chloroquine was once thought to be a promising treatment for COVID-19 but it quickly failed due to its inefficiency and association with increased mortality. Further, comorbidities such as hypertension may have contributed this failure. The safety and toxicity of chloroquine at doses required for treating SARS-CoV-2 infection in hypertensive patients remain unknown. Herein, to investigate these effects, we performed a safety evaluation of chloroquine at the approved dose (63 mg/kg) and at a high dose (126 mg/kg) in hypertensive rats. We found that chloroquine increased the mortality of hypertensive rats to 18.2% and 100%, respectively, after 7 days. During the chloroquine exposure period, the bodyweight, feed, and water consumption of hypertensive rats were decreased significantly. In addition, we show that chloroquine induces prolongation of QTc interval, elevation of LDH and CK, and histopathological damage of the myocardium in hypertensive rats. Ocular toxicity was observed in hypertensive rats in the form of hemorrhage in the eyes and retinal damage. Furthermore, we also observed intestinal toxicity in hypertensive rats, which presented as thinning intestinal walls with hemorrhagic contents, and histopathological changes of the jejunum. Hepatotoxicity was also evidenced by elevated ALT, and vacuolization of hepatocytes was also observed. Nephrotoxicity was observed only in high dose chloroquine-treated hypertensive rats, presenting as alterations of urinalysis and renal function. Immune alterations were also found in high-dose chloroquine-treated hypertensive rats with elevation of serum IL-10, IL-1ß and GRO, and moderate damage to the spleen. In summary, this study partially explains the reason for the failure of chloroquine as a COVID-19 therapy, and underlines the importance of safety evaluation and medical supervision of chloroquine to avoid patient harm, especially to those with hypertension.

Substance P and Glucagon-like Peptide-17-36 Amide Mediate Anorexic Responses to Trichothecene Deoxynivalenol and Its Congeners.

Type B trichothecenes commonly contaminate cereal grains and include five structurally related congeners: deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX), and nivalenol (NIV). These toxins are known to have negative effects on human and animal health, particularly affecting food intake. However, the pathophysiological basis for anorexic effect is not fully clarified. The purpose of this study is to explore the potential roles of the brain-gut peptides substance P (SP) and glucagon-like peptide-17-36 amide (GLP-1) in anorexic responses induced by type B trichothecenes following both intraperitoneal (IP) and oral administration. SP and GLP-1 were elevated at 1 or 2 h and returned to basal levels at 6 h following exposure to DON and both ADONs. FX induced the production of both brain gut peptides with initial time at 1 or 2 h and duration > 6 h. Similar to FX, exposing IP to NIV caused elevations of SP and GLP-1 at 1 h and lasted more than 6 h, whereas oral exposure to NIV only increased both brain gut peptides at 2 h. The neurokinin-1 receptor (NK-1R) antagonist Emend® dose-dependently attenuated both SP- and DON-induced anorexic responses. Pretreatment with the GLP-1 receptor (GLP-1R) antagonist Exending9-39 induced a dose-dependent attenuation of both GLP-1- and DON-induced anorexic responses. To summarize, the results suggest that both SP and GLP-1 play important roles in anorexia induction by type B trichothecenes.

Glaesserella parasuis serotype 5 breaches the porcine respiratory epithelial barrier by inducing autophagy and blocking the cell membrane Claudin-1 replenishment.

Glaesserella parasuis (G. parasuis), the primary pathogen of Glässer's disease, colonizes the upper respiratory tract and can break through the epithelial barrier of the respiratory tract, leading to lung infection. However, the underlying mechanisms for this adverse effect remain unclear. The G. parasuis serotype 5 SQ strain (HPS5-SQ) infection decreased the integrity of piglets' lung Occludin and Claudin-1. Autophagy regulates the function of the epithelial barrier and tight junction proteins (TJs) expression. We tested the hypothesis that HPS5-SQ breaking through the porcine respiratory epithelial barrier was linked to autophagy and Claudin-1 degradation. When HPS5-SQ infected swine tracheal epithelial cells (STEC), autophagosomes encapsulated, and autolysosomes degraded oxidatively stressed mitochondria covered with Claudin-1. Furthermore, we found that autophagosomes encapsulating mitochondria resulted in cell membrane Claudin-1 being unable to be replenished after degradation and damaged the respiratory tract epithelial barrier. In conclusion, G. parasuis serotype 5 breaks through the porcine respiratory epithelial barrier by inducing autophagy and interrupting cell membrane Claudin-1 replenishment, clarifying the mechanism of the G. parasuis infection and providing a new potential target for drug design and vaccine development.

HIF-1α inhibits T-2 toxin-mediated "immune evasion" process by negatively regulating PD-1/PD-L1.

Trichothecene mycotoxins have a strong immunosuppressive effect, which may even escape host immune surveillance and damage the immune repair to show an "immune evasion" effect. Increasing lines of evidence have shown that hypoxia and hypoxia-inducible factors (HIFs) are key mediators of trichothecenes, and these toxins appear to be closely related to the "immune evasion" mechanisms. Therefore, we used RAW264.7 cell model to explore the association of T-2 toxins with "immune evasion" process and hypoxia, as well as their cross-linking effects induced by T-2 toxin. Our results showed that HIF-1α is an important toxicity target of T-2 toxin, which could induce intracellular hypoxia. T-2 toxin induced an "immune evasion" process by activating the PD-1/PD-L1 signaling pathway. Interestingly, when HIF-1α activation was blocked, the "immune evasion" process regulated by PD-1/PD-L1 signaling was activated, resulting in the cells damage, suggesting that hypoxia induced by T-2 toxin plays a protective role for RAW264.7 cell damage. Thus, our work shows that HIF-1α inhibits T-2 toxin-mediated "immune evasion" process by negatively regulating PD-1/PD-L1signaling. This study contributes to a better understanding of the immunotoxicity mechanism of trichothecenes.