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.

COL5A2 drives regorafenib resistance-induced metastatic phenotype via reducing LIFR expression in hepatocellular carcinoma.

Systemic therapies, the ultimate strategies for patients with advanced hepatocellular carcinoma (HCC), are suffering from serious clinical challenges, such as the occurrence and development of drug resistance. Treatment resistance aggravates tumor progression partly by inducing tumor metastasis. Regorafenib-resistant HCC cells exhibit a highly striking metastatic phenotype, but the detailed mechanisms underlying these aggressive behaviors remain elusive. Here, we conduct transcriptome sequencing analysis to identify COL5A2 as a crucial driver of the metastatic characteristics of regorafenib-resistant HCC cells. COL5A2 is aberrantly highly expressed in resistant cells, and its genetic depletion significantly suppresses proliferation, migration, invasion, vasculogenic mimicry (VM) formation and lung metastasis in vitro and in vivo, concomitant with the downregulation of VE-cadherin, EphA2, Twist1, p-p38 and p-STAT3 expressions. LIFR is confirmed to be an essential downstream molecule of COL5A2, and its expression is observably elevated by COL5A2 depletion. Ectopic overexpression of LIFR drastically attenuates the proliferation, migration, invasion and VM of regorafenib-resistant cells and represses the expressions of VM-related molecules and the activation of p38/STAT3 signaling pathway. Interestingly, rescue experiments show that the inhibition of the above aggressive features of resistant cells by COL5A2 loss is clearly alleviated by silencing of LIFR. Collectively, our results reveal that COL5A2 promotes the ability of regorafenib-resistant HCC cells to acquire a metastatic phenotype by attenuating LIFR expression and suggest that therapeutic regimens targeting the COL5A2/LIFR axis may be beneficial for HCC patients with therapeutic resistance.

Caveolin 1 in bovine liver is associated with fatty acid-induced lipid accumulation and the ER unfolded protein response: role in fatty liver development.

Disruption of endoplasmic reticulum (ER) homeostasis, i.e., ER stress, is intrinsically linked with lipid metabolism disorders in dairy cows. Caveolin 1 (CAV1) is a ubiquitously-expressed membrane-associated scaffolding protein involved in regulating the secretory pathway within the ER. Whether inhibiting the activity of CAV1 affects the ER and its potential role in hepatic lipid deposition in dairy cows is unknown. Biopsies of liver tissue from Holstein cows (days in milk: median = 13 d, range = 5 to 21) diagnosed as healthy (n = 6, hepatic TAG levels < 1%, milk production: median = 38.9 kg/day, Interquartile range = 38.0 and 40.8) or suffering from fatty liver (n = 6, hepatic TAG levels > 5%, milk production: median = 36.6 kg/day, Interquartile range = 35.7 and 38.1) revealed that fatty liver was associated with lower abundance of CAV1 gene and protein, higher phosphorylation (p) levels of PERK and IRE1α, and increased abundance of ATF6, GRP78, CHOP protein, and several unfolded protein response (UPR) genes (ATF4, sXBP1, and GRP78). Proteins related to de novo fatty acid synthesis, including ACC1, SREBP-1c, PPARγ, and downstream targets genes of SREBP1 (ACACA and FASN) also had greater abundance. This in vivo analysis highlighted a mechanistic link between CAV1 protein abundance, ER stress, and lipid metabolism during fatty liver. A mechanistic study was then performed in vitro with primary hepatocytes isolated from 5 healthy calves (weight, 40-45 kg; 1 d old). Initially, hepatocytes were treated with FFA (1.2 mM) for 1, 3, 6, or 12 h. FFA treatment reduced CAV1 protein abundance linearly while it reduced abundance of ER stress-related proteins, p-IRE1α, p-PERK, GRP78, ATF6, and CHOP. Proteins related to de novo fatty acid synthesis (ACC1, SREBP-1c, PPARγ) also increased linearly, and lipid droplets accumulated progressively over time following FFA treatment. Subsequently, to assess the role of CAV1 in FFA-induced ER stress and de novo fatty acid synthesis, hepatocytes were transfected with pCMV-CAV1 (cattle)-3 × FLAG-Neo (pc-CAV1) plasmid to overexpress CAV1 or with siRNA to silence CAV1 (siCAV1) transcription. Overexpression of CAV1 alleviated ER stress by reducing levels of p-PERK and p-IRE1α, as well as the protein abundance of ATF6, GRP78, CHOP, and several UPR genes (GRP78, ATF4, and sXBP1). Similarly, CAV1 overexpression decreased protein abundance of ACC1, SREBP-1c, PPARγ, and downstream targets genes of SREBP1 (ACACA and FASN). Conversely, silencing CAV1 exacerbated FFA-induced ER stress and de novo fatty acid synthesis. Considering the negative role of FFA-induced ER stress on lipid accumulation in hepatocytes, a second in vitro experiment involved hepatocytes treated with 0.5 µg/mL tunicamycin (TM, a typical ER stress inducer) for 24 h with or without overexpressing CAV1 (pc-CAV1). Overexpressing caveolin 1 reversed TM-induced increases in mRNA and protein associated with ER stress and de novo fatty acid synthesis. Furthermore, use of hepatocytes transfected with pc-CAV1 for 48 h and subjected to co-immunoprecipitation revealed that CAV1 interacts with IRE1α and ATF6. Overall, the data suggest that CAV1 may help reduce hepatic ER stress and mitigate fatty acid synthesis by binding to and inhibiting IRE1α and ATF6 signaling.

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.

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.

Deoxynivalenol and its modified forms: key enzymes, inter-individual and interspecies differences in metabolism.

Deoxynivalenol (DON) and its modified forms, including DON-3-glucoside (DON-3G), pose a major agricultural and food safety issue in the world. Their metabolites are relatively well-characterized; however, their metabolizing enzymes have not been fully explored. UDP-glucuronosyltransferases, 3-O-acetyltransferase, and glutathione S-transferase are involved in the formation of DON-glucuronides, 3-acetyl-DON, and DON-glutathione, respectively. There are interindividual differences in the metabolism of these toxins, including variation with respect to sex. Furthermore, interspecies differences in DON metabolism have been revealed, including differences in the major metabolites of DON, the role of de-acetylation, and the hydrolysis of DON-3G. In this review, we summarized the major enzymes involved in metabolizing DON to its modified forms, focusing on the differences in metabolism of DON and its modified forms between individuals and species. This work provides important insight into the toxicity of DON and its derivatives in humans and animals, and provides scientific basis for the development of safer and more efficient biological detoxification methods.

Targeting prolyl isomerase Pin1 as a promising strategy to overcome resistance to cancer therapies.

The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/ß-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors.

Antifungal and mycotoxin detoxification ability of essential oils: A review.

With increased popular awareness of food safety and environmental protection, plant essential oil has attracted interest due to the absence of residue, its high efficiency, antioxidant, immune regulation, antibacterial, insecticidal, and other advantages. Their application in degradation and elimination of mycotoxin toxicity has attracted increasing attention. This paper reviews the structure, antibacterial activity, antibacterial mechanism, and toxic effects of essential oils. The inhibitory effects of various essential oils on different mycotoxins were studied. The research progress on the inhibitory effects of plant essential oils on fungi and mycotoxins in recent years was summarized to provide reference for the application of plant essential oils.

Hypothesis: JNK signaling is a therapeutic target of neurodegenerative diseases.

The exact signaling leading to neurological dysfunction in neurodegenerative diseases is currently unknown. We hypothesize that the c-Jun N-terminal kinase (JNK) signaling pathway is a potential therapeutic target for neurodegenerative diseases. This postulate rests on extensive data from cell and animal experimental studies, demonstrating that JNK signaling plays a crucial role in the pathogenesis of neurodegenerative diseases. The sustained activation of JNK leads to synaptic dysfunction and even neuronal apoptosis, ultimately resulting in memory deficits and neurodegeneration. JNK phosphorylates the amyloid precursor protein and tau, ultimately resulting in the formation of extraneuronal senile plaques and intraneuronal neurofibrillary tangles. Our hypothesis could be validated by investigating the cerebral cortex of elderly chimpanzees injected with phosphorylated JNK or transgenic pig and chimpanzee models established using gene editing technology including CRISPR. This hypothesis provides clues for further understanding the molecular mechanisms of neurodegenerative diseases and the development of potential target therapeutic drugs.

An Energy-Dense, Powerful, Robust Bipolar Zinc-Ferrocene Redox-Flow Battery.

Zinc metal represents a low-cost, high-capacity anode material to develop energy-dense aqueous redox-flow batteries (RFB). However, the energy-storage applications of traditional inorganic Zn halide flow batteries are primarily plagued by the material challenges of traditional halide cathode electrolytes (e.g., bromine), including corrosion, toxicity, and severe crossover. Herein, we report a bipolar zinc-ferrocene salt compound, zinc 1,1'-bis(3-sulfonatopropyl)ferrocene, Zn[Fc(SPr)2 ] (1.80 M solubility or 48.2 Ah L- charge storage capacity)-a robust, energy-dense, bipolar redox-active electrolyte material for RFBs. Zn[Fc(SPr)2 ]-based redox-flow batteries operated at high current densities of up to 200 mA cm-2 and delivered an energy efficiency of up to 81.5 % and a power density of up to 270.5 mW cm-2 . A Zn[Fc(SPr)2 ] flow battery demonstrated an energy density of 20.2 Wh L-1 and displayed nearly 100 % capacity retention for 2000 cycles (1284 h or 53.5 days).

The role of hypoxia-inducible factor 1 in tumor immune evasion.

Hypoxia-inducible factor 1 (HIF-1) plays an indispensable role in the hypoxic tumor microenvironment. Hypoxia and HIF-1 are involved in multiple aspects of tumor progression, such as metastasis, angiogenesis, and immune evasion. In innate and adaptive immune systems, malignant tumor cells avoid their recognition and destruction by HIF-1. Tumor immune evasion allows cancer cells to proliferate and metastasize and is associated with immunotherapy failure and chemoresistance. In the hypoxic tumor microenvironment, HIF-1 signaling suppresses the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules, including vascular endothelial growth factor, prostaglandin E2 , and programmed death-ligand 1/programmed death-1. Moreover, HIF-1 blocks tumor-associated antigen presentation via major histocompatibility complex class I chain-related/natural killer group 2, member D signaling. Tumor-associated autophagy and the release of tumor-derived exosomes contribute to HIF-1-mediated immune evasion. This review focuses on recent findings on the potential mechanism(s) underlying the effect of hypoxia and HIF-1 signaling on tumor immune evasion in the hypoxic tumor microenvironment. The effects of HIF-1 on immune checkpoint molecules, immunosuppressive molecules, autophagy, and exosomes have been described. Additionally, the potential role of HIF-1 in the regulation of tumor-derived exosomes, as well as the roles of HIF-1 and exosomes in tumor evasion, are discussed. This study will contribute to our understanding of HIF-1-mediated tumor immune evasion, leading to the development of effective HIF-1-targeting drugs and immunotherapies.

Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1-mediated EMT.

Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34- /PAS+ ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.

Regulatory mechanisms and therapeutic targeting of vasculogenic mimicry in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a typical hyper-vascular solid tumor; aberrantly rich in tumor vascular network contributes to its malignancy. Conventional anti-angiogenic therapies seem promising but transitory and incomplete efficacy on HCC. Vasculogenic mimicry (VM) is one of functional microcirculation patterns independent of endothelial vessels which describes the plasticity of highly aggressive tumor cells to form vasculogenic-like networks providing sufficient blood supply for tumor growth and metastasis. As a pivotal alternative mechanism for tumor vascularization when tumor cells undergo lack of oxygen and nutrients, VM has an association with the malignant phenotype and poor clinical outcome for HCC, and may challenge the classic anti-angiogenic treatment of HCC. Current studies have contributed numerous findings illustrating the underlying molecular mechanisms and signaling pathways supporting VM in HCC. In this review, we summarize the correlation between epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and VM, the role of hypoxia and extracellular matrix remodeling in VM, the involvement of adjacent non-cancerous cells, cytokines and growth factors in VM, as well as the regulatory influence of non-coding RNAs on VM in HCC. Moreover, we discuss the clinical significance of VM in practice and the potential therapeutic strategies targeting VM for HCC. A better understanding of the mechanism underlying VM formation in HCC may optimize anti-angiogenic treatment modalities for HCC.

Hypoxia, oxidative stress, and immune evasion: a trinity of the trichothecenes T-2 toxin and deoxynivalenol (DON).

T-2 toxin and deoxynivalenol (DON) are type A and B trichothecenes, respectively. They widely occur as pollutants in food and crops and cause a series of toxicities, including immunotoxicity, hepatotoxicity, and neurotoxicity. Oxidative stress is the primary mechanistic basis of these toxic effects. Increasing amounts of evidence have shown that mitochondria are significant targets of apoptosis caused by T-2 toxin- and DON-induced oxidative stress via regulation of Bax/B-cell lymphoma-2 and caspase-3/caspase-9 signaling. DNA methylation and autophagy are involved in oxidative stress related to apoptosis, and hypoxia and immune evasion are related to oxidative stress in this context. Hypoxia induces oxidative stress by stimulating mitochondrial reactive oxygen species production and regulates the expression of cytokines, such as interleukin-1ß and tumor necrosis factor-α. Programmed cell death-ligand 1 is upregulated by these cytokines and by hypoxia-inducible factor-1, which allows it to bind to programmed cell death-1 to enable escape of immune cell surveillance and achievement of immune evasion. This review concentrates on novel findings regarding the oxidative stress mechanisms of the trichothecenes T-2 toxin and DON. Importantly, we discuss the new evidence regarding the connection of hypoxia and immune evasion with oxidative stress in this context. Finally, the trinity of hypoxia, oxidative stress and immune evasion is highlighted. This work will be conducive to an improved understanding of the oxidative stress caused by trichothecene mycotoxins.

Bacillus amyloliquefaciens B10 can alleviate aflatoxin B1-induced kidney oxidative stress and apoptosis in mice.

Aflatoxin B1(AFB1) widely exists in food and feed, which seriously endangers human and animal health. How to detoxify AFB1 is a research hotspot at present. This study attempts to use the Bacillus amyloliquefaciens B10, one of probiotics strain as the research object to ascertain whether it can alleviate the kidney injury induced by AFB1 in mice and its mechanism. Fifty-six mice were divided into four groups (control, AFB1, AFB1 + B10, and B10). The mice that received intragastric administration for 28 days were euthanised, and serum was collected for biochemical index detection with fresh kidney tissue taken for HE staining, TUNEL detection, and protein expression detection. Our results showed that the biochemical indices changed, significant pathological changes appeared, the number of apoptotic cells increased in the kidney tissue of the AFB1 group mice; the protein expressions of Nrf2, HO-1,AKT, P-AKT, and Bcl-2 in the AFB1 group were significantly decreased; the protein expressions of Keap-1, PTEN, Bax, Caspase-9, and Caspase-3 were significantly increased. After B. amyloliquefaciens B10 co-treatment, compared with the AFB1 group, the biochemical indices, pathological changes, and protein expressions were significantly reversed. The results indicated that B. amyloliquefaciens B10 can alleviate AFB1-induced kidney injury in mice.

Chemistry and Toxicology of Major Bioactive Substances in Inocybe Mushrooms.

Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It attracts the attention of researchers, especially in the aspects of toxin composition, toxic mechanism and toxin application in poisonous mushroom. Inocybe is a large genus of mushrooms and contains toxic substances including muscarine, psilocybin, psilocin, aeruginascin, lectins and baeocystin. In order to prevent and remedy mushroom poisoning, it is significant to clarify the toxic effects and mechanisms of these bioactive substances. In this review article, we summarize the chemistry, most known toxic effects and mechanisms of major toxic substances in Inocybe mushrooms, especially muscarine, psilocybin and psilocin. Their available toxicity data (different species, different administration routes) published formerly are also summarized. In addition, the treatment and medical application of these toxic substances in Inocybe mushrooms are also discussed. We hope that this review will help understanding of the chemistry and toxicology of Inocybe mushrooms as well as the potential clinical application of its bioactive substances to benefit human beings.

Nickel-Catalyzed Electrochemical C(sp3 )-C(sp2 ) Cross-Coupling Reactions of Benzyl Trifluoroborate and Organic Halides*.

Reported here is the redox neutral electrochemical C(sp2 )-C(sp3 ) cross-coupling reaction of bench-stable aryl halides or ß-bromostyrene (electrophiles) and benzylic trifluoroborates (nucleophiles) using nonprecious, bench-stable NiCl2 ⋅glyme/polypyridine catalysts in an undivided cell configuration under ambient conditions. The broad reaction scope and good yields of the Ni-catalyzed electrochemical coupling reactions were confirmed by 50 examples of aryl/ß-styrenyl chloride/bromide and benzylic trifluoroborates. Potential applications were demonstrated by electrosynthesis and late-stage functionalization of pharmaceuticals and natural amino acid modification, and three reactions were run on gram-scale in a flow-cell electrolyzer. The electrochemical C-C cross-coupling reactions proceed through an unconventional radical transmetalation mechanism. This method is highly productive and expected to find wide-spread applications in organic synthesis.

An update on T-2 toxin and its modified forms: metabolism, immunotoxicity mechanism, and human exposure assessment.

T-2 toxin is the most toxic trichothecene mycotoxin, and it exerts potent toxic effects, including immunotoxicity, neurotoxicity, and reproductive toxicity. Recently, several novel metabolites, including 3',4'-dihydroxy-T-2 toxin and 4',4'-dihydroxy-T-2 toxin, have been uncovered. The enzymes CYP3A4 and carboxylesterase contribute to T-2 toxin metabolism, with 3'-hydroxy-T-2 toxin and HT-2 toxin as the corresponding primary products. Modified forms of T-2 toxin, including T-2-3-glucoside, exert their immunotoxic effects by signaling through JAK/STAT but not MAPK. T-2-3-glucoside results from hydrolyzation of the corresponding parent mycotoxin and other metabolites by the intestinal microbiota, which leads to enhanced toxicity. Increasing evidence has shown that autophagy, hypoxia-inducible factors, and exosomes are involved in T-2 toxin-induced immunotoxicity. Autophagy promotes the immunosuppression induced by T-2 toxin, and a complex crosstalk between apoptosis and autophagy exists. Very recently, "immune evasion" activity was reported to be associated with this toxin; this activity is initiated inside cells and allows pathogens to escape the host immune response. Moreover, T-2 toxin has the potential to trigger hypoxia in cells, which is related to activation of hypoxia-inducible factor and the release of exosomes, leading to immunotoxicity. Based on the data from a series of human exposure studies, free T-2 toxin, HT-2 toxin, and HT-2-4-glucuronide should be considered human T-2 toxin biomarkers in the urine. The present review focuses on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 toxin and its modified forms. In particular, the immunotoxicity mechanisms of T-2 toxin and the toxicity mechanism of its modified form, as well as human T-2 toxin biomarkers, are discussed. This work will contribute to an improved understanding of the immunotoxicity mechanism of T-2 toxin and its modified forms.

Selective inhibitors for JNK signalling: a potential targeted therapy in cancer.

c-Jun N-terminal kinase (JNK) signalling regulates both cancer cell apoptosis and survival. Emerging evidence show that JNK promoted tumour progression is involved in various cancers, that include human pancreatic-, lung-, and breast cancer. The pro-survival JNK oncoprotein functions in a cell context- and cell type-specific manner to affect signal pathways that modulate tumour initiation, proliferation, and migration. JNK is therefore considered a potential oncogenic target for cancer therapy. Currently, designing effective and specific JNK inhibitors is an active area in the cancer treatment. Some ATP-competitive inhibitors of JNK, such as SP600125 and AS601245, are widely used in vitro; however, this type of inhibitor lacks specificity as they indiscriminately inhibit phosphorylation of all JNK substrates. Moreover, JNK has at least three isoforms with different functions in cancer development and identifying specific selective inhibitors is crucial for the development of targeted therapy in cancer. Some selective inhibitors of JNK are identified; however, their clinical studies in cancer are relatively less conducted. In this review, we first summarised the function of JNK signalling in cancer progression; there is a focus on the discussion of the novel selective JNK inhibitors as potential targeting therapy in cancer. Finally, we have offered a future perspective of the selective JNK inhibitors in the context of cancer therapies. We hope this review will help to further understand the role of JNK in cancer progression and provide insight into the design of novel selective JNK inhibitors in cancer treatment.