Xanthohumol inhibits non-small cell lung cancer via directly targeting T-lymphokine-activated killer cell-originated protein kinase.

Xanthohumol is a principal prenylated chalcone isolated from hops. Previous studies have shown that xanthohumol was effective against various types of cancer, but the mechanisms, especially the direct targets for xanthohumol to exert an anticancer effect, remain elusive. Overexpression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes tumorigenesis, invasion and metastasis, implying the likely potential for targeting TOPK in cancer prevention and treatment. In the present study, we found that xanthohumol significantly inhibited the cell proliferation, migration and invasion of non-small cell lung cancer (NSCLC) in vitro and suppressed tumor growth in vivo, which is well correlated with inactivating TOPK, evidenced by reduced phosphorylation of TOPK and its downstream signaling histone H3 and Akt, and decreased its kinase activity. Moreover, molecular docking and biomolecular interaction analysis showed that xanthohumol was able to directly bind to the TOPK protein, suggesting that TOPK inactivation by xanthohumol is attributed to its ability to directly interact with TOPK. The findings of the present study identified TOPK as a direct target for xanthohumol to exert its anticancer activity, revealing novel insight into the mechanisms underlying the anticancer activity of xanthohumol.

Trimethylamine N-oxide exacerbates acetaminophen-induced liver injury by interfering with macrophage-mediated liver regeneration.

Acetaminophen (APAP)-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Trimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota and is relatively high in the circulation of the elderly, individuals with diabetes, and heart disease. Herein, we showed that TMAO exacerbates APAP hepatotoxicity. It is possible that delayed liver repair and regeneration that resulted from reduced macrophage accumulation was responsible for this combined hepatotoxicity. Moreover, matrix metalloproteinase 12 (Mmp12), expressed predominantly by macrophages, were reduced by TMAO in vitro and in vivo. This led to the inhibition of macrophage migration and a subsequent decrease in the recruitment of proresolving macrophages to the necrosis area. Furthermore, the administration of recombinant Mmp12 mitigated the enhanced hepatotoxicity in mice cotreated with TMAO and APAP. Overall, this study indicates that TMAO exacerbates APAP-induced hepatotoxicity by hindering macrophage-mediated liver repair, which might stem from the inhibition of Mmp12. These findings imply that liver damage in patients with high levels of circulating TMAO may be more severe in AILI and should exercise caution when treating with NAC.

Non-Contact Heart Rate Detection When Face Information Is Missing during Online Learning.

Research shows that physiological signals can provide objective data support for the analysis of human emotions. At present, non-contact heart rate data have been employed in the research of medicine, intelligent transportation, smart education, etc. However, it is hard to detect heart rate data using non-contact traditional methods during head rotation, especially when face information is missing in scenarios such as online teaching/learning. Traditional remote photoplethysmography (rPPG) methods require a static, full frontal face within a fixed distance for heart rate detection. These strict requirements make it impractical to measure heart rate data in real-world scenarios, as a lot of videos only partially record the subjects' face information, such as profile, too small distance, and wearing a mask. The current algorithm aims to solve the problem of head deflections between 30 degrees and 45 degrees by employing a symmetry substitution method, which can replace the undetected region of interest (ROI) with the detectable one. When face information is partially missing, our algorithm uses face-eye location to determine ROI. The results show that the method in this paper can solve certain practical problems related to heart rate detection, with a root mean square error (RMSE) under 7.64 bpm.

Glycyrol exerts potent therapeutic effect on lung cancer via directly inactivating T-LAK cell-originated protein kinase.

Molecular targeted therapy for non-small cell lung cancer (NSCLC) has demonstrated promising outcomes. T-lymphokine-activated killer cell-originated protein kinase (TOPK) is found overexpressed in many cancer types such as NSCLC, and is considered to be an effective target for lung cancer treatment. In the present study, we found that glycyrol (GC), a representative coumarin compound isolated from licorice, was highly effective against several human NSCLC cell lines in vitro, and significantly suppressed tumor growth in vivo. Mechanistically, we demonstrated that GC can strongly bind to the TOPK protein and inhibited its kinase activity, leading to the activation of apoptotic signaling pathways. The findings of the present study suggest that GC is a novel promising TOPK inhibitor and this compound deserves to be further investigated for its potential anti-NSCLC activity.

Naringin ameliorates obesity via stimulating adipose thermogenesis and browning, and modulating gut microbiota in diet-induced obese mice.

Naringin, a natural flavanone primarily found in citrus fruits, has garnered increased attention due to its recognized antioxidative, anti-inflammatory, and cardioprotective attributes. However, the functions of naringin in regulating energy expenditure are poorly understood. In the present study, we observed that twelve weeks of naringin supplementation substantially reshaped the metabolic profile of high-fat diet (HFD)-fed mice, by inhibiting body weight gain, reducing liver weight, and altering body compositions. Notably, naringin exhibited a remarkable capacity to augment whole-body energy expenditure of the tested mice by enhancing the thermogenic activity of brown adipose tissue (BAT) and stimulating browning of inguinal white adipose tissue (iWAT). Furthermore, our results showed naringin supplementation modified gut microbiota composition, specifically increasing the abundance of Bifidobacterium and Lachnospiraceae_bacterium_28-4, while reducing the abundance of Lachnospiraceae_bacterium_DW59 and Dubosiella_newyorkensis. Subsequently, we also found naringin supplementation altered fecal metabolite profile, by significantly promoting the production of taurine, tyrosol, and thymol, which act as potent activators of thermoregulation. Interestingly, the metabolic effects of naringin were abolished upon gut microbiota depletion through antibiotic intervention, concurrently leading the disappearance of naringin-induced thermogenesis and protective actions on diet-induced obesity. This discovery revealed a novel food-driven cross-sectional communication between gut bacteria and adipose tissues. Collectively, our data indicate that naringin supplementation stimulates BAT thermogenesis, alters fat distribution, promotes the browning process, and consequently inhibits body weight gain; importantly these metabolic effects require the participation of gut bacteria.

Combination of Selenite and Butyrate Enhances Efficacy Against Colon Cancer by Targeting ASCT2-Mediated Amino Acid Metabolism.

Drug combination is considered to be an effective approach to improve the efficacy of cancer therapy and chemoprevention. Selenite, a representative of inorganic form of selenium, and butyrate, a major short-chain fatty acid, are two well-documented colon cancer dietary chemopreventive agents with distinct molecular mechanisms. We hypothesized that combination of selenite and butyrate might produce improved outcome against colon cancer. This hypothesis was tested using both HCT116 human colon cancer cells and its xenograft mouse model in the present study. The in vitro study showed a synergistically inhibitory effect on HCT116 colon cancer cells but not on NCM460 normal human colon mucosal epithelial cells. Consistent with the in vitro study, results of the xenograft mouse model further demonstrated that combination of selenite and butyrate led to improved efficacy in comparison with each agent alone. Mechanistically, the induction of alanine-serine-cysteine transporter 2 (ASCT2) by selenite repressed its inhibitory effect on colon cancer cells, which was reversed by its co-treatment with butyrate. The findings of the present study denote the likely potential for developing selenite/butyrate combination remedy to combat against colon cancer.

A homogeneous hybridization magnetic biosensor based on electric field assistance for ultrafast nucleic acid detection.

Electrochemical biosensing is a sensitive strategy widely used in the field of nucleic acid detection. However, electrochemical biosensors generally involve time-consuming and labor-intensive probe immobilization processes. In this study, an electrochemical DNA biosensor based on homogeneous hybridization in solution was designed for nucleic acid detection without probe immobilization, which is different from most biosensors. The capture probe, detection probe, and target DNA were hybridized rapidly under an electric field to form a "sandwich" structure within 90 s, and the "sandwich" hybrid could be specifically coupled to streptavidin-modified magnetic beads within 5 min. Finally, the magnetic beads were enriched by using polypyrrole (PPy)/carbon nanotube (CNT)-modified magnetic electrodes and the signal was detected by differential pulse voltammetry (DPV). The magnetic biosensor constructed in this study could detect targets over a good linear dynamic range spanning 100 pM to 100 nM in 400 s, while those involving conventional hybridization methods always take 2 h or more. Because of the specific binding of streptavidin and biotin, this strategy showed high specificity. Taken together, the homogenous hybridization magnetic biosensor constructed with electric field assistance presents a potential diagnostic method for rapid DNA detection and provides a new idea for rapid nucleic acid detection in clinical practice.

Methylseleninic acid overcomes gefitinib resistance through asparagine-MET-TOPK signaling axis in non-small cell lung cancer cells.

Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC.

Glucose Limitation Sensitizes Cancer Cells to Selenite-Induced Cytotoxicity via SLC7A11-Mediated Redox Collapse.

Combination of intermittent fasting and chemotherapy has been drawn an increasing attention because of the encouraging efficacy. In this study, we evaluated the anti-cancer effect of combination of glucose limitation and selenite (Se), a representative inorganic form of selenium, that is preferentially accumulated in tumors. Results showed that cytotoxic effect of selenite on cancer cells, but not on normal cells, was significantly enhanced in response to the combination of selenite and glucose limitation. Furthermore, in vivo therapeutic efficacy of combining selenite with fasting was dramatically improved in xenograft models of lung and colon cancer. Mechanistically, we found that SLC7A11 expression in cancer cells was up-regulated by selenite both in vitro and in vivo. The elevated SLC7A11 led to cystine accumulation, NADPH depletion and the conversion of cystine to cysteine inhibition, which in turn boosted selenite-mediated reactive oxygen species (ROS), followed by enhancement of selenite-mediated cytotoxic effect. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.

Heart rate prediction from facial video with masks using eye location and corrected by convolutional neural networks.

Remote photoplethysmography (rPPG), which aims at measuring heart activities without any contact, has great potential in many applications. The emergence of novel coronavirus pneumonia COVID-19 has attracted worldwide attentions. Contact photoplethysmography (cPPG) methods need to contact the detection equipment with the patient, which may accelerate the spread of the epidemic. In the future, the non-contact heart rate detection will be an urgent need. However, existing heart rate measuring methods from facial videos are vulnerable to the less-constrained scenarios (e.g., with head movement and wearing a mask). In this paper, we proposed a method of heart rate detection based on eye location of region of interest (ROI) to solve the problem of missing information when wearing masks. Besides, a model to filter outliers based on residual network was conceived first by us and the better heart rate measurement accuracy was generated. To validate our method, we also created a mask dataset. The results demonstrated that after using our method for correcting the heart rate (HR) value measured with the traditional method, the accuracy reaches 4.65 bpm, which is 0.42 bpm higher than that without correction.

Patulin disrupts SLC7A11-cystine-cysteine-GSH antioxidant system and promotes renal cell ferroptosis both in vitro and in vivo.

Patulin (PAT) is a common food-borne mycotoxin with diverse toxic effects including nephrotoxicity. The induction of oxidative stress is suggested to be a key mechanism contributed to toxicities of PAT. Reduced glutathione (GSH), a sulfhydryl-containing tripeptide, is a key reason for PAT-mediated oxidative stress. Cystine/glutamate antiporter (system xc-)-mediated cystine uptake plays a critical role in maintaining redox balance via promoting GSH biosynthesis. In this study, we addressed if GSH reduction by PAT was associated with inhibition of system xc--mediated GSH biosynthesis. Results showed that PAT significantly decreased activity of SLC7A11, a core subunit of system xc-, through activating AMPK-mediated formation of beclin1-SLC7A11 complex. Furthermore, PAT promoted ferroptosis induced by a known ferroptosis inducer RSL3 in normal renal cells, and exacerbated folic acid-induced nephrotoxicity in a mouse model of acute kidney injury. The findings of the present study provide new insights into PAT-induced kidney toxicity, and implicate that patients with ferroptosis-associated diseases maybe more susceptible to PAT.

Combining Patulin with Cadmium Induces Enhanced Hepatotoxicity and Nephrotoxicity In Vitro and In Vivo.

Food can be contaminated by various types of contaminants such as mycotoxins and toxic heavy metals. Therefore, it is very likely that simultaneous intake of more than one type of food contaminant by consumers may take place, which provides a strong rationale for investigating the combined toxicities of these food contaminants. Patulin is one of the most common food-borne mycotoxins, whereas cadmium is a representative of toxic heavy metals found in food. The liver and kidneys are the main target organ sites for both patulin and cadmium. We hypothesized that simultaneous exposure to patulin and cadmium could produce synergistic hepatotoxicity and nephrotoxicity. Alpha mouse liver 12 (AML12) and Human embryonic kidney (HEK) 293 (HEK293) cell lines together with a mouse model were used to explore the combination effect and mechanism. The results demonstrated, for the first time, that the co-exposure of liver or renal cells to patulin and cadmium caused synergistic cytotoxicity in vitro and enhanced liver toxicity in vivo. The synergistic toxicity caused by the co-administration of patulin and cadmium was attributed to the boosted reactive oxygen species (ROS) generation. c-Jun N-terminal kinase 1 (JNK1) and p53 as downstream mediators of oxidative stress contributed to the synergistic toxicity by co-exposure of patulin and cadmium, while p53/JNK1 activation promoted the second-round ROS production through a positive feedback loop. The findings of the present study extend the toxicological knowledge about patulin and cadmium, which could be beneficial to more precisely perform risk assessments on these food contaminants.

Extractions and rheological properties of polysaccharide from okra pulp under mild conditions.

This study investigated the extraction of polysaccharide from okra pulp (POP), its chemical components, and rheological properties. The results showed that the optimal extraction temperature, time, and the ration of water to material were 20-30 °C, 30 mins, and 150, respectively, giving a maximum yield of 29.4%. The POP extracted under the mild condition showed different properties. The molecular weight of POP varied from 6436 kDa to 7432 kDa. The GalA/Rha and Gal/Rha in POP suggests the domain of rhamnogalacturonan I with long galactose side chains. The POP presented pseudoplastic shear-thinning behavior, which can be described by the Ostward-DeWaele model. The apparent viscosity of POP decreased with temperature rising from 25 °C to 80 °C. In addition, sucrose, CaCl2, and NaCl led to the reduction of its apparent viscosity which was more sensitive to Ca2+ than to Na+ and sucrose. A closed hysteresis loop was obtained when the POP concentration reached to 6 g/L. The POP showed an elastic behavior (G' > G″) at concentration of 6 g/L, while it showed predominantly viscous response (G' < G″) at concentration of 2 and 4 g/L, over a wide range of frequencies (0.1-10 Hz). These results are potentially useful for the application of POP in food processing.

Inorganic Selenium Induces Nonapoptotic Programmed Cell Death in PC-3 Prostate Cancer Cells Associated with Inhibition of Glycolysis.

Previous studies have shown that selenite, a representative of inorganic form selenium, exerts its anticancer effect by inducing apoptosis in androgen-dependent LNCaP prostate cancer cells, but few studies have determined the nature of cell death induced by selenite in metastatic androgen-refractory PC-3 cells. Our study showed that necrosis-like cell death rather than apoptosis, pyroptosis, or autophagic cell death was caused by selenite in PC-3 cells. Mechanistically, this type of cell death was caused by ATP depletion (26.28 ± 3.39 nmol/mg of control versus 9.12 ± 2.44 nmol/mg of 10 µM selenite treatment) that resulted from phosphofructokinase activity reduction (100.17 ± 0.17% of control versus 21.74 ± 6.65% of 10 µM selenite treatment). Our study also showed that ROS production is necessary for the decrease in cellular ATP levels and in phosphofructokinase activity. To our knowledge, this is the first study showing that selenite can induce necrosis-like cell death in PC-3 cells. Our findings support selenite as an effective compound for the therapy of apoptosis-resistant prostate cancer.

Combination of Patulin and Chlorpyrifos Synergistically Induces Hepatotoxicity via Inhibition of Catalase Activity and Generation of Reactive Oxygen Species.

Patulin (PAT) is the most common food-borne mycotoxin found in fruits and fruit-derived products, while chlorpyrifos (CPF) is a widely used pesticide on fruit and other crops. On the basis of the residue data, certain types of fruits can be contaminated simultaneously by patulin and chlorpyrifos. However, there are no available data about the combined toxicity. Since liver is a possible toxic target of both patulin and chlorpyrifos, we tested whether the combination exposure can cause enhanced hepatotoxicity using both cell culture and animal models. Results showed that the combination resulted in synergistic cytotoxicity in vitro and significantly enhanced liver toxicity in vivo. Mechanistically, PAT inhibited catalase activity via PIG3 induction, while CPF decreased catalase expression. These two mechanisms were converged in response to the combination, leading to enhanced inactivating catalase and boosted reactive oxygen species generation. The finding implicated that it is necessary to consider the combined toxicity in safety assessment of these food-borne contaminants.

Glycycoumarin protects mice against acetaminophen-induced liver injury predominantly via activating sustained autophagy.

BACKGROUND AND PURPOSE: Acetaminophen-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Given the significant limitations associated with N-acetyl cysteine, the only antidote used to treat AILI, the development of novel therapeutic approaches that can offer a wide range of therapeutic time-windows is clearly needed. Glycycoumarin (GCM), a natural coumarin purified from liquorice, has been previously demonstrated to possess potent hepatoprotective effects. In the present study, we aimed to investigate the therapeutic potential of GCM against AILI. EXPERIMENTAL APPROACH: Acetaminophen (300 mg·kg-1 ) was administered to male C57BL/6 mice, with and without GCM. Serum transaminases, haematoxylin and eosin staining and Western blot were used to assess hepatic damage. KEY RESULTS: GCM (50 mg·kg-1 ) was highly effective against acetaminophen-induced hepatotoxicity. Moreover, GCM was superior to N-acetyl cysteine, in terms of the dosage and the therapeutic time-windows. Further mechanistic investigations revealed that the therapeutic action of GCM was not a result of inhibition of acetaminophen metabolic activation or associated with Nrf2. Instead, the protective effect of GCM appeared to be predominantly dependent on sustained activation of autophagy, which attenuated acetaminophen-induced mitochondrial oxidative stress and JNK activation. CONCLUSIONS AND IMPLICATIONS: Collectively, our results indicate that GCM alleviated acetaminophen-induced oxidative stress through activating autophagy, thereby protecting against AILI. Our findings suggest that GCM has potential as a novel therapeutic agent for treating AILI.