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Owing to the lack of selection and limited intelligence in mechanical picking, some immature tomatoes that contain alkaloids are thrown away. Tomatine alkaloids are steroidal alkaloids naturally present in Solanaceae plants, which are distributed in small amounts in immature tomato fruits and decrease as the fruits ripen. Tomato glycoalkaloids are harmful to human health. However, in small quantities, there is some evidence that these compounds might be beneficial, as other non-antioxidant bioactivities. This article considers recent research on the biological effects of tomato glycoalkaloids in immature tomatoes, providing reference value for the potential development of these compounds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lin Shi reports financial support was provided by Shenyang Agricultural University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Although evidence on the association between per- and polyfluoroalkyl substances (PFASs) and human health outcomes has grown exponentially, specific health outcomes and their potential associations with PFASs have not been conclusively evaluated., Methods: We conducted a comprehensive search through the databases of PubMed, Embase, and Web of Science from inception to February 29, 2024, to identify systematic reviews with meta-analyses of observational studies examining the associations between the PFASs and multiple health outcomes. The quality of included studies was evaluated using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) tool, and credibility of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The protocol of this umbrella review (UR) had been registered in PROSPERO (CRD 42023480817)., Results: The UR identified 157 meta-analyses from 29 articles. Using the AMSTAR measurement tool, all articles were categorized as of moderate-to-high quality. Based on the GRADE assessment, significant associations between specific types of PFASs and low birth weight, tetanus vaccine response, and triglyceride levels showed high certainty of evidence. Moreover, moderate certainty of evidence with statistical significance was observed between PFASs and health outcomes including lower BMI z-score in infancy, poor sperm progressive motility, and decreased risk of preterm birth as well as preeclampsia. Fifty-two (33%) associations (e.g., PFASs and gestational hypertension, cardiovascular disease, etc) presented low certainty evidence. Additionally, eighty-five (55%) associations (e.g., PFASs with infertility, lipid metabolism, etc) presented very low certainty evidence., Conclusion: High certainty of evidence supported that certain PFASs were associated with the incidence of low birth weight, low efficiency of the tetanus vaccine, and low triglyceride levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The electrocatalytic reduction of NO 2 - (NO 2 RR) holds promise as a sustainable pathway to both promoting the development of emerging NH 3 economies and allowing the closing of the NO x loop. Highly efficient electrocatalysts that could facilitate this complex six-electron transfer process are urgently desired. Herein, tremella-like CoNi-LDH intercalated by cyclic polyoxometalate (POM) anion P 8 W 48 (P 8 W 48 /CoNi-LDH) prepared by a simple two-step hydrothermal-exfoliation assembly method is proposed as an effective electrocatalyst for NO 2 - to NH 3 conversion. The introduction of POM with excellent redox ability tremendously increased the electrocatalytic performance of CoNi-LDH in the NO 2 RR process, causing P 8 W 48 /CoNi-LDH to exhibit large NH 3 yield of 0.369 mmol h -1 mg cat -1 and exceptionally high Faradic efficiency of 97.0% at -1.3 V vs the Ag/AgCl reference electrode in 0.1 M phosphate buffer saline (PBS, pH = 7) containing 0.1 M NO 2 - . Furthermore, P 8 W 48 /CoNi-LDH demonstrated excellent durability during cyclic electrolysis. This work provides a new reference for the application of POM-based nanocomposites in the electrochemical reduction of NO 2 - to obtain value-added NH 3 .

Following nearly two decades of development, significant advancements have been achieved in PROTAC technology. As of the end of 2022, more than 20 drugs have entered clinical trials, with ARV-471 targeting estrogen receptor (ER) showing remarkable progress by entering phase III clinical studies. In 2022, significant progress has been made on multiple targets. The first reversible covalent degrader designed to target the KRAS G12C mutant protein, based on cyclopropionamide, has been reported. Additionally, the activity HDCA1 degrader surpassed submicromolar levels during the same year. A novel FEM1B covalent ligand called EN106 was also discovered, expanding the range of available ligands. Furthermore, the first PROTAC drug targeting SOS1 was reported. Additionally, the first-in-class degraders that specifically target BRD4 isoforms (BRD4 L and BRD4 S) have recently been reported, providing a valuable tool for further investigating the biological functions of these isoforms. Lastly, a breakthrough was also achieved with the first degrader targeting both CDK9 and Cyclin T1. In this review, we aimed to update the PROTAC degraders as potential anticancer agents covering articles published in 2022. The design strategies, degradation effects, and anticancer activities were highlighted, which might provide an updated sight to develop novel PROTAC degraders with great potential as anticancer agents as well as favorable drug-like properties., Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

In this work, a series of novel coumarin-based derivatives were designed and synthesized as tubulin polymerization inhibitors targeting the colchicine binding site, and their antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells were evaluated. Among them, the compound I-3 (MY-1442) bearing a 6-methoxy-1,2,3,4-tetrahydroquinoline group exhibited most potent inhibitory activities on MGC-803 (IC 50  = 0.034 μM), HCT-116 (IC 50  = 0.081 μM) and KYSE30 cells (IC 50  = 0.19 μM). Further mechanism studies demonstrated that compound I-3 (MY-1442) could directly bind to the colchicine binding site of β-tubulin to inhibit tubulin polymerization and microtubules at the cellular level. The results of molecular docking indicated there were well binding interactions between compound I-3 (MY-1442) and the colchicine binding site of β-tubulin. Compound I-3 (MY-1442) also exhibited effective anti-proliferation, pro-apoptosis, and anti-migration abilities against gastric cancer cells MGC-803. Additionally, compound I-3 (MY-1442) could regulate the expression of cell cycle- and apoptosis-related proteins. Importantly, compound I-3 (MY-1442) could significantly inhibit tumor growth in the MGC-803 xenograft tumor model with a TGI rate of 65.5 % at 30 mg/kg/day. Taken together, this work suggested that the coumarin skeleton exhibited great potential to be a key pharmacophore of tubulin polymerization inhibitors for the discovery of anticancer agents., Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Orexin is a neuropeptide released from hypothalamus regulating feeding, sleeping, arousal, and cardiovascular activity. Past research has demonstrated that orexin receptor 2 (OX2R) agonist infusion in the brain results in sympathoexcitatory responses. Here, we found that epicardial administration of OX2R agonism leads to opposite responses. We proved that OX2R is expressed mainly in DRG neurons and transported to sensory nerve endings innervating the heart. In a capsaicin-induced cardiac sympathetic afferent reflex (CSAR) model, we recorded the calcium influx in DRG neurons, measured heart rate variability, and examined the PVN c-Fos activity to prove that epicardial OX2R agonism administration could attenuate capsaicin-induced CSAR. We further showed that OX2R agonism could partially rescue acute myocardial infarction by reducing sympathetic overactivation. Our data indicate that epicardial application of OX2R agonist exerts a cardioprotective effect by attenuating CSAR. This OX2R-mediated heart-brain axis may provide therapeutic targets for acute cardiovascular diseases., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f ( MY-1121 ) exhibited low nanomolar IC 50 values ranging from 0.089 to 0.238 μM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC 50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f ( MY-1121 ) could bind to the colchicine binding site of β-tubulin and directly act on β-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f ( MY-1121 ) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f ( MY-1121 ) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities.

In this study, twenty-one novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors targeting FAK were designed and synthesized based on the structure of TAE-226, and the inhibitory effects of these compounds on both the FAK enzyme and three cancer cell lines (MGC-803, HCT-116, and KYSE30) were investigated. Among them, compound 12s displayed potent inhibitory potency on FAK (IC 50  = 47 nM), and demonstrated more significant antiproliferative activities in MGC-803, HCT-116 and KYSE30 cells (IC 50 values were 0.24, 0.45 and 0.44 μM, respectively) compared to TAE-226. Furthermore, compound 12s significantly inhibited FAK activation leading to the negative regulation of FAK-related signaling pathways such as AKT/mTOR and MAPK signaling pathways. Molecular docking study suggested that compound 12s could well occupy the ATP-binding pocket site of FAK similar to TAE-226. In addition, compound 12s also efficiently inhibited the proliferation, induced apoptosis and cellular senescence in MGC-803 cells. In conclusion, compound 12s emerges a potent FAK inhibitor that could exert potent inhibitory activity against gastric cancer cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Histone deacetylases, as a new class of anticancer targets, could maintain homeostasis by catalyzing histone deacetylation and play important roles in regulating the expression of target genes. Due to the fact that simultaneous intervention with dual tumor related targets could improve treatment effects, researches on innovative design of dual-target drugs are underway. HDAC is known as a "sensitizer" for the synergistic effects with other anticancer-target drugs because of its flexible structure design. The synergistic effects of HDAC inhibitor and other target inhibitors usually show enhanced inhibitory effects on tumor cells, and also provide new strategies to overcome multidrug resistance. Many research groups have reported that simultaneously inhibiting HDAC and other targets, such as tubulin, EGFR, could enhance the therapeutic effects. The o-aminobenzamide group is often used as a ZBG group in the design of HDAC inhibitors with potent antitumor effects. Given the prolonged inhibitory effects and reduced toxic side effects of HDAC inhibitors using o-aminobenzamide as the ZBG group, the o-aminobenzamide group is expected to become a more promising alternative to hydroxamic acid. In fact, o-aminobenzamide-based dual inhibitors of HDAC with different chemical structures have been extensively prepared and reported with synergistic and enhanced anti-tumor effects. In this work, we first time reviewed the rational design, molecular docking, inhibitory activities and potential application of o-aminobenzamide-based HDAC inhibitors with dual targeting capabilities in cancer therapy, which might provide a reference for developing new and more effective anticancer drugs., Competing Interests: Declaration of competing interest The authors declared that there was no conflict of interest about this work., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

As a class of microtubule targeting agents, colchicine binding site inhibitors (CBSIs) are considered as promising drug candidates for cancer therapy. However, due to adverse reactions, there are currently no CBSIs approved by FDA for cancer treatment. Therefore, extensive efforts are still encouraged to find novel CBSIs with different chemical structures and better anticancer efficacies. In this work, we designed and synthesized a new coumarin-dihydroquinoxalone derivative, MY-673, and evaluated its anticancer potency in vitro and in vivo. We confirmed that MY-673 was a potent CBSI that it not only inhibited tubulin polymerization, but also exhibited significant inhibitory potency on the growth of 13 cancer cells with IC 50 values from 11.7 nM to 395.9 nM. Based on the results of kinase panel screening, MY-673 could inhibit ERK (extracellular regulated protein kinases) pathways-related kinases. We further confirmed that MY-673 could inhibit ERK signaling pathway in MGC-803 and HGC-27 cells, and then affected the expression level of SMAD4 protein in TGF-β (transforming growth factor β) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, compound MY-673 could effectively inhibit cell proliferation, migration and induce cell apoptosis. We also further confirmed the in vivo efficacy of MY-673 in inhibiting tumor growth using the MGC-803 xenograft tumor model. At 20 mg/kg, the TGI rate was 85.9%, and it did not cause obvious toxicity to the main organs of mice. Together, the results we report here indicated that MY-673 was a promising CBSI for cancer treatment, which was capable of inhibiting the ERK pathway with potent antiproliferative activities in vitro and in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Climate change not only directly affects the phenotype of organisms but also indirectly impacts their physiology, for example, by altering their susceptibility to insecticides. Changed diurnal temperature fluctuations are an important aspect of climate change; ignoring the impact of these fluctuations on the biological effects of various chemical insecticides can lead to inaccurate assessments of insecticide risk under the current and future climate change scenarios. Methods: In this study, we studied effects of different temperature amplitudes (± 0, ± 6, ± 12°C) at the same mean temperature (22°C) on the life history traits of a globally distributed pest ( Sitobion avenae , wheat aphid), in response to low doses of two insecticides. The first, imidacloprid shows a positive temperature coefficient; the second, beta-cypermethrin has a negative temperature coefficient. Results: Compared with the results seen with the constant temperature (22°C), a wide temperature amplitude (± 12°C) amplified the negative effects of imidacloprid on the survival, longevity, and fecundity of S. avenae , but significantly increased the early fecundity of the wheat aphid. Beta-cypermethrin positively impacted the wheat aphid at all temperature amplitudes studied. Specifically, beta-cypermethrin significantly increased the survival, longevity, and fecundity of S. avenae under medium temperature amplitude (± 6°C). There were no significant differences in the survival, longevity, and the early fecundity of S. avenae when it was treated with beta-cypermethrin at the wide temperature amplitude (± 12°C). However, the negative effect of beta-cypermethrin on the intrinsic rate of increase of S. avenae decreased gradually with the increase in temperature amplitude. Discussion: In conclusion, the response of S. avenae to positive temperature coefficient insecticides was markedly affected by temperature amplitude, while negative temperature coefficient insecticides increased the environmental adaptability of S. avenae to various temperature amplitudes. Our results highlight the importance of the integrated consideration of diurnal temperature fluctuations and different temperature coefficient insecticide interactions in climate-change-linked insecticide risk assessment; these results emphasize the need for a more fine-scale approach within the context of climate change and poison sensitivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xing, Zhang, Jia and Zhao.)

In this work, N-benzylarylamide-dithiocarbamate based derivatives were designed, synthesized, and their biological activities as anticancer agents were explored. Some of the 33 target compounds displayed significant antiproliferative activities with IC 50 values at the double-digit nanomolar level. The representative compound I-25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC 50  = 0.017 μM), HCT-116 (IC 50  = 0.044 μM) and KYSE450 (IC 50  = 0.030 μM), but also exhibited low nanomolar IC 50 values from 0.019 to 0.253 μM against the other 11 cancer cells. Compound I-25 (MY-943) effectively inhibited tubulin polymerization and suppressed LSD1 at the enzymatic levels. Compound I-25 (MY-943) could act on the colchicine binding site of β-tubulin, thus disrupting the construction of cell microtubule network and affecting the mitosis. In addition, compound I-25 (MY-943) could dose-dependently induce the accumulation of H3K4me1/2 (MGC-803 and SGC-7091 cells) and H3K9me2 (SGC-7091 cells). Compound I-25 (MY-943) could induce G2/M phase arrest and cell apoptosis, and suppress migration in MGC-803 and SGC-7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cycle-related proteins. Furthermore, the binding modes of compound I-25 (MY-943) with tubulin and LSD1 were explored by molecular docking. The results of in vivo anti-gastric cancer assays using in situ tumor models showed that compound I-25 (MY-943) effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. All these findings suggested that the N-benzylarylamide-dithiocarbamate based derivative I-25 (MY-943) was an effective dual inhibitor of tubulin polymerization and LSD1 that inhibited gastric cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However, for its high-risk type, even with various intensive treatment options, the prognosis is still unsatisfactory. At the same time, a large number of research data show that the abnormal amplification and high-level expression of the MYCN gene are positively correlated with the malignant progression, poor prognosis, and mortality of neuroblastoma. In this context, this article explores the role of the N-Myc, MYCN gene expression product on its target genes related to the cell cycle and reveals its regulatory network in promoting tumor proliferation and malignant progression. We hope it can provide ideas and direction for the research and development of drugs targeting N-Myc and its downstream target genes.

Purpose: Salivary gland carcinomas (SGCs) can be classified into more than 20 subtypes with various clinical behaviors. The present study aimed to analyze the clinical and pathological features of SGCs and evaluate their long-term prognosis., Methods: A retrospective cohort study was performed. This study investigated cases of histologically confirmed SGC at the authors' institution from January 1963 to December 2014. Data on sex, age, site, histopathological diagnosis, tumor-node-metastasis classification, postoperative radiotherapy and/or chemotherapy, local and regional recurrence, and distant metastasis (DM) were collected as covariates. The overall survival (OS) rate was analyzed as the outcome. Kaplan-Meier survival analysis and Cox multivariate analysis were used for survival analysis. The cohort was divided into 2 groups-before and after 1989. The clinicopathological characteristics of the 2 groups were compared using the χ 2 test., Results: The cohort included 1,637 patients who met the admission criteria and had a male-to-female ratio of 0.9:1. The median age was 47 years (range, 8 months to 86 years). The median follow-up time was 54 months (range, 1-432 months). The majority of the tumors occurred in the parotid gland (35.3%), followed by the palate gland (25.2%). Adenoid cystic carcinoma was the most common tumor type (34.3%), and mucoepidermoid carcinoma (29%) was the second most common type. In the 1,637 patients, the neck lymph node metastasis rate was 8.7% at the first surgery, and the overall DM rate was 14.1%. The 5-, 10-, and 15-year OS rates of the 1,637 cases were 93.1%, 87.2%, and 79.3%, respectively. Comparative analysis before and after 1989 showed statistically significant differences in sex, site, histologic subtype, T classification, local and regional recurrence rate, and radiotherapy (P < .05), while no significant differences were found in age, N classification, M staging, DM, or chemotherapy., Conclusions: The OS rates of SGC have improved significantly over the past 30 years. This is attributable to an increase in the proportion of patients diagnosed at the early stage and receiving radiotherapy, as this has led to a reduction in the local and regional recurrence rate and, consequently, an improvement in the survival rates., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Anterior gradient 2 (AGR2), a protein disulfide isomerase (PDI), is a multifunctional protein under physiological and pathological conditions. In this study we investigated the roles of AGR2 in regulating cholesterol biogenesis, lipid-lowering efficiency of lovastatin as well as in protection against hypercholesterolemia/statin-induced liver injury. We showed that AGR2 knockout significantly decreased hepatic and serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in mice with whole-body or hepatocyte-specific Agr2-null mutant, compared with the levels in their wild-type littermates fed a normal chow diet (NCD) or high-fat diet (HFD). In contrast, mice with AGR2 overexpression (Agr2/Tg) exhibited an increased cholesterol level. Mechanistic studies revealed that AGR2 affected cholesterol biogenesis via activation of AKT/sterol regulatory element-binding protein-2 (SREBP2), to some extent, in a PDI motif-dependent manner. Moreover, elevated AGR2 led to a significant decrease in the lipid-lowering efficacy of lovastatin (10 mg· kg -1 · d -1 , ip, for 2 weeks) in mice with hypercholesterolemia (hyperCho), which was validated by results obtained from clinical samples in statin-treated patients. We showed that lovastatin had limited effect on AGR2 expression, but AGR2 was inducible in Agr2/Tg mice fed a HFD. Further investigations demonstrated that drug-induced liver toxicity and inflammatory reactions were alleviated in hypercholesterolemic Agr2/Tg mice, suggesting the dual functions of AGR2 in lipid management and hyperCho/statin-induced liver injury. Importantly, the AGR2-reduced lipid-lowering efficacy of lovastatin was attenuated, at least partially, by co-administration of a sulfhydryl-reactive compound allicin (20 mg· kg -1 · d -1 , ip, for 2 weeks). These results demonstrate a novel role of AGR2 in cholesterol metabolism, drug resistance and liver protection, suggesting AGR2 as a potential predictor for selection of lipid-lowering drugs in clinic., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Metastasis is an important cause of cancer-related death. Previous studies in our laboratory found that pregnane alkaloids from Pachysandra terminalis had antimetastatic activity against breast cancer cells. In the current study, we demonstrated that treatment with one of the alkaloid derivatives, ( Z )-3β-ethylamino-pregn-17(20)-en ( 1 ), led to the downregulation of the HIF-1α/VEGF/VEGFR2 pathway, suppressed the phosphorylation of downstream molecules Akt, mTOR, FAK, and inhibited breast cancer metastasis and angiogenesis both in vitro and in vivo. Furthermore, the antimetastasis and antiangiogenesis effects of 1 treatment (40 mg/kg) were more effective than that of Sorafenib (50 mg/kg). Surface plasmon resonance (SPR) analysis was performed and the result suggested that HSP90α was a direct target of 1 . Taken together, our results suggested that compound 1 might represent a candidate antitumor agent for metastatic breast cancer.

Fibrosis is a common pathological outcome of chronic injuries, characterized by excessive deposition of extracellular matrix components in organs, as seen in most chronic inflammatory diseases. At present, there is an increasing tendency of the morbidity and mortality of diseases caused by fibrosis, but the treatment measures for fibrosis are still limited. Fibroblast growth factor 21 (FGF21) belongs to the FGF19 subfamily, which also has the name endocrine FGFs because of their endocrine manner. In recent years, it has been found that plasma FGF21 level is significantly correlated with fibrosis progression. Furthermore, there is evidence that FGF21 has a pronounced antifibrotic effect in a variety of fibrotic diseases. This review summarizes the biological effects of FGF21 and discusses what is currently known about this factor and fibrosis disease, highlighting emerging insights that warrant further research., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 Min-Qi Jia et al.)

Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.

Children are high-risk groups of burns, with unique physiological, psychological, and anatomical states, and the management of anxiety and pain for burn children are extremely challenging. Non-pharmacological interventions are very important for pain management in burn children, but are often inadequate for treating pain and anxiety, so pharmacological sedation and analgesia are necessary. This article reviewed the clinical treatment and research progress in this field in the past 10 years at home and abroad, including the pain assessment of burn children, monitoring in sedative and analgesic treatment, main therapeutic drugs and research progress, and some controversies in clinical practice. Besides, some suggestions have been put forward for clinical reference.

Objective: The 2019 novel coronavirus disease (COVID-19) is threatening global health and is especially pronounced in patients with chronic metabolic syndromes. Meanwhile, a significant proportion of patients present with digestive symptoms since angiotensin-converting enzyme 2 (ACE2), which is the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the intestine. The aim of this study was to evaluate the effects of a high-fat diet (HFD) and a maternal HFD on the intestinal ACE2 levels in adults and neonates., Methods: We examined intestinal ACE2 protein levels in mice with diet-induced obesity (DIO) and neonatal mice exposed to a maternal HFD. We also investigated Ace2 mRNA expression in intestinal macrophages., Results: Intestinal ACE2 protein levels were increased in DIO mice but decreased in offspring exposed to a maternal HFD compared with chow-fed controls. Ace2 mRNA expression in intestinal macrophages was detected and downregulated in DIO mice. Additionally, higher intestinal ACE2 protein levels were observed in neonates than in adult mice., Conclusions: The influence of an HFD on intestinal ACE2 protein levels is opposite in adults and neonates. Macrophages might also be involved in SARS-CoV-2 intestinal infection. These findings provide some clues for the outcomes of patients with COVID-19 with metabolic syndromes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Breast cancer has become the number one killer of women. In our previous study, an active compound, ION-31a, with potential anti-metastasis activity against breast cancer was identified through the synthesis of ionone alkaloid derivatives. In the present study, we aimed to identify the therapeutic target of ION-31a. We used a fluorescence tag labeled probe, molecular docking simulation, and surface plasmon resonance (SPR) analysis to identify the target of ION-31a. The main target of ION-31a was identified as heat shock protein 90 (HSP90). Thus, ION-31a is a novel HSP90 inhibiter that could suppress the metastasis of breast cancer and angiogenesis significantly in vitro and in vivo. ION-31a acts via inhibiting the HSP90/hypoxia inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway and downregulating downstream signal pathways, including protein kinase B (AKT)/mammalian target of rapamycin (mTOR), AKT2/protein kinase C epsilon (PKCζ), extracellular regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and mitogen-activated protein kinase 14 (p38MAPK) pathways. ION-31a affects multiple effectors implicated in tumor metastasis and has the potential to be developed as an anti-metastatic agent to treat patients with breast cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Novel chiral ionone alkaloid derivatives were synthesized and their antimetastatic effects were evaluated in human breast cancer cells using chemotaxis assay. Compared with positive control LY294002, a PI3 K inhibitor, derivatives 10 a, 11 a, 11 c, 11 g, 11 j, 11 k and 11 w exhibited significant inhibitory effects against cancer cell migration. Especially, the IC 50 for compound 11 g was as low as 0.035±0.004 μM. Further investigations on compound 11 g revealed that it could exert inhibitory effects on the adhesion, migration and invasion of MDA-MB-231 cells. The mechanisms for the antitumor metastatic effects of 11 g might be through the inhibition of HIF-1α/VEGF/VEGFR2/Akt pathway, which suppressed the downstream signaling molecules, including Akt1/mTOR/p70S6K and Akt2/PKCζ/integrin β1 pathways. Taken together, chiral ionone alkaloid derivative 11 g has the potential to be developed into an antitumor metastatic agent for breast cancer., (© 2021 Wiley-VCH GmbH.)

The lateral arm flap (LAF) may offer an alternative option for oral cavity repair. Twenty-five Chinese patients with oral cavity defects were reconstructed with a LAF. The anatomical characteristics of the flap, the donor site complications, and the functional and aesthetic assessments of recipient site were reviewed. The overall flap survival was 96.0% (24/25patients). The average pedicle length was 7.07±1.09cm when it was cut off at the insert of the deltoid, with an average arterial diameter of 1.30±0.37mm and vein diameter of 2.06±0.48mm. The average flap length was 7.06±1.01cm, and the average flap breadth was 5.28±0.66cm, with the average flap size ranging from 18 to 42cm 2 . One to three reliable perforators supplied the flap, with the proximal, middle, and distal perforators being located at 9.9±1.1cm, 8.6±1.4cm, and 5.7±1.2cm from the lateral epicondyle, respectively. The donor defect was closed primarily and healed uneventfully. A longitudinal scar was the most common morbidity of the donor site. The function and shape of the reconstructed tissues were well restored. The LAF provides a reliable choice for reconstructing medium-sized oral cavity defects, with minimal donor-site morbidity and ideally functional and aesthetic rehabilitation of the recipient site., (Copyright © 2020 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Normal epithelial cells rapidly undergo apoptosis as soon as they lose contact with the extracellular matrix (ECM), which is termed as anoikis. However, cancer cells tend to develop a resistance mechanism to anoikis. This acquired ability is termed as anoikis resistance. Cancer cells, with anoikis resistance, can spread to distant tissues or organs via the peripheral circulatory system and cause cancer metastasis. Thus, inhibition of anoikis resistance blocks the metastatic ability of cancer cells., Methods: Anoikis-resistant CAL27 (CAL27 AR ) cells were induced from CAL27 cells using the suspension culture approach. Transcriptome analysis was performed using RNA-Seq to study the differentially expressed genes (DEGs) between the CAL27 AR cells and the parental CAL27 cells. Gene function annotation and Gene Ontology (GO) enrichment analysis were performed using DAVID database. Signaling pathways involved in DEGs were analyzed using Gene Set Enrichment Analysis (GSEA) software. Analysis results were confirmed by reverse transcription PCR (RT-PCR), western blotting, and gene correlation analysis based on the TCGA database., Results: GO enrichment analysis indicated that the biological process (BP) of the DEGs was associated with epidermal development, DNA replication, and G1/S transition of the mitotic cell cycle. The analysis of cellular component (CC) showed that the most significant up-regulated genes were related to extracellular exosome. KEGG Pathway analysis revealed that 23 signaling pathways were activated ( p -value ≤ 0.05, FDR q -value ≤ 0.05) and 22 signaling pathways were suppressed ( p -value ≤ 0.05, FDR q -value ≤ 0.05). The results from the GSEA indicated that in contrast to the inhibition of EGFR signaling pathway, the VEGF signaling pathway was activated. The VEGF signaling pathway possibly activates STAT3 though induction of STAT3 phosphorylation. Gene correlation analysis revealed that the VEGFA- STAT3-KLF4-CDKN1A signal axis was not only present in head and neck squamous carcinoma (HNSCC) but also two other epithelial-derived carcinomas that highly express VEGFA, including kidney renal clear cell carcinoma (KIRC) and ovarian serous cystadenocarcinoma (OV)., Competing Interests: The authors declare there are no competing interests.

Primary intestinal-type adenocarcinoma (ITAC) of the tongue is a rare neoplasm. The case of a 59-year-old male with a painless mass in the dorsum of the oral tongue diagnosed as primary ITAC is reported here. The particular characteristic of the case was the patient's long-term medical history of 40years. The patient underwent resection of the tongue carcinoma through a midline approach and direct suture, with postoperative chemoradiotherapy. Immunohistochemical staining indicated that the tumour was positive for CK20 and negative for CK7. A review of the English-language literature was performed, which identified six cases of primary ITAC and three cases of metastatic ITAC of the tongue. The clinical characteristics and therapeutic methods used in these cases were analysed., (Copyright © 2018 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: The treatment failure for oral squamous cell carcinoma (SCC) frequently takes the form of local and regional recurrences. We investigated the role of lingual lymph nodes (LLNs) in the recurrence of SCC of the tongue and the floor of the mouth., Methods: A total of 111 patients with SCC of the tongue and the floor of the mouth who received treatment between 2012 and 2017 were included in this study. The patients with lingual lymph nodes that were confirmed to be metastasis on pathological examination were classified into the LNN group. The demographic and clinical data differences between the No-LLN group and the LLN group were compared. Statistical analyses were performed using the Pearson chi-square test RESULTS: The total incidence of LLNs was 17.12% (19/111) and 5 patients (4.5%) demonstrated LLN metastases. All the patients with LLN metastases had a neck lymph node status of N2 classification. The incidence and metastasis of the LLNs were associated with pathological classifications of SCC of the tongue and the floor of the mouth., Conclusions: LLNs are rare in patients with SCC of the tongue and the floor of the mouth, and they would be ready to be omitted. The dissection of these LLNs would be of benefit to those patients with advanced pathological grade., (© 2018 Wiley Periodicals, Inc.)

Fatty acids (FAs) are transported by serum albumin in plasma. Studies have been undertaken to address the binding of MCFAs or LCFAs to human plasma albumin (HPA) and bovine serum albumin (BSA) by characterizing the binding affinities. Previous research on FA binding to serum albumin was usually performed in dilute solutions that are not sufficiently concentrated for the interpretation of the significance of the results under normal physiological conditions. How macromolecular crowded media affect fatty acids and bovine serum albumin (BSA) binding remains unknown. In this article, we investigated the mechanism of FA-BSA binding in a polyethylene glycol crowding environment by using thermodynamic and spectroscopic methods. Molecular crowding increased the binding constant for saturated medium-chain fatty acids (MCFAs) but significantly decreased the binding constant for unsaturated long-chain FAs. The binding sites tended to increase in all the cases. Further investigation revealed that crowding media might loosen the structure of BSA, facilitating MCFA-BSA binding. This research is useful for understanding the transportation of FAs by BSA under physiological conditions and may also help to control digestion by the eventual incorporation of macromolecular crowding agents into food formulations.

Amyloid β-protein (Aβ) is believed to contribute to the development of Alzheimer's disease (AD). Here we showed that Aβ 25-35 rapidly caused activation of autophagy, subsequently leading to reduction of autophagy associated with cellular apoptosis. Further investigation revealed that the accumulation of β-arrestin 1 (ARRB1) caused by Aβ 25-35 contributed to the induction of autophagic flux. The depletion of ARRB1 led to decreases in the expression of LC3B, Atg7, and Beclin-1, which are essential for the initiation of autophagy. ARRB1 depletion also reduced downstream ERK activity and promoted Aβ 25-35 -induced cell death. As with ARRB1, transient upregulation of ARRB2 by Aβ 25-35 was observed after short treatment durations, whereas genetic reduction of ARRB2 caused a marked increase in the expression of the α7nAch receptor at the cell surface, which resulted in partial reversal of Aβ 25-35 -induced cell death. Although expression of both ARRB1 and ARRB2 was reduced in serum from patients with AD, the levels of ARRB1 were much lower than those of ARRB2 in AD. Thus, our findings indicate that ARRB1/2 play different roles in Aβ 25-35 cytotoxicity, which may provide additional support for exploring the underlying molecular mechanism of AD.

Yupingfeng (YPF), a famous traditional Chinese medicine, which contains a large array of compounds, has been effectually used in health protection. A two-dimensional liquid chromatography (²D-LC) combined with quadrupole time-of-flight mass spectrometry (QTOF-MS) method was firstly established to separate and identify chemical components in YPF. A total of 33 compounds were identified, including 15 constituents (flavonoids and saponins) in Astragali radix ; seven constituents (sesquiterpenoids and polysaccharide) in Atractylodis rhizoma ; and 11 constituents (chromone and coumarins) in Saposhnikoviae radix . The corresponding fragmentation pathway of typical substances was investigated. Then, seven active constituents (astragaloside, calycosin, formononetin, cimicifugoside, 4- O -beta-d-glucosyl-5- O -methylvisamminol, sec- O -glucosylhamaudol, and atractylenolide II) derived from three medicinal plants were chosen to further investigate the pharmacokinetic behavior of YPF formula using ultrahigh-performance liquid chromatography with triple quadrupole mass spectrometry system. The method was sensitive, accurate and reliable. We also used the area under the plasma concentration-time curve from zero to infinity (AUC 0-∞ ) as weighting factor to make an integrated pharmacokinetic curve. Results show that the constituents of Saposhnikoviae radix have the best absorption and pharmacokinetic behavior and may play important role in leading to the changes of overall therapeutic effects of YPF. Further study is needed to confirm the association between them., Competing Interests: The authors declare no conflict of interest.