1H NMR metabolomics insights into comparative diabesity in male and female zebrafish and the antidiabetic activity of DL-limonene.

Zebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.

Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish.

Tumour-associated angiogenesis play key roles in tumour growth and cancer metastasis. Consequently, several anti-angiogenic drugs such as sunitinib and axitinib have been approved for use as anti-cancer therapies. However, the majority of these drugs target the vascular endothelial growth factor A (VEGFA)/VEGF receptor 2 (VEGFR2) pathway and have shown mixed outcome, largely due to development of resistances and increased tumour aggressiveness. In this study, we used the zebrafish model to screen for novel anti-angiogenic molecules from a library of compounds derived from natural products. From this, we identified canthin-6-one, an indole alkaloid, which inhibited zebrafish intersegmental vessel (ISV) and sub-intestinal vessel development. Further characterisation revealed that treatment of canthin-6-one reduced ISV endothelial cell number and inhibited proliferation of human umbilical vein endothelial cells (HUVECs), suggesting that canthin-6-one inhibits endothelial cell proliferation. Of note, canthin-6-one did not inhibit VEGFA-induced phosphorylation of VEGFR2 in HUVECs and downstream phosphorylation of extracellular signal-regulated kinase (Erk) in leading ISV endothelial cells in zebrafish, suggesting that canthin-6-one inhibits angiogenesis independent of the VEGFA/VEGFR2 pathway. Importantly, we found that canthin-6-one impairs tumour-associated angiogenesis in a zebrafish B16F10 melanoma cell xenograft model and synergises with VEGFR inhibitor sunitinib malate to inhibit developmental angiogenesis. In summary, we showed that canthin-6-one exhibits anti-angiogenic properties in both developmental and pathological contexts in zebrafish, independent of the VEGFA/VEGFR2 pathway and demonstrate that canthin-6-one may hold value for further development as a novel anti-angiogenic drug.

New Triclinic Perovskite-Type Oxide Ba5CaFe4O12 for Low-Temperature Operated Chemical Looping Air Separation.

We present the discovery of Ba5CaFe4O12, a new iron-based oxide with remarkable properties as a low-temperature driven oxygen storage material (OSM). OSMs, which exhibit selective and rapid oxygen intake and release capabilities, have attracted considerable attention in chemical looping technologies. Specifically, chemical looping air separation (CLAS) has the potential to revolutionize oxygen production as it is one of the most crucial industrial gases. However, the challenge lies in utilizing OSMs for energy-efficient CLAS at lower temperatures. Ba5CaFe4O12, a cost-competitive material, possesses an unprecedented 5-fold perovskite-type A5B5O15-δ structure, where both Fe and Ca occupy the B sites. This distinctive structure enables excellent oxygen intake/release properties below 400 °C. This oxide demonstrates the theoretical daily oxygen production rate of 2.41 mO23 kgOSM-1 at 370 °C, surpassing the performance of the previously reported material, Sr0.76Ca0.24FeO3-δ (0.81 mO23 kgOSM-1 at 550 °C). This discovery holds great potential for reducing costs and enhancing the energy efficiency in CLAS.

Teleosts as behaviour test models for social stress.

Stress is an important aspect of our everyday life and exposure to it is an unavoidable occurrence. In humans, this can come in the form of social stress or physical stress from an injury. Studies in animal models have helped researchers to understand the body's adaptive response to stress in human. Notably, the use of behavioural tests in animal models plays a pivotal role in understanding the neural, endocrine and behavioural changes induced by social stress. Under socially stressed conditions, behavioural parameters are often measured physiological and molecular parameters as changes in behaviour are direct responses to stress and are easily assessed by behavioural tests. Throughout the past few decades, the rodent model has been used as a well-established animal model for stress and behavioural changes. Recently, more attention has been drawn towards using fish as an animal model. Common fish models such as zebrafish, medaka, and African cichlids have the advantage of a higher rate of reproduction, easier handling techniques, sociability and most importantly, share evolutionary conserved genetic make-up, neural circuitry, neuropeptide molecular structure and function with mammalian species. In fact, some fish species exhibit a clear diurnal or seasonal rhythmicity in their stress response, similar to humans, as opposed to rodents. Various social stress models have been established in fish including but not limited to chronic social defeat stress, social stress avoidance, and social stress-related decision-making. The huge variety of behavioural patterns in teleost also aids in the study of more behavioural phenotypes than the mammalian species. In this review, we focus on the use of fish models as alternative models to study the effects of stress on different types of behaviours. Finally, fish behavioural tests against the typical mammalian model-based behavioural test are compared and discussed for their viability.

THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer.

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.

Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis.

RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.

J wave dynamicity during coronary angiography and intracoronary acetylcholine administration.

BACKGROUND: J-waves may be observed during coronary angiography (CAG) or intracoronary acetylcholine (ACh) administration, but their significance is unknown. METHODS: Forty-nine patients, 59.1 ± 11.5 years old and 59% male, were studied on suspicion of vasospastic angina, and J wave dynamicity was compared between CAG and Ach administration. RESULTS: Diagnostic (≥0.1 mV) or nondiagnostic (<0.1 mV) J waves in 9 and 3 patients, respectively, were augmented, and J waves were newly observed in 2 patients during CAG and Ach administration. Similar changes in the J-wave amplitude were observed: from 0.10 ± 0.09 mV to 0.20 ± 0.15 mV (p < .002) and from 0.10 ± 0.10 mV to 0.20 ± 0.16 mV (p < .001) during CAG and Ach administration, respectively. J waves were located in the inferior leads and changed only during the right coronary interventions. In the remaining 35 patients, J waves were absent before and during the coronary interventions. Augmentation of J waves was found when the RR interval was shortened in some patients. Injection of anoxic media into the coronary artery might induce a conduction delay from myocardial ischemia that manifests as augmentation or new occurrence of J waves. CONCLUSIONS: Both CAG and intracoronary Ach administration affected J waves similarly in the same individuals. A myocardial ischemia-induced conduction delay may be responsible for the changes in J waves, but further studies are needed.

Strigolactones in Rhizosphere Communication: Multiple Molecules With Diverse Functions.

Strigolactones (SLs) are root-secreted small molecules that influence organisms living in the rhizosphere. While SLs are known as germination stimulants for root parasitic plants and as hyphal branching factors for arbuscular mycorrhizal fungi, recent studies have also identified them as chemoattractants for parasitic plants, sensors of neighboring plants and key players in shaping the microbiome community. Furthermore, the discovery of structurally diverged SLs, including so-called canonical and non-canonical SLs in various plant species, raises the question of whether the same SLs are responsible for their diverse functions 'in planta' and the rhizosphere or whether different molecules play different roles. Emerging evidence supports the latter, with each SL exhibiting different activities as rhizosphere signals and plant hormones. The evolution of D14/KAI2 receptors has enabled the perception of various SLs or SL-like compounds to control downstream signaling, highlighting the complex interplay between plants and their rhizosphere environment. This review summarizes the recent advances in our understanding of the diverse functions of SLs in the rhizosphere.

Simultaneous activation of Kras-Akt and Notch pathways induces extrahepatic biliary cancer via the mTORC1 pathway.

Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. Therefore, we investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct (EHBD) and GB. Activation of Notch signaling and oncogenic Kras resulted in the development of biliary intraepithelial neoplasia (BilINs) in the EHBD and GB, which were premalignant lesions that progressed to adenocarcinoma in mice. The expression of genes involved in the mTORC1 pathway was increased in biliary spheroids from Hnf1b-CreERT2; KrasLSL-G12D ; Rosa26LSL-NotchIC mice and inhibition of the mTORC1 pathway suppressed spheroid growth. Additionally, simultaneous activation of the PI3K-AKT and Notch pathways in EHBD and GB induced biliary cancer development in mice. Consistent with this, we observed a significant correlation between activated NOTCH1 and phosphorylated Ribosomal Protein S6 (p-S6) expression in human eCCA. Furthermore, inhibition of the mTORC1 pathway suppressed the growth of Notch-activated human biliary cancer cells in vitro and in vivo. Mechanistically, the Kras/Notch-Myc axis activated mTORC1 through TSC2 phosphorylation in mutant biliary spheroids. These data indicate that inhibition of the mTORC1 pathway could be an effective treatment strategy for Notch-activated human eCCA. © 2023 The Pathological Society of Great Britain and Ireland.

Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer. SIGNIFICANCE: KRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.

Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC.

Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder.

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence.

Optimal Water Level Management for Mitigating GHG Emissions through Water-Conserving Irrigation in An Giang Province, Vietnam.

Rational water and fertilizer management approaches and technologies could improve water use efficiency and fertilizer use efficiency in paddy rice cultivation. A promising water-conserving technology for paddy rice farming is the alternate wetting and drying irrigation system, established by the International Rice Research Institute. However, the strategy has still not been widely adopted, because water level measurement is challenging work and sometimes leads to a decrease in the rice yield. For the easy implementation of alternate wetting and drying among farmers, we analyzed a dataset obtained from a farmer's water management study carried out over a three-year period with three cropping seasons at six locations (n = 82) in An Giang Province, Southern Vietnam. We observed a significant relationship between specific water level management and the rice yield and greenhouse gas emissions during different growth periods. The average water level during the crop period was an important factor in increasing the rice yield and reducing greenhouse gas emissions. The average water level at 2 days after nitrogen fertilization also showed a potential to increase the rice yield. The greenhouse gas emissions were reduced when the number of days of non-flooded soil use was increased by 1 day during the crop period. The results offer insights demonstrating that farmers' implementation of multiple drainage during whole crop period and nitrogen fertilization period has the potential to contribute to both the rice yield increase and reduction in greenhouse gas emissions from rice cultivation.

Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer.

The role of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been vastly studied over the last decade. This has led to the rapid development of many generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. Therefore, further molecular understanding of NSCLC mutations, bypass signalling, tumour microenvironment and the existence of cancer stem cells to overcome such resistances is warranted. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanisms of resistance towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever-evolving and adaptive nature of NSCLC.

Correction: Nickel-catalyzed 1,4-aryl rearrangement of aryl N-benzylimidates via C-O and C-H bond cleavage.

Correction for 'Nickel-catalyzed 1,4-aryl rearrangement of aryl N-benzylimidates via C-O and C-H bond cleavage' by Satoshi Ogawa et al., Chem. Commun., 2022, 58, 7909-7911, https://doi.org/10.1039/D2CC02355E.

Strigol induces germination of the facultative parasitic plant Phtheirospermum japonicum in the absence of nitrate ions.

Root parasitic plants in the family Orobanchaceae, such as Striga and Orobanche spp., infest major crops worldwide, leading to a multibillion-dollar loss annually. Host-derived strigolactones (SLs), recognized by a group of α/ß hydrolase receptors (KAI2d) in these parasites, are important determinants for germinating root parasitic plants near the roots of host plants. Phtheirospermum japonicum, a facultative hemiparasitic Orobanchaceae plant, can germinate and grow in the presence or absence of the host and can also exhibit root chemotropism to host-derived SLs that are perceived via KAI2d. However, the importance of SLs in P. japonicum germination remains unclear. In this study, we found that germination of P. japonicum was suppressed in the absence of nitrate ions and that germination of P. japonicum was promoted by exogenous strigol, an SL, under such conditions. We propose a model in which P. japonicum may select either independent living or parasitism in response to ambient nitrogen conditions and host presence.

Strigolactones are chemoattractants for host tropism in Orobanchaceae parasitic plants.

Parasitic plants are worldwide threats that damage major agricultural crops. To initiate infection, parasitic plants have developed the ability to locate hosts and grow towards them. This ability, called host tropism, is critical for parasite survival, but its underlying mechanism remains mostly unresolved. To characterise host tropism, we used the model facultative root parasite Phtheirospermum japonicum, a member of the Orobanchaceae. Here, we show that strigolactones (SLs) function as host-derived chemoattractants. Chemotropism to SLs is also found in Striga hermonthica, a parasitic member of the Orobanchaceae, but not in non-parasites. Intriguingly, chemotropism to SLs in P. japonicum is attenuated in ammonium ion-rich conditions, where SLs are perceived, but the resulting asymmetrical accumulation of the auxin transporter PIN2 is diminished. P. japonicum encodes putative receptors that sense exogenous SLs, whereas expression of a dominant-negative form reduces its chemotropic ability. We propose a function for SLs as navigators for parasite roots.

JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression.

Tumor stem cells (TSCs), capable of self-renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c-JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c-JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC.

Impact of three major risk factors on clinical outcomes in patients with nonvalvular atrial fibrillation receiving rivaroxaban: Sub-analysis from the XAPASS study.

Background: To evaluate the impact of three risk factors (age [≥75 years], renal impairment [creatinine clearance <50 ml/min], and low body weight [≤50 kg]) on the risk of any bleeding events, all-cause mortality, and stroke, non-central nervous system (non-CNS) systemic embolism (SE), and myocardial infarction (MI) in patients with nonvalvular atrial fibrillation (NVAF) treated with rivaroxaban in a real-world clinical setting. Methods: The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) is a prospective, single-arm, observational study. Enrolled patients were divided into four subgroups by the number of risk factors. Results: Overall, 9823 patients were included: 4299 with low risk, 2816 with moderate risk, 1574 with high risk, and 1134 with very high risk. The hazard ratios (95% confidence interval) (reference: low risk) for the moderate-, high-, and very-high-risk groups were 1.62 (1.19, 2.21) (p = 0.002), 2.15 (1.47, 3.15) (p < 0.001), and 2.49 (1.60, 3.87) (p <0.001) for major bleeding, and 1.98 (1.47, 2.66), 2.29 (1.59, 3.29), and 2.74 (1.81, 4.16) (p <0.001 for all) for stroke/non-CNS SE/MI, respectively. Conclusions: Age ≥75 years and renal impairment, but not low body weight, were determinants for major bleeding. The accrual of three risk factors was associated with increased risk for major bleeding and stroke/non-CNS SE/MI in patients with NVAF receiving rivaroxaban; there was no increase in the cumulative risk for these with an increasing number of risk factors.

Nickel-catalyzed 1,4-aryl rearrangement of aryl N-benzylimidates via C-O and C-H bond cleavage.

We report herein that nickel-catalyzed reaction of aryl imidates bearing an N-benzyl group results in 1,4-migration of an O-aryl group via the cleavage of C-O and C-H bonds. This protocol allows for the benzylic C-H bond arylation of benzylamine building blocks using phenols as an aryl source to form elaborate diarylmethylamine derivatives.