Synthesis of Imidazo[1,2-a]pyridine-Fused 1,3-Benzodiazepine Derivatives with Anticancer Activity via a One-Pot Cascade GBB-3CR/Pd(II)-Catalyzed Azide-Isocyanide Coupling/Cyclization Process.

A new one-pot synthesis of imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives via a sequential GBB-3CR/Pd(II)-catalyzed azide-isocyanide coupling/cyclization process was developed. The Groebke-Blackburn-Bienaymé three-component reactions (GBB-3CR) of 2-aminopyridine, 2-azidobenzaldehydes, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid gave azide intermediates without separation. The reaction was followed by using another molecule of isocyanides to produce imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives in good yields by the Pd(II)-catalyzed azide-isocyanide coupling/cyclization reaction. The synthetic approach produces novel nitrogen-fused polycyclic heterocycles under mild reaction conditions. The preliminary biological evaluation demonstrated that compound 6a inhibited glioma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Mutation of Protoporphyrinogen IX Oxidase Gene Causes Spotted and Rolled Leaf and Its Overexpression Generates Herbicide Resistance in Rice.

Protoporphyrinogen IX (Protogen IX) oxidase (PPO) catalyzes the oxidation of Protogen IX to Proto IX. PPO is also the target site for diphenyl ether-type herbicides. In plants, there are two PPO encoding genes, PPO1 and PPO2. To date, no PPO gene or mutant has been characterized in monocotyledonous plants. In this study, we isolated a spotted and rolled leaf (sprl1) mutant in rice (Oryza sativa). The spotted leaf phenotype was sensitive to high light intensity and low temperature, but the rolled leaf phenotype was insensitive. We confirmed that the sprl1 phenotypes were caused by a single nucleotide substitution in the OsPPO1 (LOC_Os01g18320) gene. This gene is constitutively expressed, and its encoded product is localized to the chloroplast. The sprl1 mutant accumulated excess Proto(gen) IX and reactive oxygen species (ROS), resulting in necrotic lesions. The expressions of 26 genes associated with tetrapyrrole biosynthesis, photosynthesis, ROS accumulation, and rolled leaf were significantly altered in sprl1, demonstrating that these expression changes were coincident with the mutant phenotypes. Importantly, OsPPO1-overexpression transgenic plants were resistant to the herbicides oxyfluorfen and acifluorfen under field conditions, while having no distinct influence on plant growth and grain yield. These finding indicate that the OsPPO1 gene has the potential to engineer herbicide resistance in rice.

Associations between healthy lifestyle behavioral patterns and mental health problems: A latent class analysis of 161,744 Chinese young adults.

BACKGROUND: Youth mental health problems are a public health priority. Multiple healthy lifestyle behaviors may cluster into healthy lifestyle behavioral patterns (HLBPs) that increase mental health risks in adolescents and older adults, but little is known regarding young adults. This study aimed to explore the associations between cluster HLBPs and mental health problems in young adults. METHODS: We selected 161,744 young adults aged 20-39 as participants from the database of a Chinese general hospital health management center for the years 2015-2020. The latent class analysis was used to identify HLBPs. RESULTS: A total of 15.0 % of young adults have at least one mental health problem. Five clusters of HLBPs were identified, characterized as low-risk class (1.6 %), moderate-risk class 1 (12.0 %), moderate-risk class 2 (2.1 %), moderate-risk class 3 (56.8 %), and high-risk class (27.4 %). The odds ratios (ORs) for young adults with two mental health problems increased with the risk grade of HLBPs, while the ORs for young adults with one or three mental health problems ranged from high to low according to the risk grade of HLBPs: high-risk class, moderate-risk class 2, moderate-risk class 3, moderate-risk class 1. LIMITATIONS: Cross-sectional design and no causal conclusions could be drawn. CONCLUSION: Young adults demonstrated a cluster phenomenon of healthy lifestyle behaviors and significant associations between HLBPs and mental health problems. Young adults with a higher risk grade for HLBPs were more likely to have mental health problems. Different HLBPs should be taken into account when implementing mental health interventions.

The immunosuppressant fingolimod ameliorates experimental autoimmune myasthenia gravis by regulating T-cell balance and cytokine secretion.

Myasthenia gravis is an autoimmune disease that affects skeletal muscle strength by impeding communication within the neuromuscular junction (NMJ). Research has shown that sphingosine-1-phosphate (S1P)/S1P receptor signaling may be involved in the process of neuromuscular diseases. Fingolimod is structurally similar to S1P, whose immunosuppressive effect has been recognized in many immune diseases. However, the mechanism underlying fingolimod's action on experimental autoimmune myasthenia gravis is still far from clear. The aim of this study was to investigate the efficacy and possible mechanism of fingolimod on experimental autoimmune myasthenia gravis. Our results showed that pretreatment with fingolimod improved experimental autoimmune myasthenia gravis symptoms in a dose-dependent manner, including decreased anti-acetylcholine receptor-2α autoantibody titer, reduced compound muscle action potential decrement, and increased acetylcholine receptor content. Further investigation indicated that fingolimod inhibited lymphocyte proliferation responses and also regulated the balance of Th1/Th2 cells and Treg/Th17 cells. Moreover, fingolimod suppressed the secretion of pro-inflammatory or inflammatory cytokines IL-17A, IL-6, and INF-γ, but did not noticeably alter the secretion of immunosuppressive cytokines TGF-ß1 and IL-4. In conclusion, our results suggest that fingolimod has a preventive effect on experimental autoimmune myasthenia gravis by interfering with lymphocyte function.

Changes in Expression of Follicular Glucose Transporters May Be Involved in Ovarian Function Impairment during Diabetic Hyperglycemia.

Diabetes-induced hyperglycemia has a direct damaging effect on ovarian function. Despite its deadly impact on ovaries, the mechanism of this condition has not been fully elucidated. Glucose transporters are involved in glucose uptake and utilization. Many transporters have been detected in the ovaries, but their roles in diabetes-induced ovarian impairment are still unclear. In this study, the goal is to analyze glucose transporter expression in the ovarian follicles of type 1 diabetes mellitus patients and determine their roles within ovarian function impairment. The ovarian function of a mouse model of type 1 diabetes mellitus was evaluated by observing its estrus cycle, follicular development, and ovulation. Subtypes of the glucose transporter (GLUT2, GLUT3, GLUT4, SGLT1, and SGLT2), adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK (Thr172) were found to be simultaneously present in follicle cells. Compared with nondiabetic control mice, the diabetic mice showed a dysregulated estrus cycle and a significantly higher number of abnormal ova. Furthermore, the expression of multiple glucose transporters was lower than that of phosphorylated AMPK. Phosphorylated AMPK possessed more follicular granulosa cells and oocytes of diabetic mice than in those of the control mice. These results suggest that diabetes-induced hyperglycemia reduces the capability of ovarian follicle cells by downregulating glucose transporter expression, causing decreased glucose uptake and energy deprivation. This impact can potentially impair egg maturation and ovulation.