Metabolic Reprogramming: A Byproduct or a Driver of Cardiomyocyte Proliferation?

Defining mechanisms of cardiomyocyte proliferation should guide the understanding of endogenous cardiac regeneration and could lead to novel treatments for diseases such as myocardial infarction. In the neonatal heart, energy metabolic reprogramming (phenotypic alteration of glucose, fatty acid, and amino acid metabolism) parallels cell cycle arrest of cardiomyocytes. The metabolic reprogramming occurring shortly after birth is associated with alterations in blood oxygen levels, metabolic substrate availability, hemodynamic stress, and hormone release. In the adult heart, myocardial infarction causes metabolic reprogramming but these changes cannot stimulate sufficient cardiomyocyte proliferation to replace those lost by the ischemic injury. Some putative pro-proliferative interventions can induce the metabolic reprogramming. Recent data show that altering the metabolic enzymes PKM2 [pyruvate kinase 2], LDHA [lactate dehydrogenase A], PDK4 [pyruvate dehydrogenase kinase 4], SDH [succinate dehydrogenase], CPT1b [carnitine palmitoyl transferase 1b], or HMGCS2 [3-hydroxy-3-methylglutaryl-CoA synthase 2] is sufficient to partially reverse metabolic reprogramming and promotes adult cardiomyocyte proliferation. How metabolic reprogramming regulates cardiomyocyte proliferation is not clearly defined. The possible mechanisms involve biosynthetic pathways from the glycolysis shunts and the epigenetic regulation induced by metabolic intermediates. Metabolic manipulation could represent a new approach to stimulate cardiac regeneration; however, the efficacy of these manipulations requires optimization, and novel molecular targets need to be defined. In this review, we summarize the features, triggers, and molecular regulatory networks responsible for metabolic reprogramming and discuss the current understanding of metabolic reprogramming as a critical determinant of cardiomyocyte proliferation.

Ceria Nanoparticle Systems Alleviate Degenerative Changes in Mouse Postovulatory Aging Oocytes by Reducing Oxidative Stress and Improving Mitochondrial Functions.

Postovulatory aging oocytes usually feature diminished potential for fertilization and poor embryonic development due to enhanced oxidative damage to the subcellular organelles and macromolecules, which stands as a formidable obstacle in assisted reproductive technologies (ART). Here, we developed lipoic acid (LA) and polyethylene glycol (PEG)-modified CeO2 nanoparticles (LA-PEG-CeNPs) with biocompatibility, enzyme-like autocatalytic activity, and free radical scavenging capacity. We further investigated the LA-PEG-CeNPs effect in mouse postovulatory oocytes during in vitro aging. The results showed that LA-PEG-CeNPs dramatically reduced the accumulation of ROS in aging oocytes, improving mitochondrial dysfunction; they also down-regulated the pro-apoptotic activity by rectifying cellular caspase-3, cleaved caspase-3, and Bcl-2 levels. Consistently, this nanoenzyme prominently alleviated the proportion of abnormalities in spindle structure, chromosome alignment, microtubule stability, and filamentous actin (F-actin) distribution in aging oocytes, furthermore decreased oocyte fragmentation, and improved its ability of fertilization and development to blastocyst. Taken together, our finding suggests that LA-PEG-CeNPs can alleviate oxidative stress damage on oocyte quality during postovulatory aging, implying their potential value for clinical practice in assisted reproduction.

Plexin B3 guides axons to cross the midline in vivo.

During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal axons are crossing the midline to form the chiasm. Plexin B3 has been characterized to be related to neurodevelopmental disorders. However, the investigation of its pathological mechanisms is hampered by the lack of appropriate animal model. We provide evidence that Plexin B3 is critical for axon guidance in vivo. Plexin B3 might function as a receptor for Sema3E while Neuropilin1 could be a co-receptor. The intracellular domain of Plexin B3 is required for Semaphorin signaling transduction. Our data suggest that zebrafish could be an ideal animal model for investigating the role and mechanisms of Sema3E and Plexin B3 in vivo.

Nano La(OH)3 modified lotus seedpod biochar: A novel solution for effective phosphorus removal from wastewater.

Effective removal of phosphorus from water is crucial for controlling eutrophication. Meanwhile, the post-disposal of wetland plants is also an urgent problem that needs to be solved. In this study, seedpods of the common wetland plant lotus were used as a new raw material to prepare biochar, which were further modified by loading nano La(OH)3 particles (LBC-La). The adsorption performance of the modified biochar for phosphate was evaluated through batch adsorption and column adsorption experiments. Adsorption performance of lotus seedpod biochar was significantly improved by La(OH)3 modification, with adsorption equilibrium time shortened from 24 to 4 h and a theoretical maximum adsorption capacity increased from 19.43 to 52.23 mg/g. Moreover, LBC-La maintained a removal rate above 99% for phosphate solutions with concentrations below 20 mg/L. The LBC-La exhibited strong anti-interference ability in pH (3-9) and coexisting ion experiments, with the removal ratio remaining above 99%. The characterization analysis indicated that the main mechanism is the formation of monodentate or bidentate lanthanum phosphate complexes through inner sphere complexation. Electrostatic adsorption and ligand exchange are also the mechanisms of LBC-La adsorption of phosphate. In the dynamic adsorption experiment of simulated wastewater treatment plant effluent, the breakthrough point of the adsorption column was 1620 min, reaching exhaustion point at 6480 min, with a theoretical phosphorus saturation adsorption capacity of 6050 mg/kg. The process was well described by the Thomas and Yoon-Nelson models, which indicated that this is a surface adsorption process, without the internal participation of the adsorbent.

Design and motion control of exoskeleton robot for paralyzed lower limb rehabilitation.

Introduction: Patients suffering from limb movement disorders require more complete rehabilitation treatment, and there is a huge demand for rehabilitation exoskeleton robots. Flexible and reliable motion control of exoskeleton robots is very important for patient rehabilitation. Methods: This paper proposes a novel exoskeleton robotic system for lower limb rehabilitation. The designed lower limb rehabilitation exoskeleton robot mechanism is mainly composed of the hip joint mechanism, the knee joint mechanism and the ankle joint mechanism. The forces and motion of the exoskeleton robot were analyzed in detail to determine its design parameters. The robot control system was developed to implement closed-loop position control and trajectory planning control of each joint mechanism. Results: Multiple experiments and tests were carried out to verify robot's performance and practicality. In the robot angular response experiments, the joint mechanism could quickly adjust to different desired angles, including 15°, 30°, 45°, and 60°. In the trajectory tracking experiments, the exoskeleton robot could complete tracking movements of typical actions such as walking, standing up, sitting down, go upstairs and go downstairs, with a maximum tracking error of ±5°. Robotic wearing tests on normal people were performed to verify the assistive effects of the lower limb rehabilitation exoskeleton at different stages. Discussion: The experimental results indicated that the exoskeleton robot has excellent reliability and practicality. The application of this exoskeleton robotic system will help paralyzed patients perform some daily movements and sports.

Constructing "smart" chelators by using an activatable prochelator strategy for the treatment of Wilson's disease.

Wilson's disease (WD) is a genetic disorder that primarily leads to the pathological accumulation of copper (Cu) in the liver, causing an abnormal increase in reactive oxygen species (ROS). The prevailing clinical therapy for WD involves lifelong use of Cu chelation drugs to facilitate Cu excretion in patients. However, most available drugs exert severely side-effects due to their non-specific excretion of Cu, unsuitable for long-term use. In this study, we construct a prochelator that enables precise and controlled delivery of Cu chelator drugs to the liver in WD model, circumventing toxic side effects on other organs and normal tissues. This innovative prochelator rapidly releases the chelator and the fluorescent molecule methylene blue (MB) upon activation by ROS highly expressed in the liver of WD. The released chelator coordinates with Cu, efficiently aiding in Cu removal from the body and effectively inhibiting the pathological progression of WD.

Exposure to ambient oxidant pollution associated with ceramide changes and cardiometabolic responses.

Evidence of impact of ambient oxidant pollution on cardiometabolic responses remains limited. We aimed to examine associations of oxidant pollutants with cardiometabolic responses, and effect modification by ceramides. During 2019-2020, 152 healthy adults were visited 4 times in Beijing, China, and indicators of ceramides, glucose homeostasis, and vascular function were measured. We found significant increases in ceramides of 13.9% (p = 0.020) to 110.1% (p = 0.005) associated with an interquartile increase in oxidant pollutants at prior 1-7 days. Exposure to oxidant pollutants was also related to elevations in insulin and reductions in adiponectin, and elevations in systolic and diastolic blood pressure. Further, stratified analyses revealed larger changes in oxidant pollutant related cardiometabolic responses among participants with higher ceramide levels compared to those with lower levels. Our findings suggested cardiometabolic effects associated with exposure to oxidant pollutants, which may be modified by ceramide levels.

Ambient Anthropogenic Carbons and Pediatric Respiratory Infections: A Case-Crossover Analysis in the Megacity Beijing.

Carbon loading in airway cells has shown to worsen function of antimicrobial peptides, permitting increased survival of pathogens in the respiratory tract; however, data on the impacts of carbon particles on childhood acute respiratory infection (ARI) is limited. We assembled daily health data on outpatient visits for ARI (bronchitis, pneumonia, and total upper respiratory infection [TURI]) in children aged 0-14 years between 2015 and 2019 in Beijing, China. Anthropogenic carbons, including black carbon (BC) and its emission sources, and wood smoke particles (delta carbon, ultra-violet absorbing particulate matter, and brown carbon) were continuously monitored. Using a time-stratified case-crossover approach, conditional logistic regression was performed to derive risk estimates for each outcome. A total of 856,899 children were included, and a wide range of daily carbon particle concentrations was observed, with large variations for BC (0.36-20.44) and delta carbon (0.48-57.66 µg/m3). Exposure to these particles were independently associated with ARI, with nearly linear exposure-response relationships. Interquartile range increases in concentrations of BC and delta carbon over prior 0-8 days, we observed elevation of the odd ratio of bronchitis by 1.201 (95% confidence interval, 1.180, 1.221) and 1.048 (95% CI, 1.039, 1.057), respectively. Stronger association was observed for BC from traffic sources, which increased the odd ratio of bronchitis by 1.298 (95% CI, 1.273, 1.324). Carbon particles were also associated with elevated risks of pneumonia and TURI, and subgroup analyses indicated greater risks among children older than 6 years. Our findings suggested that anthropogenic carbons in metropolitan areas may pose a significant threat to clinical manifestations of respiratory infections in vulnerable populations.

Antifungal activity of compounds from Gordonia sp. WA8-44 isolated from the gut of Periplaneta americana and molecular docking studies.

Invasive fungal infections are on the rise, leading to a continuous demand for antifungal antibiotics. Rare actinomycetes have been shown to contain a variety of interesting compounds worth exploring. In this study, 15 strains of rare actinobacterium Gordonia were isolated from the gut of Periplaneta americana and screened for their anti-fungal activity against four human pathogenic fungi. Strain WA8-44 was found to exhibit significant anti-fungal activity and was selected for bioactive compound production, separation, purification, and characterization. Three anti-fungal compounds, Collismycin A, Actinomycin D, and Actinomycin X2, were isolated from the fermentation broth of Gordonia strain WA8-44. Of these, Collismycin A was isolated and purified from the secondary metabolites of Gordonia for the first time, and its anti-filamentous fungi activity was firstly identified in this study. Molecular docking was carried out to determine their hypothetical binding affinities against nine target proteins of Candida albicans. Chitin Synthase 2 was found to be the most preferred antimicrobial protein target for Collismycin A, while 1,3-Beta-Glucanase was the most preferred anti-fungal protein target for Actinomycin D and Actinomycin X2. ADMET prediction revealed that Collismycin A has favorable oral bioavailability and little toxicity, making it a potential candidate for development as an orally active medication.

Pro-inflammation and pro-atherosclerotic responses to short-term air pollution exposure associated with alterations in sphingolipid ceramides and neutrophil extracellular traps.

Air pollution has been associated with the development of atherosclerosis; however, the pathophysiological mechanisms underlying pro-atherosclerotic effects of air pollution exposure remain unclear. We conducted a prospective panel study in Beijing and recruited 152 participants with four monthly visits from September 2019 to January 2020. Linear mixed-effect models were applied to estimate the associations linking short-term air pollution exposure to biomarkers relevant to ceramide metabolism, pro-inflammation (neutrophil extracellular traps formation and systemic inflammation) and pro-atherosclerotic responses (endothelial stimulation, plaque instability, coagulation activation, and elevated blood pressure). We further explored whether ceramides and inflammatory indicators could mediate the alterations in the profiles of pro-atherosclerotic responses. We found that significant increases in levels of circulating ceramides of 9.7% (95% CIs: 0.7, 19.5) to 96.9% (95% CIs: 23.1, 214.9) were associated with interquartile range increases in moving averages of ambient air pollutant metrics, including fine particulate matter (PM2.5), black carbon, particles in size fractions of 100-560 nm, nitrogen dioxide, carbon monoxide and sulfur dioxide at prior up to 7 days. Higher air pollution levels were also associated with activated neutrophils (increases in citrullinated histone H3, neutrophil elastase, double-stranded DNA, and myeloperoxidase) and exacerbation of pro-atherosclerotic responses (e.g., increases in vascular endothelial growth factor, lipoprotein-associated phospholipase A2, matrix metalloproteinase-8, P-selectin, and blood pressure). Mediation analyses further showed that dysregulated ceramide metabolism and potentiated inflammation could mediate PM2.5-associated pro-atherosclerotic responses. Our findings extend the understanding on potential mechanisms of air pollution-associated atherosclerosis, and suggest the significance of reducing air pollution as priority in urban environments.

The Transcription Factor RUNX1 Aggravates Hypoxia-Induced Human Retinal Microvascular Endothelial Cell Dysfunction by Negatively Regulating TFF1 Promoter.

OBJECTIVE: As a retinal vaso-proliferative disorder, retinopathy of prematurity (ROP) is characterized by neovascularization and angiogenesis, causing irreversible retinal damage and even visual loss among premature infants. Trefoil factor 1 (TFF1) has been identified as a key regulator in mediating retinal angiogenesis in diabetic retinopathy. However, whether TFF1 can mediate the angiogenic process in ROP remains unknown. Here, we aimed to investigate the regulatory function of TFF1 and its underlying mechanisms in hypoxia-exposed human retinal vascular endothelial cells (HRVECs) in vitro. METHODS: HRVECs were exposed to hypoxia condition to establish the in vitro ROP models. HRVEC viability was validated using CCK-8 assay. The migratory and angiogenic capacities of HRVECs were assessed by wound healing and tube formation assays, respectively. RT-qPCR was performed to detect gene levels. Western blotting was used to measure the protein levels of TFF1 and Runt-related transcription factor 1 (RUNX1). The binding relationship between RUNX1 to TFF1 promoter was confirmed by chromatin immunoprecipitation and luciferase reporter assays. RESULTS: Hypoxia downregulated TFF1 expression and elevated RUNX1 expression in HRVECs. Moreover, hypoxic condition increased HRVEC viability and accelerated HRVEC migration and angiogenesis, which were antagonized by TFF1 elevation or RUNX1 knockdown. RUNX1 as a transcription factor bound to TFF1 promoter and transcriptionally repressed TFF1 expression in HRVECs. In rescue assays, overexpression of TFF1 counteracted the promotive effect of RUNX1 overexpression on the viability, migratory and angiogenic abilities of HRVECs under hypoxia. CONCLUSIONS: RUNX1 transcriptionally suppresses TFF1 expression to aggravate hypoxia-induced HRVEC dysfunction.

circPTK2 promotes proliferation, migration and invasion of trophoblast cells through the miR-619/WNT7B pathway in preeclampsia.

It has been shown that the circular RNA (circRNA) circPTK2 modulates many types of diseases. However, the possible functions as well as the molecular mechanisms of circPTK2 in preeclampsia (PE) and their effects on trophoblast are unknown. Herein, we obtained the placental tissues from 20 pregnant women with PE who delivered in the Yueyang Maternal Child Medicine Health Hospital between 2019 and 2021 to serve as the PE group, and a normal group was composed of 20 healthy pregnant women with normal prenatal examinations. The circPTK2 level was significantly reduced in tissues from the PE group. The expression and localization of circPTK2 were verified using RT-qPCR. CircPTK2 silencing inhibited HTR-8/SVneo growth and migration in vitro. To investigate the underlying mechanism of circPTK2 in PE progression, dual-luciferase reporter assays were conducted. It was found that circPTK2 and WNT7B could bind directly to miR-619, and that circPTK2 affected WNT7B expression by sponging miR-619. To conclude, this study identified the functions and mechanisms of the circPTK2/miR-619/WNT7B axis in PE progression. In this way, circPTK2 has the potential to be used both in diagnostic and therapeutic settings for PE.

Placental Barrier on Cadmium Transfer from Mother to Fetus in Related to Pregnancy Complications.

Purpose: As two of the most severe and common medical disorders during pregnancy, gestational diabetes mellitus (GDM) and hypertensive disorder complicating pregnancy (HDCP) cause adverse effects on placental barrier function and thus may lead to a high risk of intrauterine exposure to toxic metals from mother to fetus. This study investigates the impact of the placental barrier on the transfer of cadmium (Cd) from mother to fetus and the relationship between pregnancy complications. Methods: A total of 107 pairs of samples were collected in Kunming, China; 29 were from healthy pregnant women, and 78 were from patients with pregnancy complications. Cd was measured in each mother's placenta and maternal and umbilical cord blood. The expressions of MT and Cd-MT complex in blood and placental tissue samples were determined by enzyme-linked immunosorbent assay (ELISA). Results: The cesarean section rate in the whole pathological group (60.7%) was higher than that in the normal group (20.7%), and the ratio of the effective barrier (ratio of maternal blood to umbilical cord blood>1) in the pathological group (74%) was lower than that in the normal group (79%). In addition, the proportion of practical placental barriers in women aged 20-25 years was 83.3%, 76.3% in women aged 26-30 years, 74.3% in women aged 31-35 years, 70% in women aged 36-40 years, and 71% in women aged 40-45 years. The Cd content in the placenta of the three pathological groups was significantly higher than that in maternal and umbilical cord blood (P<0.05), and the distribution of Cd was the same as that in the normal group. However, there was no significant difference between maternal and umbilical cord blood Cd concentrations in the pathological group. The Cd concentration in the normal group's maternal blood was significantly higher than that in cord blood (P<0.05). In addition, the expression levels of both metallothionein (MT) and Cd-MT complex in placenta is much higher than in maternal and umbilical blood, and which in normal group are significantly higher than those in pathological group. Conclusion: Both mothers and fetuses are at increased health risk for pregnancy disorders when maternal age, BMI, or body weight increases. Increased maternal age increases the likelihood of Cd transfer from the mother to the fetus. Pregnancy complications may induce lower expression of MT, thus reducing the Cd-MT complex in the placenta, weakening the placental barrier, and increasing the risk of Cd transfer and exposure to the fetus.

[Structure and Function of Soil Fungal Community in Rotation Fallow Farmland in Alluvial Plain of Lower Yellow River].

This study was conducted to clarify the structure and function of the fungal community and the microecology change characteristics of farmland soil fertility response to different fallow rotation patterns. It aimed to provide a reference for promoting farmland ecological restoration and farmland quality improvement in the alluvial plain of the lower Yellow River. Farmland soil subject to a long-term rotation fallow experiment since 2018 was studied using Illumina MiSeq high-throughput sequencing technology, and the 'FUNGuild' fungal function prediction tool was used to analyze differences in soil fungal community structure and function under the following four rotation fallow regimes: long fallow (LF), winter wheat and summer fallow (WF), winter fallow and summer maize (FM), and annual rotation of winter wheat and summer maize (WM). The results showed that LF (fallow lasting two years) increased the richness and diversity of fungal communities in the topsoil (0-20 cm layer), whereas WF increased the richness and diversity of fungi in the deep soil (20-40 cm layer) after winter wheat harvest. A total of 2262 OTU were obtained from all soil samples, which were divided into 14 phyla, 34 classes, 75 orders, 169 families, 309 genera, and 523 species. OTU shared by the two soil layers included 420 types (0-20 cm layer) and 253 types (20-40 cm layer), respectively. The fungal community structure of the four rotation fallow soils was similar at the phylum level, mainly including Ascomycota, Basidiomycota, and Mortierellomycota. The total abundances of the three dominant bacteria were 91.69%-96.91% (0-20 cm layer) and 91.67%-94.86% (20-40 cm layer), respectively. Principal component analysis showed that the first principal component (PC1) and the second principal component (PC2) could explain the difference in community structure by 45.56% (0-20 cm layer) and 46.20% (20-40 cm layer). Additionally, the LDA results of LEfSe (threshold was 4.0) showed that there were 64 fungal evolutionary branches in LF, FM, WF, and WM with statistically significant differences (P<0.05). According to RDA analysis, total organic carbon (TOC), total phosphorus (TP), available nitrogen (AN), and soil water content (SWC) were the main environmental factors that significantly affected fungal community in the 0-40 cm soil layer (P<0.05). The functional prediction with FUNGuild showed that the main nutrient types among different treatments in different soil layers were saprotrophic, saprotrophic-symbiotrophic, pathotrophic-saprotrophic-symbiotrophic, and pathotrophic. In LF, the nutrient type of topsoil was mainly pathotrophic-saprotrophic-symbiotrophic, whereas in deep soil, the relative abundance of pathotrophic fungi was the highest. Additionally, in the treatments with planted wheat or corn (FM, WF, and WM), saprotrophic was the main type in both soil layers. Therefore, different fallow patterns were linked to variation in the structure, diversity, and nutrient types of soil fungal communities. Based on these results, seasonal fallow practices could regulate the farmland soil micro-ecological environment of intensive planting and promote the health and harmony of farmland soil ecosystems.

N-Fluorobenzamide-Directed Formal [4+2] Cycloaddition Reaction with Maleic Anhydride: Access to Fluorescent Aminonaphthalic Anhydrides.

We have developed a formal [4+2] cycloaddition reaction of N-fluorobenzamides and maleic anhydride in the presence of CuI and LiOH, and a series of fluorescent 1-amino-2,3-naphthalic anhydrides were produced in good yields. This reaction proceeded via a multistep process involving nitrogen-centered radical generation, 1,5-hydrogen atom transfer, and benzylic radical addition to the amide carbonyl oxygen to generate an N-(tert-butyl) isobenzofuran-1(3H)-imine intermediate, which isomerized to an N-(tert-butyl) isobenzofuran-1-amine via deprotonation and protonation with the aid of LiOH; finally, the amine underwent a [4+2] cycloaddition reaction with maleic anhydride to give the 1-amino-2,3-naphthalic anhydride product upon dehydrating aromatization. Notably, the corresponding naphthalic anhydride products could be transformed into a diverse array of naphthalimides. Both the naphthalic anhydrides and the naphthalimides exhibited similar fluorescent features.

Chaetonigrisins A-L, a group of 3-Indole-1,2-Propanediol derived alkaloids from Chaetomium nigricolor YT-2.

Thirteen new alkaloids (1-13) as well as ten known compounds were isolated from the solid-state fermented rice medium of the fungus Chaetomium nigricolor YT-2. Their structures were elucidated on the basis of spectroscopic data, quantum calculations, and single crystal X-ray crystallographic analysis. Chaetonigrisin A (1) represents an unprecedented carbon skeleton featuring a polycyclic 1H-pyrano[3,2:3,4-]​furo[2,​3-​b]​indole. Chaetonigrisin B (2) displays a unique carbon skeleton with a 1,3­dioxolane bridged-ring. Chaetonigrisin C (3) is a spirocyclic indole alkaloid. Chaetonigrisins D-H (4-8) are a group of asymmetric dimers, formed with two 3-indol-3yl-1,2-propanediol (4-6) or with a 3-indol-3yl-1,2-propanediol and a 3-indol-2yl-1,2-propanediol (7-8) by a pyran ring. Chaetonigrisins I-L (9-12) each contains a 3-indol-3yl-1,2-propanediol or 3-indol-2yl-1,2-propanediol substructure. Chaetonigrisin M (13) is a new quinoline alkaloid. The neuroprotective activity assay showed that at the concentration of 40 µM, compounds (4-7, 11, and 12) improved the cell viability of PC12 cells were 49.26 %, 74.69 %, 74.76 %, 86.63 %, 66.89 %, and 69.92 %, respectively induced by 6-OHDA, compound 7 showed significant neuroprotective activity via upregulation of SOD1 mRNA and Bcl-2 mRNA.

Divergent Copper-salt-controlled Reactions of Donor-Acceptor Cyclopropanes and N-Fluorobenzene Sulfonimide: Access to the 1,3-Haloamines and Aminoindanes.

We herein report a method for divergent copper salt controlled reactions of donor-acceptor cyclopropanes and N-fluorobenzene sulfonimide (NFSI). Specifically, in the presence of CuX2 (X=Cl, Br), the cyclopropanes underwent formal umpolung 1,3-aminohalogenation bifunctionalization via a free radical mediated ring-opening process to afford 1,3-aminochlorination and 1,3-aminobromination products in moderate to good yields. In addition, by using CuI as a catalyst, we synthesized various aminoindane derivatives via 1,3-aminoarylation cyclization of D-A cyclopropanes, the reactions involved a free radical mediated ring-opening and subsequent ring expansion via C-H bond activation.

An excipient-free "sugar-coated bullet" for the targeted treatment of orthotopic hepatocellular carcinoma.

Several components of traditional nanoformulations that result in structural heterogeneity, poor reproducibility, excipient-trigged biotoxicity, and low retention of antitumor drugs in neoplastic foci are important barriers limiting clinical translation. We report an excipient-free nanoformulation prepared by a reactive oxygen species (ROS)-responsive amphiphilic prodrug (Gal-MB-DOX) for the targeted treatment of orthotopic hepatocellular carcinoma (HCC). Gal-MB-DOX can form monocomponent nanoparticles with a galactose-rich surface similar to a "sugar-coated bullet" through self-assembly in aqueous solution. This nanoformulation can be decomposed quickly by ROS and release free hydrophobic drugs that further precipitate into larger particles, potentially promoting the retention of drugs in tumor cells. These sugar-coated bullets selectively target tumor cells through passive and active targeting, resulting in high in vivo therapeutic efficacy in an orthotopic HCC mouse model. This monocomponent nanomedicine system provides a simple but effective strategy for the treatment of tumors.

The Analysis of Transcriptomes and Microorganisms Reveals Differences between the Intestinal Segments of Guinea Pigs.

The intestine is a tubular organ with multiple functions such as digestion absorption and immunity, but the functions of each intestinal segments are different. Intestinal regionalization is necessary for normal physiological function, but it also means the research results obtained at specific sites may not be applicable to other intestinal segments. In order to comprehensively describe the functional changes in the intestine, different intestinal segments and their contents (duodenum, jejunum, ileum, cecum, colon, and rectum) of guinea pigs were collected for RNA seq and 16S rRNA seq, respectively. The results showed differential genes of each intestinal segment mainly involve mucosa, digestion, absorption, and immunity. The gene sets related to fat, bill salts, vitamins, aggregates, amino acids, and water absorption were highly expressed in the small intestine, and the gene sets related to metal ions, nucleotides, and SCFAs were highly expressed in the large intestine. In terms of immunity, the CD8+ T, Th1, eosinophils, pDCs, and natural killer (NK) T cells in the small intestine showed higher scores than those in the large intestine, while the pattern-recognition receptor signaling pathway-related genes are highly expressed in the large intestine. In terms of microbial composition, Proteobacteria and Actinobacteria are abundant in the small intestine, while Firmicutes and Spirochaete are abundant in large intestine. The correlation analysis showed a high correlation between intestinal microorganisms and gene modules related to digestion and absorption. In addition, cross-species analysis showed the SCFA metabolism gene expression trends in human and rodent intestine were different. In conclusion, we analyzed the changes in substance transport, immune and microbial composition between different intestinal segments of guinea pigs, and explored the relationship between intestinal transcriptome and microorganisms, our research will provides a reference for subsequent intestinal-related research.