Synthesis and biological evaluations of oleanolic acid indole derivatives as hyaluronidase inhibitors with enhanced skin permeability

Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC50 = 80.3 vs. 9.97 and 9.57 µg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading to reduced enzyme activity. In addition, OA indole derivatives showed feasible skin permeability in a slightly acidic environment (pH = 6.5) and 6c exerted skin protective effect by reducing cellular reactive oxygen species in human skin keratinocytes. Findings from the current study support that OA indole derivatives are potential cosmeceuticals with anti-hyaluronidase activity

Multiscale 3D genome organization underlies duck fatty liver with no adipose inflammation or serious injury

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Little is known about how gene expression and chromatin structure are regulated in NAFLD due to lack of suitable model. Ducks naturally develop fatty liver similar to serious human non-alcoholic fatty liver (NAFL) without adipose inflammation and liver fibrosis, thus serves as a good model for investigating molecular mechanisms of adipose metabolism and anti-inflammation. Here, we constructed a NAFLD model without adipose inflammation and liver fibrosis in ducks. By performing dynamic pathological and transcriptomic analyses, we identified critical genes involving in regulation of the NF-κB and MHCII signaling, which usually lead to adipose inflammation and liver fibrosis. We further generated dynamic three-dimensional chromatin maps during liver fatty formation and recovery. This showed that ducks enlarged hepatocyte cell nuclei to reduce inter-chromosomal interaction, decompress chromatin structure, and alter strength of intra-TAD and loop interactions during fatty liver formation. These changes partially contributed to the tight control the NF-κB and the MHCII signaling. Our analysis uncovers duck chromatin reorganization might be advantageous to maintain liver regenerative capacity and reduce adipose inflammation. These findings shed light on new strategies for NAFLD control.</p

Akkermansia muciniphila: a potential candidate for ameliorating metabolic diseases

Metabolic diseases are comprehensive disease based on obesity. Numerous cumulative studies have shown a certain correlation between the fluctuating abundance of Akkermansia muciniphila and the occurrence of metabolic diseases. A. muciniphila, a potential probiotic candidate colonized in the human intestinal mucus layer, and its derivatives have various physiological functions, including treating metabolic disorders and maintaining human health. This review systematically explicates the abundance change rules of A. muciniphila in metabolic diseases. It also details the high efficacy and specific molecules mechanism of A. muciniphila and its derivatives in treating obesity, type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease

Plant Microbiome and Mycorrhizal Fungi

In this paper, the research results on the synergy between mycorrhizal fungi and plant microorganisms in China and abroad were summarized. The purpose of this paper was to elaborate the effects of the synergy mechanism between mycorrhizal fungi and plant microorganisms on crop growth and stress resistance, soil physical and chemical properties, and soil microbial diversity and to analyze the contribution of the interaction between mycorrhizal fungi and plant microorganisms in agriculture and forestry, so as to provide theoretical basis for the further preparation of composite microbial agents, the healthy and green improvement of crop yield, and the ecological restoration of forestry stress resistance. The main directions of future research in this field were also analyzed

Abnormal Entropy Modulation of the EEG Signal in Patients With Schizophrenia During the Auditory Paired-Stimulus Paradigm

The complexity change in brain activity in schizophrenia is an interesting topic clinically. Schizophrenia patients exhibit abnormal task-related modulation of complexity, following entropy of electroencephalogram (EEG) analysis. However, complexity modulation in schizophrenia patients during the sensory gating (SG) task, remains unknown. In this study, the classical auditory paired-stimulus paradigm was introduced to investigate SG, and EEG data were recorded from 55 normal controls and 61 schizophrenia patients. Fuzzy entropy (FuzzyEn) was used to explore the complexity of brain activity under the conditions of baseline (BL) and the auditory paired-stimulus paradigm (S1 and S2). Generally, schizophrenia patients showed significantly higher FuzzyEn values in the frontal and occipital regions of interest (ROIs). Relative to the BL condition, the normalized values of FuzzyEn of normal controls were decreased greatly in condition S1 and showed less variance in condition S2. Schizophrenia patients showed a smaller decrease in the normalized values in condition S1. Moreover, schizophrenia patients showed significant diminution in the suppression ratios of FuzzyEn, attributed to the higher FuzzyEn values in condition S1. These results suggested that entropy modulation during the process of sensory information and SG was obvious in normal controls and significantly deficient in schizophrenia patients. Additionally, the FuzzyEn values measured in the frontal ROI were positively correlated with positive scores of Positive and Negative Syndrome Scale (PANSS), indicating that frontal entropy was a potential indicator in evaluating the clinical symptoms. However, negative associations were found between the FuzzyEn values of occipital ROIs and general and total scores of PANSS, likely reflecting the compensation effect in visual processing. Thus, our findings provided a deeper understanding of the deficits in sensory information processing and SG, which contribute to cognitive deficits and symptoms in patients with schizophrenia

A new chromosome-scale duck genome shows a major histocompatibility complex with several expanded multigene families

BACKGROUND: The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A virus (IAV), harbors almost all subtypes of IAVs and resists to many IAVs which cause extreme virulence in chicken and human. However, the response of duck's adaptive immune system to IAV infection is poorly characterized due to lack of a detailed gene map of the major histocompatibility complex (MHC).RESULTS: We herein reported a chromosome-scale Beijing duck assembly by integrating Nanopore, Bionano, and Hi-C data. This new reference genome SKLA1.0 covers 40 chromosomes, improves the contig N50 of the previous duck assembly with highest contiguity (ZJU1.0) of more than a 5.79-fold, surpasses the chicken and zebra finch references in sequence contiguity and contains a complete genomic map of the MHC. Our 3D MHC genomic map demonstrated that gene family arrangement in this region was primordial; however, families such as AnplMHCI, AnplMHCIIβ, AnplDMB, NKRL (NK cell receptor-like genes) and BTN underwent gene expansion events making this area complex. These gene families are distributed in two TADs and genes sharing the same TAD may work in a co-regulated model.CONCLUSIONS: These observations supported the hypothesis that duck's adaptive immunity had been optimized with expanded and diversified key immune genes which might help duck to combat influenza virus. This work provided a high-quality Beijing duck genome for biological research and shed light on new strategies for AIV control.</p

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation