Transcriptome analysis of Gossypium hirsutum cultivar Zhongzhimian No.2 uncovers the gene regulatory networks involved in defense against Verticillium dahliae.

BACKGROUND: Cotton is globally important crop. Verticillium wilt (VW), caused by Verticillium dahliae, is the most destructive disease in cotton, reducing yield and fiber quality by over 50% of cotton acreage. Breeding resistant cotton cultivars has proven to be an efficient strategy for improving the resistance of cotton to V. dahliae. However, the lack of understanding of the genetic basis of VW resistance may hinder the progress in deploying elite cultivars with proven resistance. RESULTS: We planted the VW-resistant Gossypium hirsutum cultivar Zhongzhimian No.2 (ZZM2) in an artificial greenhouse and disease nursery. ZZM2 cotton was subsequently subjected to transcriptome sequencing after Vd991 inoculation (6, 12, 24, 48, and 72 h post-inoculation). Several differentially expressed genes (DEGs) were identified in response to V. dahliae infection, mainly involved in resistance processes, such as flavonoid and terpenoid quinone biosynthesis, plant hormone signaling, MAPK signaling, phenylpropanoid biosynthesis, and pyruvate metabolism. Compared to the susceptible cultivar Junmian No.1 (J1), oxidoreductase activity and reactive oxygen species (ROS) production were significantly increased in ZZM2. Furthermore, gene silencing of cytochrome c oxidase subunit 1 (COX1), which is involved in the oxidation-reduction process in ZZM2, compromised its resistance to V. dahliae, suggesting that COX1 contributes to VW resistance in ZZM2. CONCLUSIONS: Our data demonstrate that the G. hirsutum cultivar ZZM2 responds to V. dahliae inoculation through resistance-related processes, especially the oxidation-reduction process. This enhances our understanding of the mechanisms regulating the ZZM2 defense against VW.

Design, synthesis and triglyceride-lowering activity of tricyclic matrine derivatives for the intervention of non-alcoholic fatty liver disease.

Thirty new tricyclicmatrinic derivatives were successively synthesized and evaluated for their inhibitory activity on the accumulation of triglycerides (TG) in AML12 cells, using 12 N-m-trifluoromethylbenzenesulfonyl matrine (1) as the hit compound. Among the analogues, compound 7n possessing 11-trimethylbutylamine quaternary exerted the highest in vitro TG-lowering potency, as well as a good safety profile. 7n significantly attenuated the hepatic injury and steatosis, and ameliorated dyslipidemia and dysglycemia in the mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Primary mechanism study revealed that upregulation of peroxisome proliferator-activated receptors α (PPARα)-carnitine palmitoyltransferase 1A (CPT1A) pathway mediated the efficacy of 7n. Our study provides powerful information for developing this kind of compound into a new class of anti-NAFLD candidates, and compound 7n is worthy of further investigation as an ideal lead compound.

Gut microbiota-induced CXCL1 elevation triggers early neuroinflammation in the substantia nigra of Parkinsonian mice.

Gut microbiota disturbance and systemic inflammation have been implicated in the degeneration of dopaminergic neurons in Parkinson's disease (PD). How the alteration of gut microbiota results in neuropathological events in PD remains elusive. In this study, we explored whether and how environmental insults caused early neuropathological events in the substantia nigra (SN) of a PD mouse model. Aged (12-month-old) mice were orally administered rotenone (6.25 mg·kg-1·d-1) 5 days per week for 2 months. We demonstrated that oral administration of rotenone to ageing mice was sufficient to establish a PD mouse model and that microglial activation and iron deposition selectively appeared in the SN of the mice prior to loss of motor coordination and dopaminergic neurons, and these events could be fully blocked by microglial elimination with a PLX5622-formulated diet. 16 S rDNA sequencing analysis showed that the gut microbiota in rotenone-treated mice was altered, and mice receiving faecal microbial transplantation (FMT) from ageing mice treated with rotenone for 2 months exhibited the same pathology in the SN. We demonstrated that C-X-C motif chemokine ligand-1 (CXCL1) was an essential molecule, as intravenous injection of CXCL1 mimicked almost all the pathology in serum and SN induced by oral rotenone and FMT. Using metabolomics and transcriptomics analyses, we identified the PPAR pathway as a key pathway involved in rotenone-induced neuronal damage. Inhibition of the PPARγ pathway was consistent in the above models, whereas its activation by linoleic acid (60 mg·kg-1·d-1, i.g. for 1 week) could block these pathological events in mice intravenously injected with CXCL1. Altogether, these results reveal that the altered gut microbiota resulted in neuroinflammation and iron deposition occurring early in the SN of ageing mice with oral administration of rotenone, much earlier than motor symptoms and dopaminergic neuron loss. We found that CXCL1 plays a crucial role in this process, possibly via PPARγ signalling inhibition. This study may pave the way for understanding the "brain-gut-microbiota" molecular regulatory networks in PD pathogenesis. The aged C57BL/6 male mice with rotenone intragastric administration showed altered gut microbiota, which caused systemic inflammation, PPARγ signalling inhibition and neuroinflammation, brain iron deposition and ferroptosis, and eventually dopaminergic neurodegeneration in PD.

Cell senescence induced by toxic interaction between α-synuclein and iron precedes nigral dopaminergic neuron loss in a mouse model of Parkinson's disease.

Cell senescence has been implicated in the pathology of Parkinson's disease (PD). Both abnormal α-synuclein aggregation and iron deposition are suggested to be the triggers, facilitators, and aggravators during the development of PD. In this study, we investigated the involvement of α-synuclein and iron in the process of cell senescence in a mouse model of PD. In order to overexpress α-syn-A53T in the substantia nigra pars compacta (SNpc), human α-syn-A53T was microinjected into both sides of the SNpc in mice. We found that overexpression of α-syn-A53T for one week induced significant pro-inflammatory senescence-associated secretory phenotype (SASP), increased cell senescence-related proteins (ß-gal, p16, p21, H2A.X and γ-H2A.X), mitochondrial dysfunction accompanied by dysregulation of iron-related proteins (L-ferritin, H-ferritin, DMT1, IRP1 and IRP2) in the SNpc. In contrast, significant loss of nigral dopaminergic neurons and motor dysfunction were only observed after overexpression of α-syn-A53T for 4 weeks. In PC12 cells stably overexpressing α-syn-A53T, iron overload (ferric ammonium citrate, FAC, 100 µM) not only increased the level of reactive oxygen species (ROS), p16 and p21, but also exacerbated the processes of oxidative stress and cell senescence signalling induced by α-syn-A53T overexpression. Interestingly, reducing the iron level with deferoxamine (DFO) or knockdown of transferrin receptor 1 (TfR1) significantly improved both the phenotypes and dysregulated proteins of cell senescence induced by α-syn-A53T overexpression. All these evidence highlights the toxic interaction between iron and α-synuclein inducing cell senescence, which precedes nigral dopaminergic neuronal loss in PD. Further investigation on cell senescence may yield new therapeutic agents for the prevention or treatment of PD.

Genome-wide identification and analysis of a cotton secretome reveals its role in resistance against Verticillium dahliae.

BACKGROUND: The extracellular space between the cell wall and plasma membrane is a battlefield in plant-pathogen interactions. Within this space, the pathogen employs its secretome to attack the host in a variety of ways, including immunity manipulation. However, the role of the plant secretome is rarely studied for its role in disease resistance. RESULTS: Here, we examined the secretome of Verticillium wilt-resistant Gossypium hirsutum cultivar Zhongzhimian No.2 (ZZM2, encoding 95,327 predicted coding sequences) to determine its role in disease resistance against the wilt causal agent, Verticillium dahliae. Bioinformatics-driven analyses showed that the ZZM2 genome encodes 2085 secreted proteins and that these display disequilibrium in their distribution among the chromosomes. The cotton secretome displayed differences in the abundance of certain amino acid residues as compared to the remaining encoded proteins due to the localization of these putative proteins in the extracellular space. The secretome analysis revealed conservation for an allotetraploid genome, which nevertheless exhibited variation among orthologs and comparable unique genes between the two sub-genomes. Secretome annotation strongly suggested its involvement in extracellular stress responses (hydrolase activity, oxidoreductase activity, and extracellular region, etc.), thus contributing to resistance against the V. dahliae infection. Furthermore, the defense response genes (immunity marker NbHIN1, salicylic acid marker NbPR1, and jasmonic acid marker NbLOX4) were activated to varying degrees when Nicotina benthamiana leaves were agro-infiltrated with 28 randomly selected members, suggesting that the secretome plays an important role in the immunity response. Finally, gene silencing assays of 11 members from 13 selected candidates in ZZM2 displayed higher susceptibility to V. dahliae, suggesting that the secretome members confer the Verticillium wilt resistance in cotton. CONCLUSIONS: Our data demonstrate that the cotton secretome plays an important role in Verticillium wilt resistance, facilitating the development of the resistance gene markers and increasing the understanding of the mechanisms regulating disease resistance.

Arginine Regulates Skeletal Muscle Fiber Type Formation via mTOR Signaling Pathway.

The composition of skeletal muscle fiber types affects the quality of livestock meat and human athletic performance and health. L-arginine (Arg), a semi-essential amino acid, has been observed to promote the formation of slow-twitch muscle fibers in animal models. However, the precise molecular mechanisms are still unclear. This study investigates the role of Arg in skeletal muscle fiber composition and mitochondrial function through the mTOR signaling pathway. In vivo, 4-week C56BL/6J male mice were divided into three treatment groups and fed a basal diet supplemented with different concentrations of Arg in their drinking water. The trial lasted 7 weeks. The results show that Arg supplementation significantly improved endurance exercise performance, along with increased SDH enzyme activity and upregulated expression of the MyHC I, MyHC IIA, PGC-1α, and NRF1 genes in the gastrocnemius (GAS) and quadriceps (QUA) muscles compared to the control group. In addition, Arg activated the mTOR signaling pathway in the skeletal muscle of mice. In vitro experiments using cultured C2C12 myotubes demonstrated that Arg elevated the expression of slow-fiber genes (MyHC I and Tnnt1) as well as mitochondrial genes (PGC-1α, TFAM, MEF2C, and NRF1), whereas the effects of Arg were inhibited by the mTOR inhibitor rapamycin. In conclusion, these findings suggest that Arg modulates skeletal muscle fiber type towards slow-twitch fibers and enhances mitochondrial functions by upregulating gene expression through the mTOR signaling pathway.

[Applicability of H2FPEF and HFA-PEFF Scores in Chinese Patients Suffering From Heart Failure With Preserved Ejection Fraction and Heart Failure With Preserved Ejection Fraction Complicated With Atrial Fibrillation].

Objective To analyze the diagnostic values of H2FPEF and HFA-PEFF scores for heart failure with preserved ejection fraction (HFpEF) and HFpEF complicated with atrial fibrillation (HFpEF-AF) in Chinese patients and explore the related factors. Methods A cross-sectional study was conducted.A total of 835 consecutive HFpEF patients treated in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from 2009 to 2020 were selected and assigned to a HFpEF-AF group (n=267) and a HFpEF group (n=568) according to the presence of AF or not.HFA-PEFF and H2FPEF scores were used for retrospective diagnosis and the diagnostic consistency of the two scores was assessed.One hundred and thirty-six healthy volunteers with age and sex matching the patients during the same period were selected as healthy controls.The receiver operating characteristic (ROC) curves were established for H2FPEF and HFA-PEFF scores in diagnosing HFpEF-AF and HFpEF,on the basis of which the diagnostic performance of the two scores was evaluated. Results There was no difference in the HFA-PEFF score between the two groups (P=0.070).However,the HFpEF-AF group had higher mean H2FPEF score and higher proportion of patients with the score no less than 6 than the HFpEF group (P<0.001).According to the ROC curves,HFA-PEFF and H2FPEF scores demonstrated high performance in diagnosing all HFpEF patients,with the area under the curve (AUC) of 0.892 and 0.922 and the optimal cut-offs of 4 and 4,respectively.The HFA-PEFF score showed similar performance in diagnosing HFpEF and HFpEF-AF,with the AUC of 0.899 and 0.911,respectively.The H2FPEF score had higher performance in diagnosing HFpEF-AF (AUC of approximately 1.000) and low performance in diagnosing HFpEF (AUC of 0.885). Conclusions The HFA-PEFF score is applicable in the diagnosis of both HFpEF and HFpEF-AF.The H2FPEF score may underestimate HFpEF in Chinese patients,and its applicability in the Chinese patients with HFpEF alone remains to be investigated.

Genome Resource for the Verticillium Wilt Resistant Gossypium hirsutum Cultivar Zhongzhimian No. 2.

Verticillium wilt, caused by the fungal pathogen Verticillium dahliae, is the major cause of disease-related yield losses in cotton (Gossypium hirsutum). Despite these losses, the major cultivars of G. hirsutum remain highly susceptible to Verticillium wilt. The lack of understanding on the genetic basis for Verticillium wilt resistance may further hinder progress in deploying elite cultivars with proven resistance, such as the wilt resistant G. hirsutum cultivar Zhongzhimian No. 2. To help remedy this knowledge gap, we sequenced the whole genome of Zhongzhimian No. 2 and assembled it from a combination of PacBio long reads, Illumina short reads, and high-throughput chromosome conformation capture technologies. The final assembly of the genome was 2.33 Gb, encoding 95,327 predicted coding sequences. The GC content was 34.39% with 99.2% of the bases anchored to 26 pseudo-chromosomes that ranged from 53.8 to 127.7 Mb. This resource will help gain a detailed understanding of the genomic features governing high yield and Verticillium wilt resistance in this cultivar. Comparative genomics will be particularly helpful, since there are several published genomes of other Gossypium species. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Dietary nutrients mediate crosstalk between bile acids and gut microbes in animal host metabolism.

Bile acids (BAs) are synthesized by liver, then gut microbes embellish primary BAs into secondary BAs with diverse and biological functions. Over the past few decades, amounts of evidences demonstrated the importance of gut microbes in BA metabolism. There is also significant evidence that BAs are regarded as cell signals in gut-liver, gut-brain, and gut-testis axis. Moreover, the interaction between BAs and gut microbes plays a key role not only in the absorption and metabolism of nutrients, but the regulation of immune function. Herein, we collected the major information of the BA metabolism-related bacteria, nutrients, and cell signals, focused on the possible molecular mechanisms by "Microbes-Bile acids" crosstalk, highlighted the gut-liver, gut-brain, and gut-testis axis, and discussed the possibility and application of the regulation of BA metabolism by nutrients.

Gut microbiota and its metabolites: Bridge of dietary nutrients and obesity-related diseases.

While the incidence of obesity keeps increasing in both adults and children worldwide, obesity and its complications remain major threatens to human health. Over the past decades, accumulating evidence has demonstrated the importance of microorganisms and their metabolites in the pathogenesis of obesity and related diseases. There also is a significant body of evidence validating the efficacy of microbial based therapies for managing various diseases. In this review, we collected the key information pertinent to obesity-related bacteria, fermentation substrates and major metabolites generated by studies involving humans and/or mice. We then briefly described the possible molecular mechanisms by which microorganisms cause or inhibit obesity with a focus on microbial metabolites. Lastly, we summarized the advantages and disadvantages of the utilization of probiotics, plant extracts, and exercise in controlling obesity. We speculated that new targets and combined approaches (e.g. diet combined with exercise) could lead to more precise prevention and/or alleviation of obesity in future clinical research implications.

Dietary nutrition regulates intestinal stem cell homeostasis.

Intestinal stem cells (ISCs), which locate at the base of intestinal crypts, are key determinants of governing proliferation and differentiation of the intestinal epithelium. The surrounding cells of ISCs and their related growth factors form ISC niche, supporting ISC function and self-renewal. ISC has an underappreciated but emerging role as a sensor of dietary nutrients, which fate decisions is adjusted in response to nutritional states to regulate gut homeostasis. Here, we review endogenous and exogenous factors, such as caloric restriction, fasting, fat, glucose and trace element. They instruct ISCs via mTORC1, PPAR/CPT1α, PPARγ/ß-catenin, Wnt/GSK-3ß pathway, respectively, jointly affect intestinal homeostasis. These dietary responses regulate ISC regenerative capacity and may be a potential target for cancer prevention. However, without precise definitions of nutrition intervene, it will be difficult to generate sufficient data to extending our knowledge of the biological response of ISC on nutrients. More accurately modeling organoids or high-throughput automated organoid culture in microcavity arrays have provided unprecedented opportunities for modeling diet-host interactions. These major advances collectively provide new insights into nutritional regulation of ISC proliferation and differentiation and drive us ever closer to breakthroughs for regenerative medicine and disease treatment by nutrition intervention in the clinic.

Sensation of dietary nutrients by gut taste receptors and its mechanisms.

Nutrients sensing is crucial for fundamental metabolism and physiological functions, and it is also an essential component for maintaining body homeostasis. Traditionally, basic taste receptors exist in oral cavity to sense sour, sweet, bitter, umami, salty and et al. Recent studies indicate that gut can sense the composition of nutrients by activating relevant taste receptors, thereby exerting specific direct or indirect effects. Gut taste receptors, also named as intestinal nutrition receptors, including at least bitter, sweet and umami receptors, have been considered to be activated by certain nutrients and participate in important intestinal physiological activities such as eating behavior, intestinal motility, nutrient absorption and metabolism. Additionally, gut taste receptors can regulate appetite and body weight, as well as maintain homeostasis via targeting hormone secretion or regulating the gut microbiota. On the other hand, malfunction of gut taste receptors may lead to digestive disorders, and then result in obesity, type 2 diabetes and gastrointestinal diseases. At present, researchers have confirmed that the brain-gut axis may play indispensable roles in these diseases via the secretion of brain-gut peptides, but the mechanism is still not clear. In this review, we summarize the current observation of knowledge in gut taste systems in order to shed light on revealing their important nutritional functions and promoting clinical implications.

Review of machine learning-based surrogate models of groundwater contaminant modeling.

Heavy computational load inhibits the application of groundwater contaminant numerical model to groundwater pollution source identification, remediation design, and uncertainty analysis, since a large number of model runs are required for these applications. Machine learning-based surrogate models are an effective approach to enhance the efficiency of the numerical models, and have recently attracted considerable attention in the field of groundwater contaminant modeling. Here, we review 120 research articles on machine learning-based surrogate models for groundwater contaminant modeling that were published between 1994 and 2022. We outline the state of the art method, identify the most significant research challenges, and suggest potential future directions. The six major applications of machine learning-based surrogate models are groundwater pollution source identification, groundwater remediation design, coastal aquifer management, uncertainty analysis of groundwater, groundwater monitoring network design, and groundwater transport parameters inversion. Together, these account for more than 90% of the studies we review. Latin hypercube sampling (LHS) is the most widely used sampling method, and artificial neural networks (ANNs) and Kriging are the two most widely used methods for constructing surrogate model. No method is universally superior, the advantages and disadvantages of different methods, as well as the applicability of these methods for different application purposes of groundwater contaminant modeling were analyzed. Some recommendations on the method selection for various application fields are given based on the reviews and experiences. Based on our review of the state-of-the-art, we suggest several future research directions to enhance the feasibility of the machine learning-based surrogate models of groundwater contaminant modeling: the alleviation of the curse of dimensionality, enhancing transferability, practical applications for real case studies, multi-source dada fusion, and real-time monitoring and prediction.

UPLC-MS-based plasma metabolomics for identifying energy metabolism biomarkers of maintenance in growing pigs.

The purpose of this study is to explore the potential plasma metabolism biomarkers reflecting the maintenance status of growing pigs. The repeated measurement design was used in this experiment, and six barrows (28.6 ± 0.5 kg BW) were selected and kept in metabolism crates. The feeding level in growing pigs close to ad libitum was 2400 kJ ME/kg BW0.6 ·day-1 during Day 1 to Day 7, while a feeding level of 782 kJ ME/kg BW0.6 ·day-1 was provided as energy requirement for maintenance during Day 8 to Day 14. Plasma samples of each pig were collected from the anterior vena cava on the morning of Day 8 and Day 15. The metabolites of plasma were determined by high-resolution mass spectrometry using a metabolomics approach. Results showed that metabolomics analysis between ad libitum-fed state and maintained status revealed differences in 16 compounds. Identified compounds were enriched in metabolic pathways related to linoleic acid metabolism, tryptophan metabolism, and alanine, aspartate and glutamate metabolism. In conclusion, linoleic acid metabolism, tryptophan metabolism, alanine, aspartate and glutamic acid metabolism pathways played a major regulatory role in the maintenance status of growing pigs. The potential metabolism biomarkers of maintenance in growing pigs were linoleic acid, glutamine and tyrosine.

Virus-like Particles as Antiviral Vaccine: Mechanism, Design, and Application.

Virus-like particles (VLPs) are viral structural protein that are noninfectious as they do not contain viral genetic materials. They are safe and effective immune stimulators and play important roles in vaccine development because of their intrinsic immunogenicity to induce cellular and humoral immune responses. In the design of antiviral vaccine, VLPs based vaccines are appealing multifunctional candidates with the advantages such as self-assembling nanoscaled structures, repetitive surface epitopes, ease of genetic and chemical modifications, versatility as antigen presenting platforms, intrinsic immunogenicity, higher safety profile in comparison with live-attenuated vaccines and inactivated vaccines. In this review, we discuss the mechanism of VLPs vaccine inducing cellular and humoral immune responses. We outline the impact of size, shape, surface charge, antigen presentation, genetic and chemical modification, and expression systems when constructing effective VLPs based vaccines. Recent applications of antiviral VLPs vaccines and their clinical trials are summarized.

[Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine].

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid ß(Aß)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

DNA-PKcs participated in hypoxic pulmonary hypertension.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common complication of chronic lung disease, which severely affects the survival and prognosis of patients. Several recent reports have shown that DNA damage and repair plays a crucial role in pathogenesis of pulmonary arterial hypertension. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a part of DNA-PK is a molecular sensor for DNA damage that enhances DSB repair. This study aimed to demonstrate the expression and potential mechanism of DNA-PKcs on the pathogenesis of HPH. METHODS: Levels of DNA-PKcs and other proteins in explants of human and rats pulmonary artery from lung tissues and pulmonary artery smooth muscle cells (PASMC) were measured by immunohistochemistry and western blot analysis. The mRNA expression levels of DNA-PKcs and NOR1 in PASMCs were quantified with qRT-PCR. Meanwhile, the interaction among proteins were detected by Co-immunoprecipitation (Co-IP) assays. Cell proliferation and apoptosis was assessed by cell counting kit-8 assay(CCK-8), EdU incorporation and flow cytometry. Rat models of HPH were constructed to verify the role of DNA-PKcs in pulmonary vascular remodeling in vivo. RESULTS: DNA-PKcs protein levels were both significantly up-regulated in explants of pulmonary artery from HPH models and lung tissues of patients with hypoxemia. In human PASMCs, hypoxia up-regulated DNA-PKcs in a time-dependent manner. Downregulation of DNA-PKcs by targeted siRNA or small-molecule inhibitor NU7026 both induced cell proliferation inhibition and cell cycle arrest. DNA-PKcs affected proliferation by regulating NOR1 protein synthesis followed by the expression of cyclin D1. Co-immunoprecipitation of NOR1 with DNA-PKcs was severely increased in hypoxia. Meanwhile, hypoxia promoted G2 + S phase, whereas the down-regulation of DNA-PKcs and NOR1 attenuated the effects of hypoxia. In vivo, inhibition of DNA-PKcs reverses hypoxic pulmonary vascular remodeling and prevented HPH. CONCLUSIONS: Our study indicated the potential mechanism of DNA-PKcs in the development of HPH. It might provide insights into new therapeutic targets for pulmonary vascular remodeling and pulmonary hypertension.

Quorum sensing mediates gut bacterial communication and host-microbiota interaction.

Gut bacteria employ quorum sensing (QS) to coordinate their activities and communicate with one another, this process relies on the production, detection, and response to autoinducers, which are extracellular signaling molecules. In addition to synchronizing behavioral activities within the species, QS plays a crucial role in the gut host-microbiota interaction. In this review, an overview of classical QS systems is presented as well as the interspecies communication mediated by QS, and recent advances in the host-microbiota interaction mediated by QS. A greater knowledge of the communication network of gut microbiota is not only an opportunity and a challenge for developing nutritional and therapeutic strategies against bacterial illnesses, but also a means for improving gut health.

Dietary nutrients shape gut microbes and intestinal mucosa via epigenetic modifications.

The imbalance of intestinal microecology firstly impairs intestinal mucosa barrier and function, then further damages the functions and homeostasis of distal organs, leading to systemic diseases. Nutrients, transplantation of bacteria flora and modes of life can shape gut microbiota and intestinal mucosa barrier and mitigate stress. Current researches demonstrate that dynamic epigenetic modifications of intestinal tissue strongly mediate the crosstalk between gut microbes and gut mucosa barrier. Lactobacillus and Bifidobacterium species can synthesize folate to increase DNA methylation and mRNA N6-methyladenosine (m6A) of gut, which ensures intestinal normal development. Clostridial cluster, Anaerostipes and Eubacterium can induce histone acylation modifications by butyrate to enhance the development and immune balance of gut. Herein, we summarizes the present scientific understanding of how dietary nutrients shape gut microbiota and further regulate intestinal mucosa functions via epigenetic modifications, which will shed light on manipulation of gut microbiota by dietary nutrients, for prevention or clinical treatment of intestinal diseases.

Improving squalene production by blocking the competitive branched pathways and expressing rate-limiting enzymes in Rhodopseudomonas palustris.

Squalene is a medically valuable bioactive compound that can be used as a raw material for fuels. Microbial fermentation is the preferred method for the squalene production. In this study, we employed several metabolic engineering strategies to increase squalene yield in Rhodopseudomonas palustris. A 57% increase in squalene titer was achieved by blocking the carotenoid pathway, thus directing more FPP into the squalene biosynthetic pathway. In order to cut down the conversion of squalene to haponoids, a recombinant strain R. palustris [Δshc, ΔcrtB] in which both carotenoid and haponoid pathways were blocked was then constructed, resulting in a 50-fold increase in squalene titer. Based on the expression of rate-limiting enzymes involved in the squalene pathway, the final squalene content reached 23.3 mg/g DCW, which was 178-times higher than that of the wild-type strain. In this study, several methods effective in improving squalene yield have been described and the potential of R. palustris for producing squalene has been demonstrated.