mTOR in metabolic homeostasis and disease.

The ability to maintain cellular metabolic homeostasis is critical to life, in which mTOR plays an important role. This kinase integrates upstream nutrient signals and performs essential functions in physiology and metabolism by increasing metabolism and suppressing autophagy. Thus, dysregulation of mTOR activity leads to diseases, especially metabolic diseases such as cancer, type 2 diabetes and neurological disorders. Therefore, inhibition of overactivated mTOR becomes a rational approach to treat a variety of metabolic diseases. In this review, we discuss how mTOR responds to upstream signals and how mTOR regulates metabolic processes, including protein, nucleic acid, and lipid metabolism. Furthermore, we discuss the possible causes and consequences of dysregulated mTOR signaling activity, and summarize relevant applications, such as inhibition of mTOR activity to treat these diseases. This review will advance our comprehensive knowledge of the association between mTOR and metabolic homeostasis, which has significant ramifications for human health.

Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link.

Globally, the incidence of diabetes mellitus (DM) and Alzheimer's disease (AD) is increasing year by year, causing a huge economic and social burden, and their pathogenesis and aetiology have been proven to have a certain correlation. In recent years, more and more studies have shown that vacuolar adenosine triphosphatases (v-ATPases) in eukaryotes, which are biomolecules regulating lysosomal acidification and glycolipid metabolism, play a key role in DM and AD. This article describes the role of v-ATPase in DM and AD, including its role in glycolysis, insulin secretion and insulin resistance (IR), as well as its relationship with lysosomal acidification, autophagy and ß-amyloid (Aß). In DM, v-ATPase is involved in the regulation of glucose metabolism and IR. v-ATPase is closely related to glycolysis. On the one hand, v-ATPase affects the rate of glycolysis by affecting the secretion of insulin and changing the activities of key glycolytic enzymes hexokinase (HK) and phosphofructokinase 1 (PFK-1). On the other hand, glucose is the main regulator of this enzyme, and the assembly and activity of v-ATPase depend on glucose, and glucose depletion will lead to its decomposition and inactivation. In addition, v-ATPase can also regulate free fatty acids, thereby improving IR. In AD, v-ATPase can not only improve the abnormal brain energy metabolism by affecting lysosomal acidification and autophagy but also change the deposition of Aß by affecting the production and degradation of Aß. Therefore, v-ATPase may be the bridge between DM and AD.

Discussion on Brain Structure and Function in Schizophrenia by Multimodal Magnetic Resonance Imaging.

In order to explore the relationship between hippocampal structure changes and performance symptoms as well as cognitive function in adolescent schizophrenia, taking the brain response signals of psychiatric patients as the research object, the relationship between hippocampal volume drawn by schizophrenia and language memory of negative symptoms is explored based on morphological analysis method. It is found that the left hippocampal volume of schizophrenic patients is abnormal when the whole brain volume is returned, which is significantly lower than that of normal people. It is also found that the left hippocampus volume of schizophrenic patients is a mediator between negative symptoms and speech memory. The results show that the left hippocampus of schizophrenic patients plays an important role in the pathogenesis of schizophrenia.

Engineering Escherichia coli for Microbial Production of Butanone.

To expand the chemical and molecular diversity of biotransformation using whole-cell biocatalysts, we genetically engineered a pathway in Escherichia coli for heterologous production of butanone, an important commodity ketone. First, a 1-propanol-producing E. coli host strain with its sleeping beauty mutase (Sbm) operon being activated was used to increase the pool of propionyl-coenzyme A (propionyl-CoA). Subsequently, molecular heterofusion of propionyl-CoA and acetyl-CoA was conducted to yield 3-ketovaleryl-CoA via a CoA-dependent elongation pathway. Lastly, 3-ketovaleryl-CoA was channeled into the clostridial acetone formation pathway for thioester hydrolysis and subsequent decarboxylation to form butanone. Biochemical, genetic, and metabolic factors affecting relative levels of ketogenesis, acidogenesis, and alcohol genesis under selected fermentative culture conditions were investigated. Using the engineered E. coli strain for batch cultivation with 30 g liter(-1)glycerol as the carbon source, we achieved coproduction of 1.3 g liter(-1)butanone and 2.9 g liter(-1)acetone. The results suggest that approximately 42% of spent glycerol was utilized for ketone biosynthesis, and thus they demonstrate potential industrial applicability of this microbial platform.

Disruption of the Reductive 1,3-Propanediol Pathway Triggers Production of 1,2-Propanediol for Sustained Glycerol Fermentation by Clostridium pasteurianum.

UNLABELLED: Crude glycerol, the major by-product of biodiesel production, is an attractive bioprocessing feedstock owing to its abundance, low cost, and high degree of reduction. In line with the advent of the biodiesel industry, Clostridium pasteurianum has gained prominence as a result of its unique capacity to convert waste glycerol into n-butanol, a high-energy biofuel. However, no efforts have been directed at abolishing the production of 1,3-propanediol (1,3-PDO), the chief competing product of C. pasteurianum glycerol fermentation. Here, we report rational metabolic engineering of C. pasteurianum for enhanced n-butanol production through inactivation of the gene encoding 1,3-PDO dehydrogenase (dhaT). In spite of current models of anaerobic glycerol dissimilation, culture growth and glycerol utilization were unaffected in the dhaT disruption mutant (dhaT::Ll.LtrB). Metabolite characterization of the dhaT::Ll.LtrB mutant revealed an 83% decrease in 1,3-PDO production, encompassing the lowest C. pasteurianum 1,3-PDO titer reported to date (0.58 g liter(-1)). With 1,3-PDO formation nearly abolished, glycerol was converted almost exclusively to n-butanol (8.6 g liter(-1)), yielding a high n-butanol selectivity of 0.83 g n-butanol g(-1) of solvents compared to 0.51 g n-butanol g(-1) of solvents for the wild-type strain. Unexpectedly, high-performance liquid chromatography (HPLC) analysis of dhaT::Ll.LtrB mutant culture supernatants identified a metabolite peak consistent with 1,2-propanediol (1,2-PDO), which was confirmed by nuclear magnetic resonance (NMR). Based on these findings, we propose a new model for glycerol dissimilation by C. pasteurianum, whereby the production of 1,3-PDO by the wild-type strain and low levels of both 1,3-PDO and 1,2-PDO by the engineered mutant balance the reducing equivalents generated during cell mass synthesis from glycerol. IMPORTANCE: Organisms from the genus Clostridium are perhaps the most notable native cellular factories, owing to their vast substrate utilization range and equally diverse variety of metabolites produced. The ability of C. pasteurianum to sustain redox balance and glycerol fermentation despite inactivation of the 1,3-PDO pathway is a testament to the exceptional metabolic flexibility exhibited by clostridia. Moreover, identification of a previously unknown 1,2-PDO-formation pathway, as detailed herein, provides a deeper understanding of fermentative glycerol utilization in clostridia and will inform future metabolic engineering endeavors involving C. pasteurianum To our knowledge, the C. pasteurianum dhaT disruption mutant derived in this study is the only organism that produces both 1,2- and 1,3-PDOs. Most importantly, the engineered strain provides an excellent platform for highly selective production of n-butanol from waste glycerol.

Engineering Escherichia coli for high-level production of propionate.

Mounting environmental concerns associated with the use of petroleum-based chemical manufacturing practices has generated significant interest in the development of biological alternatives for the production of propionate. However, biological platforms for propionate production have been limited to strict anaerobes, such as Propionibacteria and select Clostridia. In this work, we demonstrated high-level heterologous production of propionate under microaerobic conditions in engineered Escherichia coli. Activation of the native Sleeping beauty mutase (Sbm) operon not only transformed E. coli to be propionogenic (i.e., propionate-producing) but also introduced an intracellular "flux competition" between the traditional C2-fermentative pathway and the novel C3-fermentative pathway. Dissimilation of the major carbon source of glycerol was identified to critically affect such "flux competition" and, therefore, propionate synthesis. As a result, the propionogenic E. coli was further engineered by inactivation or overexpression of various genes involved in the glycerol dissimilation pathways and their individual genetic effects on propionate production were investigated. Generally, knocking out genes involved in glycerol dissimilation (except glpA) can minimize levels of solventogenesis and shift more dissimilated carbon flux toward the C3-fermentative pathway. For optimal propionate production with high C3:C2-fermentative product ratios, glycerol dissimilation should be channeled through the respiratory pathway and, upon suppressed solventogenesis with minimal production of highly reduced alcohols, the alternative NADH-consuming route associated with propionate synthesis can be critical for more flexible redox balancing. With the implementation of various biochemical and genetic strategies, high propionate titers of more than 11 g/L with high yields up to 0.4 g-propionate/g-glycerol (accounting for ~50 % of dissimilated glycerol) were achieved, demonstrating the potential for industrial application. To our knowledge, this represents the most effective engineered microbial system for propionate production with titers and yields comparable to those achieved by anaerobic batch cultivation of various native propionate-producing strains of Propionibacteria.

Biochemical, genetic, and metabolic engineering strategies to enhance coproduction of 1-propanol and ethanol in engineered Escherichia coli.

We recently reported the heterologous production of 1-propanol in Escherichia coli via extended dissimilation of succinate under anaerobic conditions through expression of the endogenous sleeping beauty mutase (Sbm) operon. In the present work, we demonstrate high-level coproduction of 1-propanol and ethanol by developing novel engineered E. coli strains with effective cultivation strategies. Various biochemical, genetic, metabolic, and physiological factors affecting relative levels of acidogenesis and solventogenesis during anaerobic fermentation were investigated. In particular, CPC-PrOH3, a plasmid-free propanogenic E. coli strain derived by activating the Sbm operon on the genome, showed high levels of solventogenesis accounting for up to 85 % of dissimilated carbon. Anaerobic fed-batch cultivation of CPC-PrOH3 with glycerol as the major carbon source produced high titers of nearly 7 g/L 1-propanol and 31 g/L ethanol, implying its potential industrial applicability. The activated Sbm pathway served as an ancillary channel for consuming reducing equivalents upon anaerobic dissimilation of glycerol, resulting in an enhanced glycerol dissimilation and a major metabolic shift from acidogenesis to solventogenesis.

A visualized and bibliometric analysis of cancer vocational rehabilitation research using CiteSpace.

BACKGROUND: There are numerous publications on cancer vocational rehabilitation, visual techniques can help medical researchers and social workers be more familiar with the state of this field. OBJECTIVE: To summarize cancer vocational rehabilitation research, we applied visualized and bibliometric analysis to enable medical workers and social workers to identify evolving patterns of knowledge among articles and research trends, understand the current research status of vocational rehabilitation of cancer, and carry out further research on hot topics. METHODS: Based on a review of 933 papers on cancer vocational rehabilitation published in the Web of Science Core Collection, this study used Citespace software to systematically and objectively describe cancer vocational rehabilitation. RESULTS: Since 2003, the field of cancer vocational rehabilitation began to sprout. The most published and most cited country, institution, author and cited journal were the United States, University of Amsterdam, Angela G. E. M. de Boer, and Psycho-Oncology, respectively. The three most frequently cited keywords were breast cancer, quality of life and cancer survivor. The three keywords with the largest spike in citations were cohort, absence and symptom. Conducting randomized controlled trials or prospective cohort studies to help cancer survivors return to work, and using qualitative methods to understand the vocational rehabilitation experiences or perceptions of cancer survivors or medical staff are hotspots in this field. CONCLUSIONS: Cancer vocational rehabilitation has attracted the attention of researchers all over the world. Future studies may focus on other cancer types and explore more high quality interventions.

Hydrogel microrobots for biomedical applications.

Recent years have witnessed a surge in the application of microrobots within the medical sector, with hydrogel microrobots standing out due to their distinctive advantages. These microrobots, characterized by their exceptional biocompatibility, adjustable physico-mechanical attributes, and acute sensitivity to biological environments, have emerged as pivotal tools in advancing medical applications such as targeted drug delivery, wound healing enhancement, bio-imaging, and precise surgical interventions. The capability of hydrogel microrobots to navigate and perform tasks within complex biological systems significantly enhances the precision, efficiency, and safety of therapeutic procedures. Firstly, this paper delves into the material classification and properties of hydrogel microrobots and compares the advantages of different hydrogel materials. Furthermore, it offers a comprehensive review of the principal categories and recent innovations in the synthesis, actuation mechanisms, and biomedical application of hydrogel-based microrobots. Finally, the manuscript identifies prevailing obstacles and future directions in hydrogel microrobot research, aiming to furnish insights that could propel advancements in this field.

miR-328-5p functions as a critical negative regulator in early endothelial inflammation and advanced atherosclerosis.

Early proatherogenic inflammation constitutes a significant risk factor for atherogenesis development. Despite this, the precise molecular mechanisms driving this pathological progression largely remain elusive. Our study unveils a pivotal role for the microRNA miR-328-5p in dampening endothelial inflammation by modulating the stability of JUNB (JunB proto-oncogene). Perturbation of miR-328-5p levels results in heightened monocyte adhesion to endothelial cells and enhanced transendothelial migration, while its overexpression mitigates these inflammatory processes. Furthermore, miR-328-5p hinders macrophage polarization toward the pro-inflammatory M1 phenotype, and exerts a negative influence on atherosclerotic plaque formation in vivo. By pinpointing JUNB as a direct miR-328-5p target, our research underscores the potential of miR-328-5p as a therapeutic target for inflammatory atherosclerosis. Reintroduction of JUNB effectively counteracts the anti-atherosclerotic effects of miR-328-5p, highlighting the promise of pharmacological miR-328-5p targeting in managing inflammatory atherosclerosis. [BMB Reports 2024; 57(8): 375-380].