International Journal of Molecular Sciences最新文献

Complex sphingolipids are components of eukaryotic biomembranes and are involved in various physiological functions. In addition, their synthetic intermediates and metabolites, such as ceramide, sphingoid long-chain base, and sphingoid long-chain base 1-phosphate, play important roles as signaling molecules that regulate intracellular signal transduction systems. Complex sphingolipids have a large number of structural variations, and this structural diversity is considered an important molecular basis for their various physiological functions. The budding yeast Saccharomyces cerevisiae has simpler structural variations in complex sphingolipids compared to mammals and is, therefore, a useful model organism for elucidating the physiological significance of this structural diversity. In this review, we focus on the structure and function of complex sphingolipids in S. cerevisiae and summarize the response mechanisms of S. cerevisiae to metabolic abnormalities in complex sphingolipids.

GATA factors are evolutionarily conserved transcription regulators that are implicated in the regulation of physiological changes under abiotic stress. Unfortunately, there are few studies investigating the potential role of GATA genes in potato plants responding to salt and osmotic stresses. The physicochemical properties, chromosomal distribution, gene duplication, evolutionary relationships and classification, conserved motifs, gene structure, interspecific collinearity relationship, and cis-regulatory elements were analyzed. Potato plants were treated with NaCl and PEG to induce salinity and osmotic stress responses. qRT-PCR was carried out to characterize the expression pattern of StGATA family genes in potato plants subjected to salinity and osmotic stress. StGATA12 loss-of-function and gain-of-function plants were established. Morphological phenotypes and growth were indicated. Photosynthetic gas exchange was suggested by the net photosynthetic rate, transpiration rate, and stomatal conductance. Physiological indicators and the corresponding genes were indicated by enzyme activity and mRNA expression of genes encoding CAT, SOD, POD, and P5CS, and contents of H₂O₂, MDA, and proline. The expression patterns of StGATA family genes were altered in response to salinity and osmotic stress. StGATA12 protein is located in the nucleus. StGATA12 is involved in the regulation of potato plant growth in response to salinity and osmotic stress. Overexpression of StGATA12 promoted photosynthesis, transpiration, and stomatal conductance under salinity and osmotic stress. StGATA12 overexpression induced biochemical responses of potato plants to salinity and osmotic stress by regulating the levels of H₂O₂, MDA, and proline and the activity of CAT, SOD, and POD. StGATA12 overexpression induced the up-regulation of StCAT, StSOD, StPOD, and StP5CS against salinity and osmotic stress. StGATA12 could reinforce the ability of potato plants to resist salinity and osmosis-induced damages, which may provide an effective strategy to engineer potato plants for better adaptability to adverse salinity and osmotic conditions.

We investigated the influence of sex and the age of obesogenic diet initiation on the obesity phenotypes at a later age. C57Bl mice started the Cafeteria Diet (CafD, with increased fat and carbohydrates, ad libitum, from 7 weeks of age (7CafD, pre-puberty) or 17 weeks of age (7CafD, post-puberty) while control C57Bl mice were fed regular chow. At 27 weeks of age, 7CafD males (n = 9) compared to 17CafD males (n = 7) had lower body weight, white adipose tissue (WAT) relative weight, and plasma cholesterol levels, and a higher expression of thermogenic genes in WAT and brown adipose tissue (BAT), and fatty acid oxidation (FAO) and insulin signalling genes in muscles. The 7CafD females (n = 8), compared to 17CafD females (n = 6), had higher plasma triglyceride levels and hepatic glycogen content, but lower insulin sensitivity and hepatic expression of FAO and insulin signalling genes. The 7CafD females, compared to 7CafD males, had more WAT, and a reduced expression of FAO genes in muscles and thermogenic genes in WAT. The 17CafD females, compared to 17CafD males, had lower plasma leptin and insulin levels, and higher insulin sensitivity and expression of insulin signalling genes in the liver and muscles. Thus, the initiation of the obesogenic diet before puberty led to a more adaptive metabolic phenotypes in males, and after puberty, in females.

Cationic antimicrobial peptides (AMPs), also called host defence peptides, have established antimicrobial and anticancer activities. Conjugation of an AMP to a bioactive molecule with complementary activity can address some of the clinical limitations of the peptide candidate. This approach has been particularly applied in antimicrobial applications of AMPs, but it remains relatively less explored in the generation of anticancer candidates. In this study, two usnic acid derivatives, based on hydrazinothiazole and benzylidenefuranone pharmacophore moieties, respectively, were conjugated to L-K6, a lysine/leucine-rich AMP, through a new pyrazole ligation intrinsically driven by the cargo molecule. Both components, the usnic acid derivative and the peptide, are selectively active against cancer cells, by targeting the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) and through DNA damage, respectively. The two conjugates, based on a hydrazone linkage, exhibited pleiotropic effects, ranging from reduction in the activity of the parent drugs to their conservation or even enhancement. Notably, the conjugates retained some anti-TDP1 activity and displayed intermediate, or even higher, cytotoxicities against glioblastoma cells, compared to their individual components.

Vitiligo is a skin condition characterized by the loss of pigment, resulting in white patches on various parts of the body. It occurs when melanocytes, the cells that are responsible for producing skin pigment, are destroyed or stop functioning. This study aimed to investigate the melanogenic potential of various 4-methylcoumarin (4MC) derivatives, including 6-methoxy-4-methylcoumarin (6M-4MC), 7-methoxy-4-methylcoumarin (7M-4MC), 7-amino-4-methylcoumarin (7A-4MC), 6,7-dihydroxy-4-methylcoumarin (6,7DH-4MC), 7,8-dihydroxy-4-methylcoumarin (7,8DH-4MC), and 6,7-dimethoxy-4-methylcoumarin (6,7DM-4MC), in B16F10 melanoma cells. Our findings revealed that, while 4MC, 7A-4MC, 6,7DH-4MC, and 7,8DH-4MC did not exhibit any effect on melanin production, significant stimulation of melanogenesis was observed with 6M-4MC, 7M-4MC, and 6,7DM-4MC, with 6M-4MC demonstrating the most pronounced effect. 6M-4MC significantly stimulated melanin production and tyrosinase activity in a concentration-dependent manner in B16F10 cells. A Western blot analysis revealed that 6M-4MC increased the expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). Further mechanistic studies showed that 6M-4MC inhibited extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), which led to the upregulation of MITF and TRP proteins and subsequent activation of melanin synthesis. Additionally, 6M-4MC activated GSK3β phosphorylation, reduced β-catenin phosphorylation, and stimulated melanogenesis via the GSK3β/β-catenin pathway. Moreover, a primary skin irritation test was conducted on the upper backs of 32 healthy female volunteers to assess the potential irritation or sensitization from 6M-4MC when applied topically at concentrations of 50 µM and 100 µM. The test results showed no adverse effects on the skin. Collectively, these findings suggest that 6M-4MC may be a promising pigmentation stimulator for use in cosmetics and in the medical treatment of hypopigmentation disorders, particularly in the treatment of skin conditions such as vitiligo.

Exercise is a recognized non-pharmacological treatment for improving glucose homeostasis in type 2 diabetes (T2DM), with resistance exercise (RE) showing promising results. However, the mechanism of RE improving T2DM has not been clarified. This study aims to investigate the effects of RE on glucose and lipid metabolism, insulin signaling, and mitochondrial function in T2DM mice, with a focus on the regulatory role of miR-30d-5p. Our results confirmed that RE significantly improved fasting blood glucose, IPGTT, and ITT in T2DM mice. Enhanced expression of IRS-1, p-PI3K, and p-Akt indicated improved insulin signaling. RE improved glycolipid metabolism, as well as mitochondrial biogenesis and dynamics in skeletal muscle of T2DM mice. We also found that miR-30d-5p was upregulated in T2DM, and was downregulated after RE. Additionally, in vitro, over-expression of miR-30d-5p significantly increased lipid deposition, and reduced glucose uptake and mitochondrial biogenesis. These observations were reversed after transfection with the miR-30d-5p inhibitor. Mechanistically, miR-30d-5p regulates glycolipid metabolism in skeletal muscle by directly targeting SIRT1, which affects the expression of PGC-1α, thereby influencing mitochondrial function and glycolipid metabolism. Taken together, RE effectively improves glucose and lipid metabolism and mitochondrial function in T2DM mice, partly through regulating the miR-30d-5p/SIRT1/PGC-1α axis. miR-30d-5p could serve as a potential therapeutic target for T2DM management.

Autism spectrum disorder (commonly known as autism) is a complex and prevalent neurodevelopmental condition characterized by challenges in social behavior, restricted interests, and repetitive behaviors. It is projected that the annual cost of autism spectrum disorder in the US will reach USD 461 billion by 2025. However, despite being a major public health problem, effective treatment for the underlying symptoms remains elusive. As numerous literature data indicate the role of gut microbiota in autism prognosis, particularly in terms of alleviating gastrointestinal (GI) symptoms, high hopes have been placed on probiotics for autism treatment. Approximately twenty clinical studies have been conducted using single or mixed probiotic cultures. However, unequivocal results on the effect of probiotics on people with autism have not been obtained. The small sample sizes, differences in age of participants, choice of probiotics, dose and duration of treatment, outcome measures, and analytical methods used are largely inconsistent, making it challenging to draw distinctive conclusions. Here, we discuss the experimental evidence for specific gut bacteria and their metabolites and how they affect autism in light of the phenotypic and etiological complexity and heterogeneity. We propose a personalized medicine approach for using probiotics to increase the quality of life of individuals with autism by selecting specific probiotics to improve particular features of the condition.

Leishmaniasis, a disease caused by protozoan Leishmania spp., exhibits a broad range of clinical manifestations. Host resistance or susceptibility to infections is often influenced by the genetic make-up associated with natural immunity. Caspase-1, a key component of the NLRP3 inflammasome, is critical for processing pro-IL-1β into its active form, IL-1β, while CARD8 functions as an NLRP3 inflammasome inhibitor. We conducted a case-control study comparing L. guyanensis-cutaneous leishmaniasis (Lg-CL) patients with healthy individuals (HCs) by analyzing the CASP1 genetic variants rs530537A>G, rs531542C>T, rs531604A>T and rs560880G>T. Additionally, a combined analysis of CARD8rs2043211A>T with CASP1rs530537 was performed. The genotype distribution for the four variants showed no significant differences between Lg-CL patients and HCs. However, the haplotype analysis of the four CASP1 variants identified the GTTT haplotype as associated with a 19% decreased likelihood of Lg-CL development, suggesting a protective effect against disease progression. The combined analysis of CARD8 with CASP1 variants indicated that individuals homozygous for both variants (GG/TT) exhibited a 38% reduced risk of developing Lg-CL (OR = 0.62 [95%CI:0.46-0.83]) in comparison to individuals with other genotype combinations. No correlation was found between the CASP1 variant genotypes and plasma IL-1β levels. CASP1 may act as a genetic modifier in Lg-CL.

Microbial plant biostimulants offer a promising, sustainable solution for enhancing plant growth and resilience, particularly under abiotic stress conditions such as drought, salinity, extreme temperatures, and heavy metal toxicity. These biostimulants, including plant growth-promoting rhizobacteria, mycorrhizal fungi, and nitrogen-fixing bacteria, enhance plant tolerance through mechanisms such as phytohormone production, nutrient solubilization, osmotic adjustment, and antioxidant enzyme activation. Advances in genomics, metagenomics, transcriptomics, and proteomics have significantly expanded our understanding of plant-microbe molecular communication in the rhizosphere, revealing mechanisms underlying these interactions that promote stress resilience. However, challenges such as inconsistent field performance, knowledge gaps in stress-related molecular signaling, and regulatory hurdles continue to limit broader biostimulant adoption. Despite these challenges, microbial biostimulants hold significant potential for advancing agricultural sustainability, particularly amid climate change-induced stresses. Future studies and innovation, including Clustered Regularly Interspaced Short Palindromic Repeats and other molecular editing tools, should optimize biostimulant formulations and their application for diverse agro-ecological systems. This review aims to underscore current advances, challenges, and future directions in the field, advocating for a multidisciplinary approach to fully harness the potential of biostimulants in modern agriculture.

Drug leads with a high Fsp³ index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the first detailed NMR analysis of the borylated intermediate 3-deoxy-3-boronodiethanolamine-1,2:5,6-di-O-isopropylidene-α-d-galactofuranose and of the corresponding free monosaccharide analogue 3-boronic-3-deoxy-d-galactose in the early stage of the concurrent equilibrium processes of mutarotation and borarotation. A discussion of all potential equilibria is also presented alongside a comparison with relevant ¹¹B-NMR data available from the scientific literature and our own library.