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Cell Sep 2023Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria....
Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (CPP, lipid II, and lipid III). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.
Topics: Anti-Bacterial Agents; Bacteria; Biological Assay; Diphosphates; Soil Microbiology
PubMed: 37611581
DOI: 10.1016/j.cell.2023.07.038 -
Cell Metabolism Jan 2024Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (HS) is also required to safeguard the function of...
Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (HS) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates HS production. Here, we show that apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) and Bim (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced HS levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional HS. Moreover, apoptotic cells and vesicles (apoVs) express key HS-generating enzymes and generate a significant amount of HS, indicating that apoptotic metabolism is an important source of HS. Mechanistically, HS sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining HS homeostasis and the unique role of HS in regulating Th17 cell differentiation via sulfhydration of Sep15.
Topics: Adult; Mice; Humans; Animals; Hydrogen Sulfide; Th17 Cells; Mice, Inbred MRL lpr; Cell Differentiation; Apoptosis
PubMed: 38113886
DOI: 10.1016/j.cmet.2023.11.012 -
International Journal of Molecular... Jun 2023Lysosomes are acidic organelles present in all nucleated mammalian cells [...].
Lysosomes are acidic organelles present in all nucleated mammalian cells [...].
Topics: Animals; Lysosomes; Organelles; Acids; Mammals
PubMed: 37445864
DOI: 10.3390/ijms241310688 -
Cell Reports. Medicine Oct 2023Approved fibroblast growth factor receptor (FGFR) inhibitors include erdafitinib, pemigatinib, and futibatinib. We review the most common toxicities associated with FGFR... (Review)
Review
Approved fibroblast growth factor receptor (FGFR) inhibitors include erdafitinib, pemigatinib, and futibatinib. We review the most common toxicities associated with FGFR inhibitors and provide practical advice regarding their management. Hyperphosphatemia can be managed with careful monitoring, dose reduction or interruption, a prophylactic low-phosphate diet, and phosphate-lowering therapy. Ocular adverse events (AEs) are managed by withholding or adjusting the dose of the FGFR inhibitor. Dermatologic AEs include alopecia, which can be managed with minoxidil, and dry skin, which can be treated with moisturizers. Hand-foot syndrome can be prevented by lifestyle changes and managed with moisturizing creams, urea, or salicylic acid. Among gastrointestinal AEs, diarrhea may be managed with loperamide; stomatitis can be managed with baking soda rinses, mucosa-coating agents, and topical anesthetics; and dry mouth may be alleviated with salivary stimulants. Most FGFR inhibitor-associated toxicities are manageable with prophylactic measures and treatments; proactive monitoring is key to ensuring optimal clinical benefits.
Topics: Receptor, Fibroblast Growth Factor, Type 2; Phosphates
PubMed: 37757826
DOI: 10.1016/j.xcrm.2023.101204 -
Annals of Botany Jul 2023Silicon and aluminium oxides make the bulk of agricultural soils. Plants absorb dissolved silicon as silicic acid into their bodies through their roots. The silicic acid... (Review)
Review
BACKGROUND
Silicon and aluminium oxides make the bulk of agricultural soils. Plants absorb dissolved silicon as silicic acid into their bodies through their roots. The silicic acid moves with transpiration to target tissues in the plant body, where it polymerizes into biogenic silica. Mostly, the mineral forms on a matrix of cell wall polymers to create a composite material. Historically, silica deposition (silicification) was supposed to occur once water evaporated from the plant surface, leaving behind an increased concentration of silicic acid within plant tissues. However, recent publications indicate that certain cell wall polymers and proteins initiate and control the extent of plant silicification.
SCOPE
Here we review recent publications on the polymers that scaffold the formation of biogenic plant silica, and propose a paradigm shift from spontaneous polymerization of silicic acid to dedicated active metabolic processes that control both the location and the extent of the mineralization.
CONCLUSION
Protein activity concentrates silicic acid beyond its saturation level. Polymeric structures at the cell wall stabilize the supersaturated silicic acid and allow its flow with the transpiration stream, or bind it and allow its initial condensation. Silica nucleation and further polymerization are enabled on a polymeric scaffold, which is embedded within the mineral. Deposition is terminated once free silicic acid is consumed or the chemical moieties for its binding are saturated.
Topics: Silicon Dioxide; Silicic Acid; Silicon; Plants; Polymers
PubMed: 37094329
DOI: 10.1093/aob/mcad056 -
Clinical Interventions in Aging 2023Bile acids play a crucial role in promoting intestinal nutrient absorption and biliary cholesterol excretion, thereby protecting the liver from cholesterol accumulation... (Review)
Review
Bile acids play a crucial role in promoting intestinal nutrient absorption and biliary cholesterol excretion, thereby protecting the liver from cholesterol accumulation and bile acid toxicity. Additionally, bile acids can bind to specific nuclear and membrane receptors to regulate energy expenditure and specific functions of particular tissues. Vascular calcification refers to the pathological process of calcium-phosphate deposition in blood vessel walls, which serves as an independent predictor for cardiovascular adverse events. In addition to aging, this pathological change is associated with aging-related diseases such as atherosclerosis, hypertension, chronic kidney disease, diabetes mellitus, and osteoporosis. Emerging evidence suggests a close association between the bile acid network and these aforementioned vascular calcification-associated conditions. Several bile acids have been proven to participate in calcium-phosphate metabolism, affecting the transdifferentiation of vascular smooth muscle cells and thus influencing vascular calcification. Targeting the bile acid network shows potential for ameliorating these diseases and their concomitant vascular calcification by regulating pathways such as energy metabolism, inflammatory response, oxidative stress, and cell differentiation. Here, we present a summary of the metabolism and functions of the bile acid network and aim to provide insights into the current research on the profound connections between the bile acid network and these vascular calcification-associated diseases, as well as the therapeutic potential.
Topics: Humans; Bile Acids and Salts; Signal Transduction; Receptors, G-Protein-Coupled; Calcium; Cholesterol; Vascular Calcification; Phosphates
PubMed: 37885621
DOI: 10.2147/CIA.S431220 -
International Journal of Molecular... Jun 2023Plant growth-promoting bacteria (PGPB) appear to be a sensible competitor to conventional fertilization, including mineral fertilizers and chemical plant protection... (Review)
Review
Plant growth-promoting bacteria (PGPB) appear to be a sensible competitor to conventional fertilization, including mineral fertilizers and chemical plant protection products. Undoubtedly, one of the most interesting bacteria exhibiting plant-stimulating traits is, more widely known as a pathogen, . To date, several environmentally safe strains of have been isolated and described, including WSE01, MEN8, YL6, SA1, ALT1, ERBP, GGBSTD1, AK1, AR156, C1L, and T4S. These strains have been studied under growth chamber, greenhouse, and field conditions and have shown many significant traits, including indole-3-acetic acid (IAA) and aminocyclopropane-1-carboxylic acid (ACC) deaminase production or phosphate solubilization, which allows direct plant growth promotion. It includes an increase in biometrics traits, chemical element content (e.g., N, P, and K), and biologically active substances content or activity, e.g., antioxidant enzymes and total soluble sugar. Hence, has supported the growth of plant species such as soybean, maize, rice, and wheat. Importantly, some strains can also promote plant growth under abiotic stresses, including drought, salinity, and heavy metal pollution. In addition, strains produced extracellular enzymes and antibiotic lipopeptides or triggered induced systemic resistance, which allows indirect stimulation of plant growth. As far as biocontrol is concerned, these PGPB can suppress the development of agriculturally important phytopathogens, including bacterial phytopathogens (e.g., , , and ), fungal phytopathogens (e.g., , , and ), and other phytopathogenic organisms (e.g., (Nematoda) and (Protozoa)). In conclusion, it should be noted that there are still few studies on the effectiveness of under field conditions, particularly, there is a lack of comprehensive analyses comparing the PGP effects of and mineral fertilizers, which should be reduced in favor of decreasing the use of mineral fertilizers. It is also worth mentioning that there are still very few studies on the impact of on the indigenous microbiota and its persistence after application to soil. Further studies would help to understand the interactions between and indigenous microbiota, subsequently contributing to increasing its effectiveness in promoting plant growth.
Topics: Bacillus cereus; Fertilizers; Plant Development; Phosphates
PubMed: 37298706
DOI: 10.3390/ijms24119759 -
The Tohoku Journal of Experimental... Jul 2023In clinical settings, bone grafting is frequently used to treat bone defects. Therefore, the development of bone graft substitutes with superior bone formation ability... (Review)
Review
In clinical settings, bone grafting is frequently used to treat bone defects. Therefore, the development of bone graft substitutes with superior bone formation ability is expected, instead of autogenous bone grafting. Octacalcium phosphate (OCP) has been developed as a bone graft substitute, and preclinical studies using OCP have reported superior bone formation ability compared with β-tricalcium phosphate. Furthermore, OCP has been used in composite forms with natural polymers such as collagen and gelatin to improve the usability of OCP, and OCP/collagen composite forms have been clinically applied in the dental field because of their excellent usability and osteogenic potential. This review describes the development and preclinical results of OCP and OCP/gelatin (OCP/Gel) composites and prospects for future applications in orthopedics. The development of bone graft substitutes that achieve a high degree of biodegradability and strength will be needed for the clinical application of OCP composites in orthopedics in the future.
Topics: Humans; Gelatin; Bone Regeneration; Calcium Phosphates; Osteogenesis; Collagen; Bone Substitutes
PubMed: 37197945
DOI: 10.1620/tjem.2023.J040 -
International Journal of Molecular... Nov 2023The apricot ( L.) is a fruit that belongs to the Rosaceae family; it has a unique flavor and is of important economic and nutritional value. The composition and content...
The apricot ( L.) is a fruit that belongs to the Rosaceae family; it has a unique flavor and is of important economic and nutritional value. The composition and content of soluble sugars and organic acids in fruit are key factors in determining the flavor quality. However, the molecular mechanism of sugar and acid accumulation in apricots remains unclear. We measured sucrose, fructose, glucose, sorbitol, starch, malate, citric acid, titratable acid, and pH, and investigated the transcriptome profiles of three apricots (the high-sugar cultivar 'Shushanggan', common-sugar cultivar 'Sungold', and low-sugar cultivar 'F43') at three distinct developmental phases. The findings indicated that 'Shushanggan' accumulates a greater amount of sucrose, glucose, fructose, and sorbitol, and less citric acid and titratable acid, resulting in a better flavor; 'Sungold' mainly accumulates more sucrose and less citric acid and starch for the second flavor; and 'F43' mainly accumulates more titratable acid, citric acid, and starch for a lesser degree of sweetness. We investigated the DEGs associated with the starch and sucrose metabolism pathways, citrate cycle pathway, glycolysis pathway, and a handful of sugar transporter proteins, which were considered to be important regulators of sugar and acid accumulation. Additionally, an analysis of the co-expression network of weighted genes unveiled a robust correlation between the brown module and sucrose, glucose, and fructose, with being identified as a hub gene that interacted with four sugar transporter proteins (, , , and ), as well as three structural genes for sugar and acid metabolism (, , and ). Furthermore, we found some lncRNAs and miRNAs that regulate these genes. Our findings provide clues to the functional genes related to sugar metabolism, and lay the foundation for the selection and cultivation of high-sugar apricots in the future.
Topics: Transcriptome; Sugars; Prunus armeniaca; Fruit; Carbohydrates; Glucose; Acids; Sucrose; Citric Acid; Starch; Fructose; Metabolome; Sorbitol
PubMed: 38069317
DOI: 10.3390/ijms242316992 -
Nutrients Jul 2023Dietary acid load (DAL) is recognized as a risk factor for several chronic disorders, including obesity, diabetes, and osteoporosis. Recent evidence suggests that an... (Review)
Review
Dietary acid load (DAL) is recognized as a risk factor for several chronic disorders, including obesity, diabetes, and osteoporosis. Recent evidence suggests that an elevated DAL, as measured by the validated potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores, could also increase the risk for several cancers. This narrative review summarizes the potential role of DAL in Uruguayan cancer patients and outlines the potentially involved pathophysiological pathways that mediate the role of DAL in both cancer development and growth. Although Uruguay is a developing country, its average diet is a heavily meat-based Western one, translating into a supraphysiological acid burden from diet. In recent years, we have published epidemiologic evidence based on ten case-control studies involving 3736 cancer cases and 9534 hospital-based controls. Odds ratios and 95% confidence intervals were estimated for each interest variable to analyze the association between the exposure levels of DAL scores and cancer, calculated by unconditional logistic regression. In a majority of the cases, the highest DAL scores tended to double the cancer risk as compared to the lowest category. We also found high risks for methionine intake, an acidifying amino acid found in higher concentrations in animal-based foods, which may increase cancer risks at least by a joint action based on the pH and the proliferation enhancing properties of the amino acid itself.
Topics: Animals; Uruguay; Diet; Risk Factors; Obesity; Acids; Amino Acids; Neoplasms
PubMed: 37513516
DOI: 10.3390/nu15143098