Proteostasis in T cell aging.

Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.

Autophagy takes it all - autophagy inducers target immune aging.

Autophagy, as the key nutrient recycling pathway, enables eukaryotic cells to adapt to surging cellular stress during aging and, thereby, delays age-associated deterioration. Autophagic flux declines with age and, in turn, decreases in autophagy contribute to the aging process itself and promote senescence. Here, we outline how autophagy regulates immune aging and discuss autophagy-inducing interventions that target senescent immune cells, which are major drivers of systemic aging. We examine how cutting-edge technologies, such as single-cell omics methods hold the promise to capture the complexity of molecular and cellular phenotypes associated with aging, driving the development of suitable putative biomarkers and clinical bioassays. Finally, we debate the urgency to initiate large-scale human clinical trials. We give special preference to small molecule probes and to dietary interventions that can extend healthy lifespan and are affordable for most of the world's population.

ICG-001 affects DRP1 activity and ER stress correlative with its anti-proliferative effect.

Mitochondria form a highly dynamic network driven by opposing scission and fusion events. DRP1 is an essential modulator of mitochondrial fission and dynamics within mammalian cells. Its fission activity is regulated by posttranslational modifications such as activating phosphorylation at serine 616. DRP1 activity has recently been implicated as being dysregulated in numerous human disorders such as cancer and neurodegenerative diseases. Here we describe the development of a cell-based screening assay to detect DRP1 activation. We utilized this to undertake focused compound library screening and identified potent modulators that affected DRP1 activity including ICG-001, which is described as WNT/ß-catenin signaling inhibitor. Our findings elucidate novel details about ICG-001's mechanism of action (MOA) in mediating anti-proliferative activity. We show ICG-001 both inhibits mitochondrial fission and activates an early endoplasmic reticulum (ER) stress response to induce cell death in susceptible colorectal cancer cell lines.

Warkmycin, a novel angucycline antibiotic produced by Streptomyces sp. Acta 2930*.

A novel angucycline-type antibiotic, warkmycin, was isolated from the culture filtrate of Streptomyces strain Acta 2930. Its chemical structure was elucidated by HR-MS, one-dimensional and 2D NMR experiments. The compound inhibits the growth of Gram-positive bacteria and shows a strong antiproliferative activity against mouse fibroblast cell line NIH-3T3 and human cancer cell lines HepG2 and HT29.

Langkolide, a 32-membered macrolactone antibiotic produced by Streptomyces sp. Acta 3062.

A new 32-membered macrolactone antibiotic, named langkolide, was isolated from the mycelium of Streptomyces sp. Acta 3062. The langkolide structure was determined by HR-MS and 1D and 2D NMR as a 32-membered macrolactone connected from an overhanging polyketide tail to a naphthoquinone unit mediated by two carbohydrate moieties. The producing strain was isolated from a rhizosphere soil of Clitorea sp. collected at Burau Bay, Langkawi, Malaysia, and was characterized by its morphological and chemotaxonomic features in addition to its 16S rRNA gene sequence. It was identified as a member of the Streptomyces galbus clade. Langkolide exhibited various bioactivities including antimicrobial and antiproliferative activities. Furthermore, langkolide inhibited human recombinant phosphodiesterase 4 with an IC(50) value of 0.48 µM.

Abenquines A-D: aminoquinone derivatives produced by Streptomyces sp. strain DB634.

New bioactive secondary metabolites, called abenquines, were found in the fermentation broth of Streptomyces sp. strain DB634, which was isolated from the soils of the Chilean highland of the Atacama Desert. They are composed of an amino acid linked to an N-acetyl-aminobenzoquinone. Isolation of the abenquines (1-4), their structure elucidation by NMR analysis and MS, as well as the kinetics of their production are presented. The abenquines show inhibitory activity against bacteria, dermatophytic fungi and phosphodiesterase type 4b. The amino acid attached to the quinone is relevant to the enzyme inhibitory activity.

Benzoxacystol, a benzoxazine-type enzyme inhibitor from the deep-sea strain Streptomyces sp. NTK 935.

Benzoxacystol, a new 1,4-benzoxazine-type metabolite, was produced by strain NTK 935, a marine member of the Streptomyces griseus 16S rRNA clade, isolated from deep-sea sediment collected from the Canary Basin. The structure of benzoxacystol was determined by mass spectrometry, NMR experiments and X-ray analysis. The compound showed an inhibitory activity against the enzyme glycogen synthase kinase 3ß and a weak antiproliferative activity against mouse fibroblast cells.

Levantilides A and B, 20-membered macrolides from a Micromonospora strain isolated from the Mediterranean deep sea sediment.

Two new 20-membered macrolides, levantilide A and B, were isolated from the Micromonospora strain M71-A77. Strain M71-A77 was recovered from an Eastern Mediterranean deep-sea sediment sample and revealed to produce the levantilides under in situ salinity of 38.6 ‰. The chemical structures of the levantilides were elucidated on the basis of different one- and two- dimensional NMR experiments. Levantilide A exhibits a moderate antiproliferative activity against several tumor cell lines.

Phenelfamycins G and H, new elfamycin-type antibiotics produced by Streptomyces albospinus Acta 3619.

Phenelfamycins G and H are new members of the family of elfamycin antibiotics with the basic structure of phenelfamycins E and F, respectively, which are also well known as ganefromycins α and ß. Phenelfamycins G and H differ from phenelfamycins E and F by an additional hydroxy group at position C-30, which is not described so far for any of the elfamycin-type antibiotics. The actinomycete strain that produced phenelfamycins G and H was identified to be Streptomyces albospinus based on its 16S rRNA gene sequence. Phenelfamycins G and H exhibit a narrow antibacterial spectrum with a pronounced inhibitory activity against Propionibacterium acnes.

Eutypoids B-E produced by a Penicillium sp. strain from the North Sea.

Crude extracts of the Penicillium sp. strain KF620 isolated from the North Sea showed antimicrobial activities against Xanthomonas campestris and Candida glabrata. Purification of the extracts led to the isolation of the new aromatic butenolides eutypoids B (1), C (2), D (3), and E (4). Their structures were elucidated by NMR spectroscopy and supported by HRESIMS and UV data. The antibacterial activity of the crude extracts was due to the presence of the known diketopiperazine fellutanine (cyclo(Trp-Trp)). The eutypoids were neither cytotoxic nor antibacterial, but inhibited the activity of glycogen synthase kinase-3ß.

Bioactive metabolites from the sponge Suberea sp.

Two new brominated compounds, subereaphenol K (2) and 2-(3,5-dibromo-1-ethoxy-4-oxocyclohexa-2,5-dien-1-yl)acetamide (3), together with subereaphenol B (methyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate; 1) with a revised structure, and five dibromotyrosine-derived metabolites, 4-8, were isolated from the sponge Suberea sp. and characterized by 1D- and 2D-NMR spectroscopic and HR-MS spectrometric data. Compounds 1, 2, 6, and 8 exhibited various weak or moderate bioactivities, including antimicrobial and cytotoxic activities. Furthermore, compounds 1 and 2 inhibited human recombinant phosphodiesterase 4 (PDE4) with IC50 values of 2 µM, whereas compounds 6 and 8 were less active.

Nocapyrones A-D, gamma-pyrones from a Nocardiopsis strain isolated from the marine sponge Halichondria panicea.

Four new gamma-pyrones, nocapyrones A-D (1-4), were isolated from an organic extract of the Nocardiopsis strain HB383, which was isolated from the marine sponge Halichondria panicea. These are the first gamma-pyrones reported from a Nocardiopsis strain. The structures were elucidated on the basis of one- and two-dimensional NMR experiments and supported by HPLC-UV/MS and HRESIMS analyses. The biosynthesis of nocapyrone A was investigated by feeding experiments with (13)C-labeled compounds. In addition, one diketopiperazine, which was only known as a synthetic compound before, was isolated. The bioactivies of 1, 2, and the diketopiperazine were evaluated in a panel of assays.

Mayamycin, a cytotoxic polyketide from a Streptomyces strain isolated from the marine sponge Halichondria panicea.

A new benz[a]anthracene derivative called mayamycin (1) was identified in cultures of Streptomyces sp. strain HB202, which was isolated from the marine sponge Halichondria panicea and selected because of its profound antibiotic activity. The ability to produce aromatic polyketides was indicated by genetic analyses, demonstrating the presence of a type II polyketide synthase. The production of mayamycin (1) was induced by variation of the culture conditions. The structure of 1 was elucidated by HPLC-UV/MS and NMR spectroscopy. Mayamycin (1) exhibited potent cytotoxic activity against eight human cancer cell lines and showed activity against several bacteria including antibiotic-resistant strains.

Gombapyrones, new alpha-pyrone metabolites produced by Streptomyces griseoruber Acta 3662.

Gombapyrones A-D, new members of the alpha-pyrone family of secondary metabolites, were produced by Streptomyces griseoruber Acta 3662, which was isolated from bamboo tree rhizosphere. The strain was characterized by its morphological and chemotaxonomical features and by 16S rDNA sequencing as S. griseobuber. The gombapyrone structures were determined by mass spectrometry and by NMR experiments, and were found to have an inhibitory activity against protein tyrosine phosphatase 1B and glycogen synthase kinase 3beta.