Synthesis and Evaluation of Chloride-Substituted Ramalin Derivatives for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer's disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.

A novel exopolysaccharide (p-CY01) from the Antarctic bacterium Pseudoalteromonas sp. strain CY01 cryopreserves human red blood cells.

Cryopreservation of human red blood cells (RBCs) is vital for regenerative medicine and organ transplantation, but current cryoprotectants (CPAs) like glycerol and hydroxyethyl starch (HES) have limitations. Glycerol requires post-thaw washing due to cell membrane penetration, while HES causes high viscosity. To address these issues, we explored exopolysaccharides (EPS) from Antarctic Pseudoalteromonas sp. strain CY01 as a non-penetrating CPA for RBC cryopreservation. The EPS, p-CY01, consisted mainly of repeating (1-4) glucose and (1-6) galactose linkages with a molecular mass of 1.1 × 107 Da. Through mild acid hydrolysis, we obtained low molecular weight p-CY01 (p-CY01 LM) with a molecular weight of 2.7 × 105 Da, offering reduced viscosity, improved solubility, and cryoprotective properties. Notably, combining low concentrations of penetrating CPAs (>1% glycerol and dimethyl sulfoxide) with 2.5% (w/v) p-CY01 LM demonstrated significant cryoprotective effects. These findings highlight the potential of p-CY01 LM as a highly effective CPA for human RBC cryopreservation, replacing HES and glycerol and enabling the long-term storage of biological materials.

Microbial metabolic responses and CO2 emissions differentiated by soil water content variation in subarctic tundra soils.

Recent rapid air temperature increases across the northern-latitude tundra have prolonged permafrost thawing and snow melting periods, resulting in increased soil temperature (Ts) and volumetric soil water content (SWC). Under prolonged soil warming at 8°C, Alaskan tundra soils were incubated in a microcosm system and examined for the SWC differential influence on the microbial decomposition activity of large molecular weight (MW) humic substances (HS). When one microcosm soil (AKC1-1) was incubated at a constant SWC of 41% for 90 days (T = 90) and then SWC was gradually decreased from 41% to 29% for another T = 90, the initial HS was partly depolymerized. In contrast, in AKC1-2 incubated at a gradually decreasing SWC from the initial 32% to 10% for T = 90 and then increasing to 27% for another T = 90, HS depolymerization was undetected. Overall, the microbial communities in AKC1-1 could maintain metabolic activity at sufficient and constant SWC during the initial T = 90 incubation. In contrast, AKC1-2 microbes may have been damaged by drought stress during the drying SWC regimen, possibly resulting in the loss of HS decomposition activity, which did not recover even after re-wetting to an optimal SWC range (20-40%). After T = 90, the CO2 production in both treatments was attributed to the increased decomposition of small-MW organic compounds (including aerobic HS-degradative products) within an optimal SWC range. We expect this study to provide new insights into the early effects of warming- and topography-induced SWC variations on the microbial contribution to CO2 emissions via HS decomposition in northern-latitude tundra soil.

Potential of Ramalin and Its Derivatives for the Treatment of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is still unclear, and presently there is no cure for the disease that can be used for its treatment or to stop its progression. Here, we investigated the therapeutic potential of ramalin (isolated from the Antarctic lichen, Ramalina terebrata), which exhibits various physiological activities, in AD. Specifically, derivatives were synthesized based on the structure of ramalin, which has a strong antioxidant effect, BACE-1 inhibition activity, and anti-inflammatory effects. Therefore, ramalin and its derivatives exhibit activity against multiple targets associated with AD and can serve as potential therapeutic agents for the disease.

PTP1B Inhibitory Secondary Metabolites from an Antarctic Fungal Strain Acremonium sp. SF-7394.

Chemical investigation of the Antarctic lichen-derived fungal strain Acremonium sp. SF-7394 yielded a new amphilectane-type diterpene, acrepseudoterin (1), and a new acorane-type sesquiterpene glycoside, isocordycepoloside A (2). In addition, three known fungal metabolites, (-)-ternatin (3), [D-Leu]-ternatin (4), and pseurotin A (5), were isolated from the EtOAc extract of the fungal strain. Their structures were mainly elucidated by analyzing their NMR and MS data. The absolute configuration of 1 was proposed by electronic circular dichroism calculations, and the absolute configuration of the sugar unit in 2 was determined by a chemical method. The inhibitory effects of the isolated compounds on protein tyrosine phosphatase 1B (PTP1B) were evaluated by enzymatic assays; results indicated that acrepseudoterin (1) and [D-Leu]-ternatin (4) dose-dependently inhibited the enzyme activity with IC50 values of 22.8 ± 1.1 µM and 14.8 ± 0.3 µM, respectively. Moreover, compound 1 was identified as a competitive inhibitor of PTP1B.

Anti-Inflammatory Effects of Metabolites from Antarctic Fungal Strain Pleosporales sp. SF-7343 in HaCaT Human Keratinocytes.

Chemical investigation of the Antarctic fungi Pleosporales sp. SF-7343 revealed four known secondary fungal metabolites: alternate C (1), altenusin (2), alternariol (3), and altenuene (4). The compound structures were identified primarily by NMR and MS analyses. Atopic dermatitis, an inflammatory disease, is driven by the abnormal activation of T helper (Th) 2 cells and barrier dysfunction. We attempted to identify the anti-inflammatory components of SF-7343. Initial screening showed that compounds 1 and 3 inhibited the secretion of interleukin-8 and -6 in tumor necrosis factor-α/interferon-γ-treated HaCaT cells, and these compounds also showed inhibitory effects on CCL5 and CCL22. Compounds 1 and 3 also downregulated the protein expression levels of intercellular adhesion molecule-1 and upregulated the expression of filaggrin and involcurin. The mechanism study results showed that compounds 1 and 3 inhibited nuclear translocation of nuclear factor-kappa B p65 and the phosphorylation of STAT1 and STAT3. Compound 1, but not compound 3, significantly promoted the expression of heme oxygenase (HO)-1. The effects of compound 1 were partly reversed by co-treatment with a HO-1 inhibitor, tin protoporphyrin IX. Taken together, this study demonstrates the potential value of Antarctic fungal strain SF-7343 isolates as a bioresource for bioactive compounds to prevent skin inflammation.

Genome-wide identification and structural analysis of heat shock protein gene families in the marine rotifer Brachionus spp.: Potential application in molecular ecotoxicology.

Heat shock proteins (Hsp) are class of conserved and ubiquitous stress proteins present in all living organisms from primitive to higher level. Various studies have demonstrated multiple cellular functions of Hsp in living organisms as an important biomarker in response to abiotic and biotic stressors including temperature, salinity, pH, hypoxia, environmental pollutants, and pathogens. However, full understanding on the mechanism and pathway involved in the induction of Hsp still remains challenging, especially in aquatic invertebrates. In this study, the entire Hsp family and subfamily members in the marine rotifers Brachionus spp., one of the cosmopolitan ecotoxicological model organisms, have been genome-widely identified. In Brachionus spp. Hsp family was comprised of Hsp10, small hsp (sHsp), Hsp40, Hsp60, Hsp70/105, and Hsp90, with highest number of genes found within Hsp40 DnaJ homolog subfamily C members. Also, the differences in the orientation of the conserved motifs within Hsp family may have induced differences in transcriptional gene modulation in response to thermal stress in Brachionus koreanus. Overall, Hsp family-specific domains were highly conserved in all three Brachionus spp., relative to Homo sapiens and across other animal taxa and these findings will be helpful for future ecotoxicological studies focusing on Hsps.

White matter and neurological disorders.

The central nervous system is simply divided into two distinct anatomical regions based on the color of tissues, i.e. the gray and white matter. The gray matter is composed of neuronal cell bodies, glial cells, dendrites, immune cells, and the vascular system, while the white matter is composed of concentrated myelinated axonal fibers extending from neuronal soma and glial cells, such as oligodendrocyte precursor cells (OPCs), oligodendrocytes, astrocytes, and microglia. As neuronal cell bodies are located in the gray matter, great attention has been focused mainly on the gray matter regarding the understanding of the functions of the brain throughout the neurophysiological areas, leading to a scenario in which the function of the white matter is relatively underestimated or has not received much attention. However, increasing evidence shows that the white matter plays highly significant and pivotal functions in the brain based on the fact that its abnormalities are associated with numerous neurological diseases. In this review, we will broadly discuss the pathways and functions of myelination, which is one of the main processes that modulate the functions of the white matter, as well as the manner in which its abnormalities are related to neurological disorders.

Total Syntheses of Lobaric Acid and Its Derivatives from the Antarctic Lichen Stereocaulon alpinum.

The first total syntheses of the natural products lobaric acid (1) and its derivatives isolated from the Antarctic lichen Stereocaulon alpinum are reported in this study. Lobarin (3), with a pseudodepsidone structure, was synthesized first in 11 steps by utilizing an Ullmann aryl ether coupling reaction, and lobaric acid was synthesized in an additional three steps by a seven-membered lactonization reaction. Various derivatives were also obtained from the prepared lobaric acid, and the synthetic compounds exhibited significant PTP1B inhibitory activities.

Anti-Cancer Activity of Lobaric Acid and Lobarstin Extracted from the Antarctic Lichen Stereocaulon alpnum.

Lobaric acid and lobarstin, secondary metabolites derived from the antarctic lichen Stereocaulon alpnum, exert various biological activities, including antitumor, anti-proliferation, anti-inflammation, and antioxidant activities. However, the underlying mechanisms of these effects have not yet been elucidated in human cervix adenocarcinoma and human colon carcinoma. In the present study, we evaluated the anticancer effects of lobaric acid and lobarstin on human cervix adenocarcinoma HeLa cells and colon carcinoma HCT116 cells. We show that the proliferation of Hela and HCT116 cells treated with lobaric acid and lobarstin significantly decreased in a dose- and time-dependent manner. Using flow cytometry analysis, we observed that the treatment with these compounds resulted in significant apoptosis in both cell lines, following cell cycle perturbation and arrest in G2/M phase. Furthermore, using immunoblot analysis, we investigated the expression of cell cycle and apoptosis-related marker genes and found a significant downregulation of the apoptosis regulator B-cell lymphoma 2 (Bcl-2) and upregulation of the cleaved form of the poly (ADP-ribose) polymerase (PARP), a DNA repair and apoptosis regulator. These results suggest that lobaric acid and lobarstin could significantly inhibit cell proliferation through cell cycle arrest and induction of apoptosis via the mitochondrial apoptotic pathway in cervix adenocarcinoma and colon carcinoma cells. Taken together, our data suggests that lobaric acid and lobarstin might be novel agents for clinical treatment of cervix adenocarcinoma and colon carcinoma.

Anticancer Activity of Ramalin, a Secondary Metabolite from the Antarctic Lichen Ramalina terebrata, against Colorectal Cancer Cells.

Colorectal cancer is a leading cause of death worldwide and occurs through the highly complex coordination of multiple cellular pathways, resulting in carcinogenesis. Recent studies have increasingly revealed that constituents of lichen extracts exhibit potent pharmaceutical activities, including anticancer activity against various cancer cells, making them promising candidates for new anticancer therapeutic drugs. The main objective of this study was to evaluate the anticancer capacities of ramalin, a secondary metabolite from the Antarctic lichen Ramalina terebrata, in the human colorectal cancer cell line HCT116. In this study, ramalin displayed concentration-dependent anticancer activity against HCT116 cells, significantly suppressing proliferation and inducing apoptosis. Furthermore, ramalin induced cell cycle arrest in the gap 2/mitosis (G2/M) phase through the modulation of hallmark genes involved in the G2/M phase transition, such as tumour protein p53 (TP53), cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase 1 (CDK1) and cyclin B1 (CCNB1). At both the transcriptional and translational level, ramalin caused a gradual increase in the expression of TP53 and its downstream gene CDKN1A, while decreasing the expression of CDK1 and CCNB1 in a concentration-dependent manner. In addition, ramalin significantly inhibited the migration and invasion of colorectal cancer cells in a concentration-dependent manner. Taken together, these data suggest that ramalin may be a therapeutic candidate for the targeted therapy of colorectal cancer.

Differential degradation of bicyclics with aromatic and alicyclic rings by Rhodococcus sp. strain DK17.

The metabolically versatile Rhodococcus sp. strain DK17 is able to grow on tetralin and indan but cannot use their respective desaturated counterparts, 1,2-dihydronaphthalene and indene, as sole carbon and energy sources. Metabolite analyses by gas chromatography-mass spectrometry and nuclear magnetic resonance spectrometry clearly show that (i) the meta-cleavage dioxygenase mutant strain DK180 accumulates 5,6,7,8-tetrahydro-1,2-naphthalene diol, 1,2-indene diol, and 3,4-dihydro-naphthalene-1,2-diol from tetralin, indene, and 1,2-dihydronaphthalene, respectively, and (ii) when expressed in Escherichia coli, the DK17 o-xylene dioxygenase transforms tetralin, indene, and 1,2-dihydronaphthalene into tetralin cis-dihydrodiol, indan-1,2-diol, and cis-1,2-dihydroxy-1,2,3,4-tetrahydronaphthalene, respectively. Tetralin, which is activated by aromatic hydroxylation, is degraded successfully via the ring cleavage pathway to support growth of DK17. Indene and 1,2-dihydronaphthalene do not serve as growth substrates because DK17 hydroxylates them on the alicyclic ring and further metabolism results in a dead-end metabolite. This study reveals that aromatic hydroxylation is a prerequisite for proper degradation of bicyclics with aromatic and alicyclic rings by DK17 and confirms the unique ability of the DK17 o-xylene dioxygenase to perform distinct regioselective hydroxylations.