Synthesis and chemical transformations of glycol nucleic acid (GNA) nucleosides.

Xeno nucleic acids (XNA) are an increasingly important class of hypermodified nucleic acids with great potential in bioorganic chemistry and synthetic biology. Glycol nucleic acid (GNA) is constructed from a three-carbon 1,2-propanediol (propylene glycol) backbone attached to a nucleobase entity, representing the simplest known XNA. This review is intended to present GNA nucleosides from a synthetic chemistry perspective-a perspective that serves as a starting point for biological studies. Therefore this account focuses on synthetic methods for GNA nucleoside synthesis, as well as their postsynthetic chemical transformations. The properties and biological activity of GNA constituents are also highlighted. A literature survey shows four major approaches toward GNA nucleoside scaffold synthesis. These approaches pertain to glycidol ring-opening, Mitsunobu, SN2, and dihydroxylation reactions. The general arsenal of reactions used in GNA chemistry is versatile and encompasses the Sonogashira reaction, Michael addition, silyl-Hilbert-Johnson reaction, halogenation, alkylation, cyclization, Rh-catalyzed N-allylation, Sharpless catalytic dihydroxylation, and Yb(OTf)3-catalyzed etherification. Additionally, various phosphorylation reactions have enabled the synthesis of diverse types of GNA nucleotides, dinucleoside phosphates, phosphordiamidites, and oligos. Furthermore, recent advances in GNA chemistry have resulted in the synthesis of previously unknown redox-active (ferrocenyl) and luminescent (pyrenyl and phenanthrenyl) GNA nucleosides, which are also covered in this review.

Impact of 12 Weeks of Vitamin D3 Administration in Parkinson's Patients with Deep Brain Stimulation on Kynurenine Pathway and Inflammatory Status.

The current study aimed to investigate whether a 12-week Body Mass Index (BMI)-based (the higher the BMI, the higher the dosage) vitamin D3 administration may affect both the kynurenine pathway (KP) and the inflammatory state in Parkinson's disease (PD) patients with deep brain stimulation (DBS) and may be useful for developing novel therapeutic targets against PD. Patients were randomly assigned to two groups: supplemented with vitamin D3 (VitD, n = 15) and treated with vegetable oil (PL, n = 21). Administration lasted for 12 weeks. The isotope dilution method by LC-MS/MS was applied to measure KP and vitamin D metabolites. Serum concentrations of cytokines such as IL-6 and TNF-α were measured using ELISA kits. After administration, the serum concentration of TNF-α decreased in PD patients with DBS. Moreover, in KP: 3-hydroksykynurenine (3-HK) was increased in the PL group, picolinic acid was decreased in the PL group, and kynurenic acid tended to be higher after administration. Furthermore, a negative correlation between 3-HK and 25(OH)D3 and 24,25(OH)2D3 was noticed. Our preliminary results provide further evidence regarding a key link between the KP substances, inflammation status, and metabolites of vitamin D in PD patients with DBS. These findings may reflect the neuroprotective abilities of vitamin D3 in PD patients with DBS.

Determination of vitamin D status in singleton and twin gestations using CLIA and LC-MS/MS.

Objective: Vitamin D plays an important role during pregnancy. The aim was to compare vitamin D status in a group of singleton (SP) and twin pregnancies (TP) using two diagnostic methods: chemiluminescence immunoassay (CLIA) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). Design: This is a cross-sectional study. Methods: The study was conducted in the population of SP and TP at the gestational age above 20 + 0 at the Bielanski Hospital in Warsaw, Poland, between October 2020 and January 2023. All patients had their venous blood samples collected and were given an original survey containing questions on demography and vitamin D supplementation. Results: The study group included 53 Caucasian women with SP and 78 with TP aged from 21 to 47. Considering LC-MS/MS, patients with TP had lower concentrations of 25-hydroxyvitamin D (25(OH)D) than patients with SP. However, no significant difference was observed in the frequency of the occurrence of vitamin D deficiency (25(OH)D < 30 ng/mL). In both groups, the levels obtained with CLIA were significantly lower than in case of LC-MS/MS, however, strongly correlated. The intermethod agreement accounted for 52.4% and the Cohen's kappa coefficient was 0.142. Conclusions: The concentration of 25(OH)D in pregnant women depends on the type of gestation (SP/TP) and on the diagnostic methods used (CLIA/LC-MS/MS). Based on LC-MS/MS, the incidence of vitamin D deficiency was low in our group and no differences occurred in its frequency between SP and TP. The intermethod agreement between CLIA and LC-MS/MS on the detection of vitamin D deficiency was low. Significance statement: This is the first study to compare the concentration of 25(OH)D levels between SP and TP using two methods: CLIA and the gold standard - LC-MS/MS. Based on LC-MS/MS, a low incidence of vitamin D deficiency was observed in our group, in which the vast majority of patients took cholecalciferol supplements. Moreover, there were no differences in its frequency between SP and TP. However, the 25(OH)D level was significantly lower in TP. The intermethod agreement between CLIA and LC-MS/MS on the detection of vitamin D deficiency was low, which is associated with substantial clinical implications.

Effect of 12-Week BMI-Based Vitamin D3 Supplementation in Parkinson's Disease with Deep Brain Stimulation on Physical Performance, Inflammation, and Vitamin D Metabolites.

Parkinson's disease (PD) is the second most common neurodegenerative disease. To manage motor symptoms not controlled adequately with medication, deep brain stimulation (DBS) is used. PD patients often manifest vitamin D deficiency, which may be connected with a higher risk of falls. We administered a 12-week vitamin D3 supplementation based on BMI (with higher doses given to patients with higher BMI) to investigate its effects on physical performance and inflammation status in PD patients with DBS. Patients were randomly divided into two groups: treated with vitamin D3 (VitD, n = 13), and supplemented with vegetable oil as the placebo group (PL, n = 16). Patients underwent functional tests to assess their physical performance three times during this study. The serum 25(OH)D3 concentration increased to the recommended level of 30 ng/mL in the VitD group, and a significant elevation in vitamin D metabolites in this group was found. We observed significant improvement in the Up and Go and the 6 MWT in the VitD group. In inflammation status, we noticed a trend toward a decrease in the VitD group. To conclude, achieving the optimal serum 25(OH)D3 concentration is associated with better functional test performance and consequently may have a positive impact on reducing falling risk in PD.

Metal-Complexes Bearing Releasable CO Differently Modulate Amyloid Aggregation.

Neurodegenerative diseases are often associated with an uncontrolled amyloid aggregation. Hence, many studies are oriented to discover new compounds that are able to modulate self-recognition mechanisms of proteins involved in the development of these pathologies. Herein, three metal-complexes able to release carbon monoxide (CORMs) were analyzed for their ability to affect the self-aggregation of the amyloidogenic fragment of nucleophosmin 1, corresponding to the second helix of the three-helix bundle located in the C-terminal domain of the protein, i.e., NPM1264-277, peptide. These complexes were two cymantrenes coordinated to the nucleobase adenine (Cym-Ade) and to the antibiotic ciprofloxacin (Cym-Cipro) and a Re(I)-compound containing 1,10-phenanthroline and 3-CCCH2NHCOCH2CH2-6-bromo-chromone as ligands (Re-Flavo). Thioflavin T (ThT) assay, UV-vis absorption and fluorescence spectroscopies, scanning electron microscopy (SEM), and electrospray ionization mass spectrometry (ESI-MS) indicated that the three compounds have different effects on the peptide aggregation. Cym-Ade and Cym-Cipro act as aggregating agents. Cym-Ade induces the formation of NPM1264-277 fibers longer and stiffer than that formed by NPM1264-277 alone; irradiation of complexes speeds the formation of fibers that are more flexible and thicker than those found without irradiation. Cym-Cipro induces the formation of longer fibers, although slightly thinner in diameter. Conversely, Re-Flavo acts as an antiaggregating agent. Overall, these results indicate that metal-based CORMs with diverse structural features can have a different effect on the formation of amyloid fibers. A proper choice of ligands attached to metal can allow the development of metal-based drugs with potential application as antiamyloidogenic agents.

Macro-GH - A clinical entity causing a diagnostic challenge - A case report.

AIM: Presentation of a new case of a patient with macro-GH, that may interfere with different GH assays leading to false-positive results in serum samples. CASE PRESENTATION: A 61-year-old female was referred with a pituitary macroadenoma and elevated growth hormone levels. The laboratory tests showed increased fasting GH level, measured by a sandwich chemiluminescence immunoassay (LIAISON® XL) without suppression on oral glucose tolerance test and normal IGF-1. The patient did not have the typical signs and symptoms of acromegaly. The patient underwent a transsphenoidal resection of a pituitary tumor, showing only α-subunit immunostaining. Postoperative GH levels remained elevated. An interference in the determination of GH level was suspected. GH was analyzed by three different immunoassays, UniCel DxI 600, Cobas e411 and hGH-IRMA. Heterophilic antibodies and rheumatoid factor were not detected in serum sample. GH recovery after precipitation with 25 % polyethylene glycol (PEG) was 12 %. Size-exclusion chromatography confirmed the presence of macro-GH in serum sample. CONCLUSION: If results of laboratory tests are not consistent with the clinical findings, the presence of an interference within immunochemical assays could be suspected. To identify interference caused by the macro-GH, the PEG method and size-exclusion chromatography should be used.

Replacement of the phosphodiester backbone between canonical nucleosides with a dirhenium carbonyl "click" linker-a new class of luminescent organometallic dinucleoside phosphate mimics.

The first-in-class luminescent dinucleoside phosphate analogs with a [Re2(µ-Cl)2(CO)6(µ-pyridazine)] "click" linker as a replacement for the natural phosphate group are reported together with the synthesis of luminescent adenosine and thymidine derivatives having the [Re2(µ-Cl)2(CO)6(µ-pyridazine)] entity attached to positions 5' and 3', respectively. These compounds were synthesized by applying inverse-electron-demand Diels-Alder and copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reactions in three or four steps. The obtained compounds exhibited orange emission (λPL ≈ 600 nm, ΦPL ≈ 0.10, and τ = 0.33-0.61 µs) and no toxicity (except for one nucleoside) to human HeLa cervical epithelioid and Ishikawa endometrial adenocarcinoma cancer cells in vitro. Furthermore, the compounds' ability to inhibit the growth of Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacterial strains was moderate and only observed at a high concentration of 100 µM. Confocal microscopy imaging revealed that the "dirhenium carbonyl" dinucleosides and nucleosides localized mainly in the membranous structures of HeLa cells and uniformly inside S. aureus and E. coli bacterial cells. An interesting finding was that some of the tested compounds were also found in the nuclei of HeLa cells.

The Effect of a Single High Dose of Vitamin D on Serum Levels of Its Metabolites in the Elderly.

BACKGROUND: Vitamin D is a dietary micronutrient responsible for calcium and phosphorus metabolism and multiple extraskeletal actions. The assessment of vitamin D status is commonly based on measurement of 25(OH)D total concentration in serum. However, the usage of liquid chromatography with tandem mass spectrometry (LC-MS/MS) technique allows to reliably assess a panel of vitamin D metabolites in serum or plasma, which may help to investigate the metabolic paths of vitamin D, especially in populations at risk of deficiency. METHODS: A randomized, two-arms, open study was conducted on 58 patients (28 female and 30 male; aged from 61 to 96 years old). The primary aim was to assess the effects of a single, high, oral dose of vitamin D3 (120,000 IU) on serum 25(OH)D3, 25(OH)D2, 24,25(OH)2D3, 3-epi-25(OH)D3, 1,25(OH)2D3, 24,25(OH)2D3/25(OH)D3 ratio, and 25(OH)D3/3-epi-25(OH)D3 ratio concentration (measured by LC-MS/MS) at baseline, 3 days and 7 days after administration, compared to control group. The secondary aim was assessment of influence of percentage of fat tissue on serum metabolites of vitamin D and their changes after bolus dose. RESULTS: 56.6% study group attained a serum 25(OH)D3 concentration >30 ng/mL. All subjects, except for one patient achieved a serum 25(OH)D3 concentration >20 ng/mL after administration. No one exceed reference value of vitamin D (30-50 ng/mL). Among participants who received vitamin D3 there were significant increase in 25(OH)D3, 3-epi-25(OH)D3, 1,25(OH)2D3, 24,25(OH)2D3 on 3rd day after administration. 24,25(OH)2D3 concentration gradually grew, achieving the highest concentration on 7th day. The percentage increase of 25(OH)D3 was negatively correlated with baseline 25(OH)D3 (r = -0.688, p = 0.001). Positive correlation between percentage increase in 25(OH)D3 and a percentage increase serum concentration of 24,25(OH)2D3 (r = 0.954, p < 0.001), 3-epi-25(OH)D3 (r = 8.03, p < 0.001) and 1,25(OH)2D3 (r = 0.789, p <0.001) were found. None of the study participants developed hypercalcemia. The baseline concentration of analyzed metabolites of vitamin D in serum and their percentage increase were neither dependent on BMI nor percentage of fat tissue. CONCLUSIONS: High dose of vitamin D rapidly increases 25(OH)D3 concentration in the elderly patients. The response to the bolus of vitamin D includes activation of 3-epimerase, followed by production of 24,25(OH)2D3, which protects from excessive increase of active form of vitamin D.

Corrigendum to: Diversity and Functionality of Mycobacterial Mycolic Acids in Relation to Host-pathogen Interactions.

The author requested to revise the acknowledgements section of the following article [1]. In this correction, the acknowledgements have been revised in the article entitled "Diversity and Functionality of Mycobacterial Mycolic Acids in Relation to Host-pathogen Interactions" in the journal Current Medicinal Chemistry, 2017, 24(38), 4267-4278. Details of corrections are provided here. The original article can be found online at http://dx.doi.org/10.2174/0929867324666170823130445 We regret any errors and apologize to the readers. Original ACKNOWLEDGEMENTS This work was supported by National Science Centre (Poland) under grant no. 2016/21/B/NZ7/01771 and 2013/11/B/NZ6/01304. Corrected ACKNOWLEDGEMENTS This work was supported by National Science Centre (Poland) under grant no. 2013/11/B/NZ6/01304.

Electronic Coupling in 1,2,3-Triazole Bridged Ferrocenes and Its Impact on Reactive Oxygen Species Generation and Deleterious Activity in Cancer Cells.

Mixed-valence (MV) binuclear ferrocenyl compounds have long been studied as models for testing theories of electron transfer and in attempts to design molecular-scale electronic devices (e.g., molecular wires). In contrary to that, far less attention has been paid to MV binuclear ferrocenes as anticancer agents. Herein, we discuss the synthesis of six 1,2,3-triazole ferrocenyl compounds for combined (spectro)electrochemical, electron paramagnetic resonance (EPR), computational, and anticancer activity studies. Our synthetic approach was based on the copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction and enabled us to obtain in one step compounds bearing either one, two, or three ferrocenyl entities linked to the common 1,2,3-triazole core. Thus, two series of complexes were obtained, which pertain to derivatives of 3'-azido-3'-deoxythymidine (AZT) and 3-azidopropionylferrocene, respectively. Based on the experimental and theoretical data, the two mono-oxidized species corresponding to binuclear AZT and trinuclear 3-azidopropionylferrocene complexes have been categorized as class II mixed-valence according to the classification proposed by Robin and Day. Of importance is the observation that these two compounds are more active against human A549 and H1975 non-small-cell lung cancer cells than their congeners, which do not show MV characteristics. Moreover, the anticancer activity of MV species competes or surpasses, dependent on the cell line, the activity of reference anticancer drugs such as cisplatin, tamoxifen, and 5-fluorouracil. The most active from the entire series of compounds was the binuclear thymidine derivative with the lowest IC50 value of 5 ± 2 µM against lung H1975 cancer cells. The major mechanism of antiproliferative activity for the investigated MV compounds is based on reactive oxygen species generation in cancer cells. This hypothesis was substantiated by EPR spin-trapping experiments and the observation of decreased anticancer activity in the presence of N-acetyl cysteine (NAC) free-radical scavenger.

Bariatric Surgery Induced Changes in Blood Cholesterol Are Modulated by Vitamin D Status.

The effect of metabolically active bariatric surgery treatment on lipid metabolism is inconclusive. The authors of this study presume that initial vitamin D status may play a regulating role in influencing the beneficial post-effects of bariatric surgery, especially the lipid profile. The biochemical data obtained from 24 patients who had undergone laparoscopic one-anastomosis gastric bypass (OAGB) at baseline, 3 months before the surgery, at the time of surgery, and 6 months later, demonstrate that vitamin D status influenced the postoperative lipid profile. The baseline established the partition line which divided patients into two groups according to the stated calcidiol initial concentration level of 32 ng/mL. The data shows that OAGB induces a decrease in TG and hsCRP while increasing HDL. Conversely, in patients whose 25(OH)D3 was below 32 ng/mL TC significantly increased while those above this concentration remained in the normal physiological range. The changes induced by OAGB in TG, glucose, and hsCRP were similar in both groups. Unexpectedly, the surgery did not affect vitamin D metabolites. In conclusion, the results of the study suggest that a higher concentration of serum 25(OH)D3 may enhance the protective effects of OAGB.

Chemistry of glycol nucleic acid (GNA): Synthesis, photophysical characterization and insight into the biological activity of phenanthrenyl GNA constituents.

The knowledge pertaining to the chemistry and biological activity of glycol nucleic acid (GNA) components, like nucleosides and nucleotides, is still very limited. Herein we report on the preparation of the uracil nucleoside (1) and nucleotide ester GNA (2). The compounds are functionalised with a luminescent phenanthrenyl group. In DMSO, 1 and 2 are brightly fluorescent, with emission maxima at 390 nm, nanosecond decay times (0.6 and 0.75 ns, respectively), and quantum yields of ca. 0.2. In the solid phase, they show excimeric emission, with maxima at 495 nm (1) and 432 nm (2), and decay times of 3.7 ns (1) and 2.9 ns (2). The anticancer activity of the GNA components, as well as gemcitabine hydrochloride, used as a reference drug, were examined in vitro against human cancer HeLa and Ishikawa cells, as well as against normal L929 cells, using a battery of biochemical assays. Furthermore, biodistribution imaging studies were carried out in HeLa cells, with luminescence confocal microscopy, which showed that the compounds localized mainly in the lipophilic cellular compartments. Nucleoside (1) and nucleotide ester (2) features two different anticancer activity profiles. At 24 h of treatment, the nucleoside acts mainly as a toxin and induces necrosis in HeLa cells, whereas the nucleotide ester exhibits pro-apoptotic activity. At longer treatment times (72 h), the nucleoside and the reference, gemcitabine hydrochloride, featured almost identical signs of anticancer activity, such as S-phase cell cycle arrest, proliferation inhibition, and apoptosis induction. In view of this data, one can hypothesize that despite the structural differences, the newly obtained phenanthrenyl GNA nucleoside (1) and gemcitabine may share a common mechanism of anticancer activity in HeLa cancer cells. The GNA components were also examined as antiplasmodial agents against Plasmodium falciparum, in vitro. Nucleoside (1) was found to be more potent than nucleotide (2), displaying activity in the low micromolar range. Furthermore, both phenanthrene derivatives were found to display resistance indices at least 9-fold lower than chloroquine diphosphate (CQDP).

Diet, Sun, Physical Activity and Vitamin D Status in Children with Inflammatory Bowel Disease.

In the course of inflammatory bowel disease (IBD) malabsorption may lead to a vitamin D deficiency and calcium-phosphate misbalance. However, the reports on the vitamin D status in children with IBD are few and ambiguous. Here, we are presenting complex analyses of multiple factors influencing 25OHD levels in IBD children (N = 62; Crohn's disease n = 34, ulcerative colitis n = 28, mean age 14.4 ± 3.01 years, F/M 23/39) and controls (n = 47, mean age 13.97 ± 2.57, F/M 23/24). Additionally, calcium-phosphate balance parameters and inflammatory markers were obtained. In children with IBD disease, activity and location were defined. Information about therapy, presence of fractures and abdominal surgery were obtained from medical records. All subjects were surveyed on the frequency and extent of exposure to sunlight (forearms, partially legs for at least 30 min a day), physical activity (at least 30 min a day) and diet (3 days diary was analyzed with the program DIETA 5). The mean 25OHD level was higher in IBD patients compared to controls (18.1 ng/mL vs. 15.5 ng/mL; p = 0.03). Only 9.7% of IBD patients and 4.25% of controls had the optimal vitamin D level (30-50 ng/mL). Despite the higher level of 25OHD, young IBD patients showed lower calcium levels in comparison to healthy controls. There was no correlation between the vitamin D level and disease activity or location of gastrointestinal tract lesions. Steroid therapy didn't have much influence on the vitamin D level while vitamin D was supplemented. Regular sun exposure was significantly more common in the control group compared to the IBD group. We found the highest concentration of vitamin D (24.55 ng/mL) with daily sun exposure. There was no significant correlation between the vitamin D level and frequency of physical activity. The analysis of dietary diaries showed low daily intake of vitamin D in both the IBD and the control group (79.63 vs. 85.14 IU/day). Pediatric patients, both IBD and healthy individuals, require regular monitoring of serum vitamin D level and its adequate supplementation.

Plasma Amino Acids May Improve Prediction Accuracy of Cerebral Vasospasm after Aneurysmal Subarachnoid Haemorrhage.

Aneurysmal subarachnoid haemorrhages (aSAH) account for 5% of strokes and continues to place a great burden on patients and their families. Cerebral vasospasm (CVS) is one of the main causes of death after aSAH, and is usually diagnosed between day 3 and 14 after bleeding. Its pathogenesis remains poorly understood. To verify whether plasma concentration of amino acids have prognostic value in predicting CVS, we analysed data from 35 patients after aSAH (median age 55 years, IQR 39-62; 20 females, 57.1%), and 37 healthy volunteers (median age 50 years, IQR 38-56; 19 females, 51.4%). Fasting peripheral blood samples were collected on postoperative day one and seven. High performance liquid chromatography-mass spectrometry (HPLC-MS) analysis was performed. The results showed that plasma from patients after aSAH featured a distinctive amino acids concentration which was presented in both principal component analysis and direct comparison. No significant differences were noted between postoperative day one and seven. A total of 18 patients from the study group (51.4%) developed CVS. Hydroxyproline (AUC = 0.7042, 95%CI 0.5259-0.8826, p = 0.0248) and phenylalanine (AUC = 0.6944, 95%CI 0.5119-0.877, p = 0.0368) presented significant CVS prediction potential. Combining the Hunt-Hess Scale and plasma levels of hydroxyproline and phenylalanine provided the model with the best predictive performance and the lowest leave-one-out cross-validation of performance error. Our results suggest that plasma amino acids may improve sensitivity and specificity of Hunt-Hess scale in predicting CVS.

Click ferrocenyl-erlotinib conjugates active against erlotinib-resistant non-small cell lung cancer cells in vitro.

Thanks to development of erlotinib and other target therapy drugs the lung cancer treatment have improved a lot in recent years. However, erlotinib-resistant lung cancer remains an unsolved clinical problem which demands for new therapeutics to be developed. Herein we report the synthesis of a library of 1,4- and 1,5-triazole ferrocenyl derivatives of erlotinib together with their anticancer activity studies against erlotinib-sensitive A549 and H1395 as well as erlotinib-resistant H1650 and H1975 cells. Studies showed that extend of anticancer activity is mainly related to the length of the spacer between the triazole and the ferrocenyl entity. Among the series of investigated compounds two isomers commonly bearing C(O)CH2CH2 spacer have shown superior to erlotinib activity against erlotinib-resistant H1650 and H1975 cells whereas compound with short methylene spacer devoid of any activity. In-depth biological studies for the most active compound showed differences in its mechanism of action in compare to erlotinib. The latter is known EGFR inhibitor whereas their ferrocenyl congener exerts anticancer activity mainly as ROS-inducer which activates mitochondrial pathway of apoptosis in cancer cells. However, docking studies suggested that the most active compound can also binds to the active site of EGFR TK in a similar way as erlotinib.

Metallodrug Profiling against SARS-CoV-2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain-like Protease PLpro.

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro . In addition to many well-established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal-based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS-CoV-2 assays confirming activity for gold complexes with N-heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.

Brief survey on organometalated antibacterial drugs and metal-based materials with antibacterial activity.

Rising bacterial antibiotic resistance is a global threat. To deal with it, new antibacterial agents and antiseptic materials need to be developed. One alternative in this quest is the organometallic derivatization of well-established antibacterial drugs and also the fabrication of advanced metal-based materials having antibacterial properties. Metal-based agents and materials often show new modes of antimicrobial action which enable them to overcome drug resistance in pathogenic bacterial strains. This review summarizes recent (2017-2020) progress in the field of organometallic-derived antibacterial drugs and metal-based materials having antibacterial activity. Specifically, it covers organometallic derivatives of antibacterial drugs including ß-lactams, ciprofloxacin, isoniazid, trimethoprim, sulfadoxine, sulfamethoxazole, and ethambutol as well as non-antibacterial drugs like metformin, phenformin and aspirin. Recent advances and reported clinical trials in the use of metal-based nanomaterials as antibiofouling coatings on medical devices, as photocatalytic agents in indoor air pollutant control, and also as photodynamic/photothermal antimicrobial agents are also summarized.

Fasting and Exercise Induce Changes in Serum Vitamin D Metabolites in Healthy Men.

BACKGROUND: Vitamin D plays pleiotropic roles in the body and hence, changes in its metabolism and distribution during starvation could play an important role in the adaptive response to famine. We aimed to identify the responses of some vitamin D metabolites to 8 d of fasting and exercise. METHODS: A repeated-measures design was implemented, in which 14 male volunteers fasted for 8 d and performed an exercise test before and after fasting. Serum samples were collected on day 1 after night fasting and after 8 d of complete food restriction, before and 1 h and 3 h after exercise. RESULTS: After 8 d of fasting, compared with baseline values, serum 24,25(OH)2D3 and 3-epi-25(OH)D3 levels significantly increased; those of 25(OH)D3 and 1,25(OH)2D3 were unaffected; and those of 25(OH)D2 decreased. Exercise on the first day of fasting induced an increase in serum 3-epi-25(OH)D3 levels, while exercise performed after 8 d of fasting induced an increase in 25(OH)D3, 24,25(OH)2D3, 25(OH)D2, and 3-epi-25(OH)D3 levels. CONCLUSION: Increases in 24,25(OH)2D3 and 3-epi-25(OH)D3 levels imply that fasting stimulates vitamin D metabolism. The effects of exercise on serum vitamin D metabolites, which are most pronounced after fasting and in subjects with serum 25(OH)D3 above 25 ng/mL, support the notion that fasting and exercise augment vitamin D metabolism.

Muscle-derived exophers promote reproductive fitness.

Organismal functionality and reproduction depend on metabolic rewiring and balanced energy resources. However, the crosstalk between organismal homeostasis and fecundity and the associated paracrine signaling mechanisms are still poorly understood. Using Caenorhabditis elegans, we discovered that large extracellular vesicles (known as exophers) previously found to remove damaged subcellular elements in neurons and cardiomyocytes are released by body wall muscles (BWM) to support embryonic growth. Exopher formation (exopheresis) by BWM is sex-specific and a non-cell autonomous process regulated by developing embryos in the uterus. Embryo-derived factors induce the production of exophers that transport yolk proteins produced in the BWM and ultimately deliver them to newly formed oocytes. Consequently, offspring of mothers with a high number of muscle-derived exophers grew faster. We propose that the primary role of muscular exopheresis is to stimulate reproductive capacity, thereby influencing the adaptation of worm populations to the current environmental conditions.