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Molecules (Basel, Switzerland) Feb 2021Varicella-zoster virus (VZV), a common and ubiquitous human-restricted pathogen, causes a primary infection (varicella or chickenpox) followed by establishment of... (Review)
Review
Varicella-zoster virus (VZV), a common and ubiquitous human-restricted pathogen, causes a primary infection (varicella or chickenpox) followed by establishment of latency in sensory ganglia. The virus can reactivate, causing herpes zoster (HZ, shingles) and leading to significant morbidity but rarely mortality, although in immunocompromised hosts, VZV can cause severe disseminated and occasionally fatal disease. We discuss VZV diseases and the decrease in their incidence due to the introduction of live-attenuated vaccines to prevent varicella or HZ. We also focus on acyclovir, valacyclovir, and famciclovir (FDA approved drugs to treat VZV infections), brivudine (used in some European countries) and amenamevir (a helicase-primase inhibitor, approved in Japan) that augur the beginning of a new era of anti-VZV therapy. Valnivudine hydrochloride (FV-100) and valomaciclovir stearate (in advanced stage of development) and several new molecules potentially good as anti-VZV candidates described during the last year are examined. We reflect on the role of antiviral agents in the treatment of VZV-associated diseases, as a large percentage of the at-risk population is not immunized, and on the limitations of currently FDA-approved anti-VZV drugs. Their low efficacy in controlling HZ pain and post-herpetic neuralgia development, and the need of multiple dosing regimens requiring daily dose adaptation for patients with renal failure urges the development of novel anti-VZV drugs.
Topics: Antiviral Agents; Encephalitis, Varicella Zoster; Herpesvirus 3, Human; Humans; Microbial Sensitivity Tests; Pyrimidine Nucleosides
PubMed: 33672709
DOI: 10.3390/molecules26041132 -
The EMBO Journal Jan 2023Reprogramming of lipid metabolism is emerging as a hallmark of cancer, yet involvement of specific fatty acids (FA) species and related enzymes in tumorigenesis remains...
Reprogramming of lipid metabolism is emerging as a hallmark of cancer, yet involvement of specific fatty acids (FA) species and related enzymes in tumorigenesis remains unclear. While previous studies have focused on involvement of long-chain fatty acids (LCFAs) including palmitate in cancer, little attention has been paid to the role of very long-chain fatty acids (VLCFAs). Here, we show that depletion of acetyl-CoA carboxylase (ACC1), a critical enzyme involved in the biosynthesis of fatty acids, inhibits both de novo synthesis and elongation of VLCFAs in human cancer cells. ACC1 depletion markedly reduces cellular VLCFA but only marginally influences LCFA levels, including palmitate that can be nutritionally available. Therefore, tumor growth is specifically susceptible to regulation of VLCFAs. We further demonstrate that VLCFA deficiency results in a significant decrease in ceramides as well as downstream glucosylceramides and sphingomyelins, which impairs mitochondrial morphology and renders cancer cells sensitive to oxidative stress and cell death. Taken together, our study highlights that VLCFAs are selectively required for cancer cell survival and reveals a potential strategy to suppress tumor growth.
Topics: Humans; Stearates; Fatty Acids; Mitochondria; Palmitates; Neoplasms
PubMed: 36408830
DOI: 10.15252/embj.2022111268 -
Current Opinion in Chemical Biology Oct 2022Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as... (Review)
Review
Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as alkynes (CC), nitriles (CN), and carbon-deuterium (C-D) bonds, have been employed in recent years as Raman tags to detect target molecules in cells. In this article, we review some recent advances in applications using deuterated fatty acids for lipid analysis, such as investigation of tumor-selective cytotoxicity of γ-linolenic acid (GLA), simultaneous two-color imaging of stearate and oleate using deuterated and protonated alkynes, Raman hyperspectral imaging, and analyses of the physical properties of lipids through spectral unmixing of the C-D vibrational frequencies. In addition, we review some advanced methods for observing intracellular metabolic activities, such as de novo lipogenesis from deuterium-labeled precursors.
Topics: Alkynes; Carbon; Deuterium; Fatty Acids; Nitriles; Oleic Acid; Spectrum Analysis, Raman; Stearates; gamma-Linolenic Acid
PubMed: 35792373
DOI: 10.1016/j.cbpa.2022.102181 -
International Journal of Molecular... Jun 2022Tissue-specific cardiolipin fatty acyl profiles are achieved by remodeling of de novo synthesized cardiolipin, and four remodeling enzymes have thus far been identified....
Tissue-specific cardiolipin fatty acyl profiles are achieved by remodeling of de novo synthesized cardiolipin, and four remodeling enzymes have thus far been identified. We studied the enzyme phospholipase A and acyltransferase 1 (PLAAT1), and we report the discovery that it has phosphatidylcholine (PC):monolysocardiolipin (MLCL) transacylase activity. Subcellular localization was analyzed by differential centrifugation and immunoblotting. Total levels of major phospholipids, and the fatty acyl profile of cardiolipin, were analyzed in HEK293 cells expressing murine PLAAT1 using gas chromatography. Apparent enzyme kinetics of affinity-purified PLAAT1 were calculated using radiochemical enzyme assays. This enzyme was found to localize predominantly to the endoplasmic reticulum (ER) but was detected at low levels in the mitochondria-associated ER matrix. Cells expressing PLAAT1 had higher levels of total cardiolipin, but not other phospholipids, and it was primarily enriched in the saturated fatty acids myristate, palmitate, and stearate, with quantitatively smaller increases in the n-3 polyunsaturated fatty acids linolenate, eicosatrienoate, and eicosapentanoate and the monounsaturated fatty acid erucate. Affinity-purified PLAAT1 did not catalyze the transacylation of MLCL using 1-palmitoyl-2-[C]-linoleoyl-PC as an acyl donor. However, PLAAT1 had an apparent V of 1.61 μmol/min/mg protein and Km of 126 μM using [9,10-H]-distearoyl-PC as an acyl donor, and 0.61 μmol/min/mg protein and Km of 16 μM using [9,10-H]-dioleoyl-PC. PLAAT1 is therefore a novel PC:MLCL transacylase.
Topics: Acyltransferases; Animals; Cardiolipins; HEK293 Cells; Humans; Lecithins; Lysophospholipids; Mice; Phospholipases A
PubMed: 35743156
DOI: 10.3390/ijms23126714 -
Molecules (Basel, Switzerland) Jun 2022Ascites is a common complication of decompensated liver cirrhosis, and yet relatively little is known about its biochemical composition. We conducted two metabolomic...
Ascites is a common complication of decompensated liver cirrhosis, and yet relatively little is known about its biochemical composition. We conducted two metabolomic investigations, comparing the profile of ascites from 33 cirrhotic patients and postoperative peritoneal drainage fluid from 33 surgical patients (Experiment 1). The profile of paired ascites and plasma was also compared in 17 cirrhotic patients (Experiment 2). Gas chromatography−mass spectrometry-based metabolomics identified 29 metabolites that significantly characterized ascites fluid, whether postoperative drainage fluid or plasma were used as controls. Ten elevated amino acids (glutamine, proline, histidine, tyrosine, glycine, valine, threonine, methionine, lysine, phenylalanine) and seven diminished lipids (laurate, myristate, palmitate, oleate, vaccenate, stearate, cholesterol) largely comprised the cirrhotic ascites metabolomic phenotype that differed significantly (adjusted p < 0.002 to 0.03) from peritoneal drainage fluid or plasma. The pattern of upregulated amino acids in cirrhotic ascites did not indicate albumin proteolysis by peritoneal bacteria. Bidirectional clustering showed that the more severe the cirrhosis, the lower the lipid concentration in ascitic fluid. The metabolomic compartment of ascites in patients with decompensated cirrhosis is characterized by increased amino acids and decreased lipids. These novel findings have potential relevance for diagnostic purposes.
Topics: Amino Acids; Ascites; Cholesterol; Humans; Liver Cirrhosis; Metabolomics
PubMed: 35745058
DOI: 10.3390/molecules27123935 -
The Cochrane Database of Systematic... Jun 2017Pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localised injury to the skin or underlying tissue, or both. The... (Review)
Review
BACKGROUND
Pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localised injury to the skin or underlying tissue, or both. The ulcers usually arise over a bony prominence, and are recognised as a common medical problem affecting people confined to a bed or wheelchair for long periods of time. Anabolic steroids are used as off-label drugs (drugs which are used without regulatory approval) and have been used as adjuvants to usual treatment with dressings, debridement, nutritional supplements, systemic antibiotics and antiseptics, which are considered to be supportive in healing of pressure ulcers. Anabolic steroids are considered because of their ability to stimulate protein synthesis and build muscle mass. Comprehensive evidence is required to facilitate decision making, regarding the benefits and harms of using anabolic steroids.
OBJECTIVES
To assess the effects of anabolic steroids for treating pressure ulcers.
SEARCH METHODS
In March 2017 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting.
SELECTION CRITERIA
Published or unpublished randomised controlled trials (RCTs) comparing the effects of anabolic steroids with alternative treatments or different types of anabolic steroids in the treatment of pressure ulcers.
DATA COLLECTION AND ANALYSIS
Two review authors independently carried out study selection, data extraction and risk of bias assessment.
MAIN RESULTS
The review contains only one trial with a total of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV. The participants were mainly male (98.2%, 106/108) with a mean age of 58.4 (standard deviation 10.4) years in the oxandrolone group and were all male (100%, 104/104) with a mean age of 57.3 (standard deviation 11.6) years in the placebo group. This trial compared oxandrolone (20 mg/day, administered orally) with a dose of placebo (an inactive substance consisting of 98% starch and 2% magnesium stearate) and reported data on complete healing of ulcers and adverse events. There was very low-certainty evidence on the relative effect of oxandrolone on complete ulcer healing at the end of a 24-week treatment period (risk ratio RR) 0.81, 95% confidence interval (CI) 0.52 to 1.26) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, we are uncertain whether oxandrolone improves or reduces the complete healing of pressure ulcers, as we assessed the certainty of the evidence as very low.There was low-certainty evidence on the risk of non-serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 3.85, 95% CI 1.12 to 13.26) (downgraded once for imprecision and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, the treatment with oxandrolone may increase the risk of non-serious adverse events reported in participants.There was very low-certainty evidence on the risk of serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 0.54, 95% CI 0.25 to 1.17) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Of the five serious adverse events reported in the oxandrolone-treated group, none were classed by the trial teams as being related to treatment. We are uncertain whether oxandrolone increases or decreases the risk of serious adverse events as we assessed the certainty of the evidence as very low.Secondary outcomes such as pain, length of hospital stay, change in wound size or wound surface area, incidence of different type of infection, cost of treatment and quality of life were not reported in the included trial.Overall the evidence in this study was of very low quality (downgraded for imprecision and indirectness). This trial stopped early when the futility analysis (interim analysis) in the opinion of the study authors showed that oxandrolone had no benefit over placebo for improving ulcer healing.
AUTHORS' CONCLUSIONS
There is no high quality evidence to support the use of anabolic steroids in treating pressure ulcers.Further well-designed, multicenter trials, at low risk of bias, are necessary to assess the effect of anabolic steroids on treating pressure ulcers, but careful consideration of the current trial and its early termination are required when planning future research.
Topics: Female; Humans; Male; Middle Aged; Off-Label Use; Oxandrolone; Pressure Ulcer; Starch; Stearic Acids; Testosterone Congeners; Wound Healing
PubMed: 28631809
DOI: 10.1002/14651858.CD011375.pub2 -
PloS One 2023We hypothesize that synbiotic supplementation could modulate the intestinal microbiota and subsequently, improve the condition of hypothyroid patients. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We hypothesize that synbiotic supplementation could modulate the intestinal microbiota and subsequently, improve the condition of hypothyroid patients.
METHODS
Fifty-six adult hypothyroid patients were recruited to this double-blind, placebo-controlled, randomized clinical trial. The intervention was 10 weeks of synbiotic (500 mg of 109 CFU/g probiotics plus fructo-oligosaccharide, n = 28) compared to placebo (lactose, magnesium stearate, talc, and silicon dioxide, n = 28). Randomization and allocation to trial groups were carried out using random number sequences drawn from https://sealedenvelope.com/. Primary outcomes were serum thyroid stimulating hormone (TSH) and free thyroxine (FT4), and secondary outcomes were depression, quality of life, and blood pressure (BP). P-values< 0.05 were considered statistically significant.
RESULTS
Analysis on 51 patients who completed the trial showed that TSH and depression (p> 0.05) did not change significantly, while serum FT4 significantly increased in both groups (p = 0.03 and p = 0.02 in symbiotic and placebo respectively). A significant decrease in systolic BP occurred only in the synbiotic group (p = 0.05). Significant improvements occurred regarding different domains and areas of quality of life in the crude and adjusted analysis, including perceived mental health (p = 0.02), bodily pain (p = 0.02), general health perception (p = 0.002), and wellbeing (p = 0.002), which were significantly higher in the synbiotic group.
CONCLUSIONS
Ten-week supplementation with synbiotic had no favorable effect on depression and TSH, but it improved blood pressure and quality of life in patients with hypothyroidism. More trials are needed to support or reject these findings.
TRIAL REGISTRATION
IRCT20210926052583N1, Iranian Registry of Clinical Trials (IRCT), registered October 1st, 2021.
Topics: Adult; Humans; Synbiotics; Iran; Quality of Life; Hypothyroidism; Thyrotropin; Double-Blind Method
PubMed: 36745650
DOI: 10.1371/journal.pone.0277213 -
Polymers Apr 2023This study presents the development of new formulations consisting of dextran (Dex) and chitosan (Ch) matrices, with fillings such as chitosan stearate (MCh), citric...
This study presents the development of new formulations consisting of dextran (Dex) and chitosan (Ch) matrices, with fillings such as chitosan stearate (MCh), citric acid, salicylic acid, or ginger extract. These materials were characterized using Fourier-Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and mechanical tests, and evaluated for antioxidant properties, including scavenging activities, metal chelation, and ferric ion reducing power, as well as anti-inflammatory properties, measuring the binding affinity between serum albumin and the bioactive substances, which can influence their bioavailability, transport, and overall anti-inflammatory effect. Compounds in ginger such as 6-gingerol reduce inflammation by inhibiting the production of inflammatory substances, such as prostaglandin, cytokines, interleukin-1β, and pro-inflammatory transcription factor (NF-κB) and, alongside citric and salicylic acids, combat oxidative stress, stabilizes cell membranes, and promote membrane fluidity, thereby preserving membrane integrity and function. Incorporating chitosan stearate in chitosan:dextran samples created a dense, stiff film with an elastic modulus approximately seventeen times higher than for the chitosan:dextran matrix. The Dex:Ch:MCh sample exhibited low compressibility at 48.74 ± 1.64 kPa, whereas the Dex:Ch:MCh:citric acid:salicylic acid composite had a compact network, allowing for 70.61 ± 3.9% compression at 109.30 kPa. The lipid peroxidation inhibitory assay revealed that Dex:Ch:MCh:citric acid had the highest inhibition value with 83 ± 0.577% at 24 h. The study highlights that adding active substances like ginger extract and citric acid to Dex:Ch composites enhances antioxidant properties, while modified chitosan improves mechanical properties. These composites may have potential medical applications in repairing cell membranes and regulating antioxidant enzyme activities.
PubMed: 37177127
DOI: 10.3390/polym15091980 -
Scientific Reports Jan 2023Building materials with hydrophobic surfaces can exhibit increased service life by preventing moisture absorption or diffusion through their surfaces. For concrete used...
Building materials with hydrophobic surfaces can exhibit increased service life by preventing moisture absorption or diffusion through their surfaces. For concrete used in construction, this hydrophobicity can prevent the corrosion of reinforcing steel bars. Geopolymers are a new cement-free binding material that have been extensively studied to replace Portland cement. However, similar to normal concrete, geopolymers are susceptible to the intake of moisture. This paper presents the fabrication of a superhydrophobic and self-cleaning surface on a fly ash geopolymer as a method to prevent moisture intake. A composite coating of polydimethylsiloxane (PDMS) solution containing dispersed polytetrafluoroethylene (PTFE) or calcium stearate (CS) microparticles was applied by dip-coating to form the hydrophobic surface. Additionally, fly ash was incorporated with the PTFE and CS microparticles to increase surface roughness and reduce material cost. The experimental results showed that the coating containing CS microparticles yielded a hydrophobic surface with a contact angle of 140°, while those containing PTFE microparticles provided a superhydrophobic surface with a contact angle of 159°. The incorporation of fly ash resulted in increased surface roughness, leading to a larger contact angle and a smaller sliding angle. A contact angle of 153° with a sliding angle of 8.7° was observed on the PTFE/fly ash-coated surface. The cleaning process was demonstrated with a test whereby dust was removed by water droplets rolling off the surface. The tested coating exhibited self-cleaning and waterproofing properties and could thus improve the sustainability of materials in building construction.
Topics: Coal Ash; Hydrophobic and Hydrophilic Interactions; Polytetrafluoroethylene
PubMed: 36593234
DOI: 10.1038/s41598-022-27061-6 -
Pharmaceutics Aug 2022Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical...
Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical properties of mixed powders to determine the formulation and preparation factors, followed by D-optimal mixture experimental design to optimize the final parameters. The type and amount of lactose monohydrate (SuperTab®14SD, 19.53−26.91%), microcrystalline cellulose (MCC PH102, 32.86−43.31%), pre-gelatinized starch (Starch-1500, 10.96−15.91%), and magnesium stearate (0.7%) were determined according to the compressive work, stress relaxation curves, and Py value. Then, the compression mechanism of the mixed powder was investigated by the Kawakita equation, Shapiro equation, and Heckel analysis, and the mixed powder was classified as a Class-II powder. The compaction pressure (150−300 MPa) and tableting speed (1200−2400 Tab/h) were recommended. A D-optimal mixture experimental design was utilized to select the optimal formulation (No 1, 26.027% lactose monohydrate, 32.811% MCC PH102, and 15.462% pregelatinized starch) according to the drug dissolution rate, using Hyzaar® tablets as a control. Following oral administration in beagle dogs, there were no significant differences in bioavailability between the No. 1 tablet and the Hyzaar® tablet in HCTZ, losartan carboxylic acid (E-3174), and LOS-K (F < F0.05). Thus, formulation and preparation factors were determined according to the combination of the compression and mechanical properties of the mixed powder and quality of tablets, which was demonstrated to be a feasible method in direct powder compression.
PubMed: 36015367
DOI: 10.3390/pharmaceutics14081741