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The Journal of Organic Chemistry Jul 2024The [5-6-7] azatricyclic ABC core, found in several alkaloids, has been synthesized through a novel route involving ring expansion of a perhydroindolone to afford the...
The [5-6-7] azatricyclic ABC core, found in several alkaloids, has been synthesized through a novel route involving ring expansion of a perhydroindolone to afford the AC ring system and a radical B ring closure as key steps. The level of functionalization of the reported octahydro-1,7-ethanocyclohepta[]pyrroles suggests that they can serve as valuable building blocks in this alkaloid field. Also reported is the first synthesis of homomorphans by the ring enlargement of 2-azabicyclo[3.3.1]nonanes.
PubMed: 38950520
DOI: 10.1021/acs.joc.4c01090 -
PloS One 2024A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and... (Comparative Study)
Comparative Study
A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and acute liver injury is the common bile duct ligation (cBDL). Modifications of this model include ligation of the left hepatic bile duct (pBDL) or ligation of the left bile duct with the corresponding left hepatic artery (pBDL+pAL). Both modifications induce cholestasis only in the left liver lobe. After induction of total or partial cholestasis in mice, the well-being of these animals was evaluated by assessing burrowing behavior, body weight, and a distress score. To compare the pathological features of these animal models, plasma levels of liver enzymes, bile acids, bilirubin, and within the liver tissue, necrosis, fibrosis, inflammation, as well as expression of genes involved in the synthesis or transport of bile acids were assessed. The survival rate of the animals and their well-being was comparable between pBDL+pAL and pBDL. However, surgical intervention by pBDL+pAL caused confluent necrosis and collagen depositions at the edge of necrotic tissue, whereas pBDL caused focal necrosis and fibrosis in between portal areas. Interestingly, pBDL animals had a higher survival rate and their well-being was significantly improved compared to cBDL animals. On day 14 after cBDL liver aspartate, as well as alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, bile acids, and bilirubin were significantly elevated, but only glutamate dehydrogenase activity was increased after pBDL. Thus, pBDL may be primarily used to evaluate local features such as inflammation and fibrosis or regulation of genes involved in bile acid synthesis or transport but does not allow to study all systemic features of cholestasis. The pBDL model also has the advantage that fewer mice are needed, because of its high survival rate, and that the well-being of the animals is improved compared to the cBDL animal model.
Topics: Animals; Ligation; Mice; Disease Models, Animal; Cholestasis; Liver; Bile Ducts; Bile Acids and Salts; Male; Bilirubin; Mice, Inbred C57BL; Common Bile Duct
PubMed: 38950046
DOI: 10.1371/journal.pone.0303786 -
Frontiers in Immunology 2024The identification of novel, yet easily measurable biomarkers of inflammation and oxidative stress might assist in the diagnosis and management of patients with... (Meta-Analysis)
Meta-Analysis
UNLABELLED
The identification of novel, yet easily measurable biomarkers of inflammation and oxidative stress might assist in the diagnosis and management of patients with rheumatic diseases (RDs). We conducted a systematic review and meta-analysis of studies investigating the circulating concentrations of bilirubin, the end product of heme metabolism and a potent endogenous antioxidant with anti-inflammatory properties, in patients with RDs and healthy controls. The electronic databases PubMed, Scopus, and Web of Science were searched from inception to 31 December 2023 for relevant articles. We evaluated the risk of bias and the certainty of evidence using the Joanna Briggs Checklist and the Grades of Recommendation, Assessment, Development, and Evaluation Working Group system, respectively. In 17 eligible studies, all with low risk of bias, compared to controls, patients with RDs had significantly lower concentrations of total bilirubin (standard mean difference, SMD=-0.68, 95% CI -0.91 to -0.44, p<0.001; I = 92.5%, p<0.001; low certainty of evidence), direct (conjugated) bilirubin (SMD=-0.67, 95% CI -0.92 to -0.41, p<0.001; I = 81.7%, p<0.001; very low certainty of evidence), and the active antioxidant and anti-inflammatory indirect (unconjugated) form of bilirubin (SMD=-0.71, 95% CI -1.18 to -0.24, p=0.003; I = 95.1%, p<0.001; very low certainty of evidence). The results of the meta-analysis were stable in sensitivity analysis. In meta-regression, there were no significant associations between the SMD of total bilirubin and several clinical and demographic characteristics, including age, male to female ratio, number of participants, liver enzymes and erythrocyte sedimentation rate. In subgroup analysis, the SMD of total bilirubin was significant across a range of RDs, including rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, and myositis. Therefore, the results of our systematic review and meta-analysis suggests that the reductions in bilirubin concentrations observed in patients with RDs reflect a state of impaired antioxidant and anti-inflammatory defence due to bilirubin consumption and highlight the promising role of this endogenous product as a biomarker of RDs.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42023500649.
Topics: Female; Humans; Bilirubin; Biomarkers; Oxidative Stress; Rheumatic Diseases; Male
PubMed: 38947324
DOI: 10.3389/fimmu.2024.1369284 -
Frontiers in Immunology 2024Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from...
Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.
BACKGROUND
Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.
METHODS
Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following heme treatment was also examined.
RESULTS
Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.
CONCLUSIONS
Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
Topics: Humans; Heme; Burns; Male; Adult; Female; Middle Aged; Cytokines; Wounds and Injuries; Young Adult; Aged; THP-1 Cells; Leukocytes, Mononuclear; Biomarkers; Lipopolysaccharides; Heme Oxygenase-1
PubMed: 38947312
DOI: 10.3389/fimmu.2024.1416820 -
ACS Central Science Jun 2024Electron transport chains (ETCs) are ubiquitous in nearly all living systems. Replicating the complexity and control inherent in these multicomponent systems using...
Electron transport chains (ETCs) are ubiquitous in nearly all living systems. Replicating the complexity and control inherent in these multicomponent systems using ensembles of small molecules opens up promising avenues for molecular therapeutics, catalyst design, and the development of innovative energy conversion and storage systems. Here, we present a noncovalent, multistep artificial electron transport chains comprising cyclo[8]pyrrole (), a -aryl hexaphyrin(1.0.1.0.1.0) (naphthorosarin ), and the small molecules I and trifluoroacetic acid (TFA). Specifically, we show that 1) electron transfer occurs from to give I upon the addition of I, 2) proton-coupled electron transfer (PCET) from to give and upon the addition of TFA to a dichloromethane mixture of and , and 3) that further, stepwise treatment of and with I and TFA promotes electron transport from to give first I and then and . The present findings are substantiated through UV-vis-NIR, H NMR, electron paramagnetic resonance (EPR) spectroscopic analyses, cyclic voltammetry studies, and DFT calculations. Single-crystal structure analyses were used to characterize compounds in varying redox states.
PubMed: 38947209
DOI: 10.1021/acscentsci.4c00165 -
Pulmonary Medicine 2024Bilothorax is defined as the presence of bile in the pleural space. It is a rare condition, and diagnosis is confirmed with a pleural fluid-to-serum bilirubin ratio of...
BACKGROUND
Bilothorax is defined as the presence of bile in the pleural space. It is a rare condition, and diagnosis is confirmed with a pleural fluid-to-serum bilirubin ratio of >1.
METHODS
The PubMed, Embase, Google Scholar, and CINAHL databases were searched using predetermined Boolean parameters. The systematic literature review was done per PRISMA guidelines. Retrospective studies, case series, case reports, and conference abstracts were included. The patients with reported pleural fluid analyses were pooled for fluid parameter data analysis.
RESULTS
Of 838 articles identified through the inclusion criteria and removing 105 duplicates, 732 articles were screened with abstracts, and 285 were screened for full article review. After this, 123 studies qualified for further detailed review, and of these, 115 were pooled for data analysis. The mean pleural fluid and serum bilirubin levels were 72 mg/dL and 61 mg/dL, respectively, with a mean pleural fluid-to-serum bilirubin ratio of 3.47. In most cases, the bilothorax was reported as a subacute or remote complication of hepatobiliary surgery or procedure, and traumatic injury to the chest or abdomen was the second most common cause. Tube thoracostomy was the main treatment modality (73.83%), followed by serial thoracentesis. Fifty-two patients (51.30%) had associated bronchopleural fistulas. The mortality was considerable, with 18/115 (15.65%) reported death. Most of the patients with mortality had advanced hepatobiliary cancer and were noted to die of complications not related to bilothorax.
CONCLUSION
Bilothorax should be suspected in patients presenting with pleural effusion following surgical manipulation of hepatobiliary structures or a traumatic injury to the chest. This review is registered with CRD42023438426.
Topics: Female; Humans; Bile; Bilirubin; Pleural Effusion; Thoracentesis; Thoracostomy; Aged
PubMed: 38947176
DOI: 10.1155/2024/3973056 -
Frontiers in Cellular and Infection... 2024In infants with cholestasis, variations in the enterohepatic circulation of bile acids and the gut microbiota (GM) characteristics differ between those with biliary...
INTRODUCTION
In infants with cholestasis, variations in the enterohepatic circulation of bile acids and the gut microbiota (GM) characteristics differ between those with biliary atresia (BA) and non-BA, prompting a differential analysis of their respective GM profiles.
METHODS
Using 16S rDNA gene sequencing to analyse the variance in GM composition among three groups: infants with BA (BA group, n=26), non-BA cholestasis (IC group, n=37), and healthy infants (control group, n=50). Additionally, correlation analysis was conducted between GM and liver function-related indicators.
RESULTS
Principal component analysis using Bray-Curtis distance measurement revealed a significant distinction between microbial samples in the IC group compared to the two other groups. IC-accumulated co-abundance groups exhibited positive correlations with aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, and total bile acid serum levels. These correlations were notably reinforced upon the exclusion of microbial samples from children with BA.
CONCLUSION
The varying "enterohepatic circulation" status of bile acids in children with BA and non-BA cholestasis contributes to distinct GM structures and functions. This divergence underscores the potential for targeted GM interventions tailored to the specific aetiologies of cholestasis.
Topics: Humans; Biliary Atresia; Gastrointestinal Microbiome; Cholestasis; Infant; Bile Acids and Salts; Male; Female; RNA, Ribosomal, 16S; Bilirubin; Bacteria; DNA, Ribosomal; Feces
PubMed: 38947125
DOI: 10.3389/fcimb.2024.1402329 -
Physiologia Plantarum 2024Maximal sunlight intensity varies diurnally due to the earth's rotation. Whether this slow diurnal pattern influences the photoprotective capacity of plants throughout...
Maximal sunlight intensity varies diurnally due to the earth's rotation. Whether this slow diurnal pattern influences the photoprotective capacity of plants throughout the day is unknown. We investigated diurnal variation in NPQ, along with NPQ capacity, induction, and relaxation kinetics after transitions to high light, in tomato plants grown under diurnal parabolic (DP) or constant (DC) light intensity regimes. DP light intensity peaked at midday (470 μmol m s while DC stayed constant at 300 μmol m s at a similar 12-hour photoperiod and daily light integral. NPQs were higher in the morning and afternoon at lower light intensities in DP compared to DC, except shortly after dawn. NPQ capacity increased from midday to the end of the day, with higher values in DP than in DC. At high light Φ did not vary throughout the day, while Φ varied consistently with NPQ capacity. Reduced Φ suggested less susceptibility to photodamage at the end of the day. NPQ induction was faster at midday than at the start of the day and in DC than in DP, with overshoot occurring in the morning and midday but not at the end of the day. NPQ relaxation was faster in DP than in DC. The xanthophyll de-epoxidation state and reduced demand for photochemistry could not explain the observed diurnal variations in photoprotective capacity. In conclusion, this study showed diurnal variation in regulated photoprotective capacity at moderate growth light intensity, which was not explained by instantaneous light intensity or increasing photoinhibition over the day and was influenced by acclimation to constant light intensity.
Topics: Solanum lycopersicum; Circadian Rhythm; Light; Photosynthesis; Photoperiod; Xanthophylls; Sunlight; Chlorophyll; Photosystem II Protein Complex; Kinetics; Plant Leaves
PubMed: 38945685
DOI: 10.1111/ppl.14410 -
Physiologia Plantarum 2024Chlorophyll (Chl) plays a crucial role in photosynthesis, functioning as a photosensitizer. As an integral component of this process, energy absorbed by this pigment is...
Chlorophyll (Chl) plays a crucial role in photosynthesis, functioning as a photosensitizer. As an integral component of this process, energy absorbed by this pigment is partly emitted as red fluorescence. This signal can be readily imaged by fluorescence microscopy and provides a visualization of photosynthetic activity. However, due to limited resolution, signals cannot be assigned to specific subcellular/organellar membrane structures. By correlating fluorescence micrographs with transmission electron microscopy, researchers can identify sub-cellular compartments and membranes, enabling the monitoring of Chl distribution within thylakoid membrane substructures in cyanobacteria, algae, and higher plant single cells. Here, we describe a simple and effective protocol for correlative light-electron microscopy (CLEM) based on the autofluorescence of Chl and demonstrate its application to selected photosynthetic model organisms. Our findings illustrate the potential of this technique to identify areas of high Chl concentration and photochemical activity, such as grana regions in vascular plants, by mapping stacked thylakoids.
Topics: Thylakoids; Chlorophyll; Photosynthesis; Microscopy, Fluorescence; Microscopy, Electron, Transmission
PubMed: 38945684
DOI: 10.1111/ppl.14417 -
Journal of Hazardous Materials Jun 2024Extracellular electron transfer was essential for degrading recalcitrant pollutants by anaerobic digestion (AD). Therefore, existing studies improved AD efficiency by...
Extracellular electron transfer was essential for degrading recalcitrant pollutants by anaerobic digestion (AD). Therefore, existing studies improved AD efficiency by enhancing the electron transfer from microbes-to-pollutants or inter-microbes. This study synthesized a novel Fe, N co-doped biochar (Fe, N-BC), which could enhance both the microbes-to-pollutants and inter-microbes electron transfer in AD. Detailed characterization data indicated that Fe, N-BC has an ordered mesoporous structure, high specific surface area (463.46 m/g), and abundant redox functional groups (Fe/Fe, pyrrolic-N), which translate into excellent biocompatibility and electrochemical properties of Fe, N-BC. By adding Fe, N-BC, the stability and efficiency of the medium-temperature AD system in the treatment of methyl orange (MO) wastewater were improved: obtained a high degradation efficiency of MO (96.8 %) and enhanced the methane (CH) production by 65 % compared to the control group. Meanwhile, Fe, N-BC reduced the accumulation of volatile fatty acids in the AD system, and the activity of anaerobic granular sludge electron transport system and coenzyme F was enhanced. In addition, Fe, N-BC showed positive enrichment of azo dyes decolorization bacteria (Georgenia) and direct interspecies electron transfer (DIET) synergistic partners (Syntrophobacter, Methanosarcina). Overall, the rapid degradation of MO and enhanced CH production in AD systems by Fe, N-BC is associated with enhancing two electronic pathways, i.e., microbes to MO and DIET between syntrophic bacteria and methanogenic archaea. This study introduced an enhanced "two-pathways of electron transfer" theory, realized by Fe, N-BC. These findings provided new insights into the interactions within AD systems and offer strategies for enhancing their performance with recalcitrant pollutants.
PubMed: 38944989
DOI: 10.1016/j.jhazmat.2024.135030