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Biomolecules Jun 2024Plasmacytoid dendritic cells (pDCs) are vital players in antiviral immune responses because of their high levels of IFN-α secretion. However, this attribute has also...
Plasmacytoid dendritic cells (pDCs) are vital players in antiviral immune responses because of their high levels of IFN-α secretion. However, this attribute has also implicated them as critical factors behind the immunopathogenesis of inflammatory diseases, and no currently available therapy can efficiently inhibit pDCs' aberrant activation. Mesenchymal stromal cells (MSCs) possess stromal immunomodulatory functionality, regulating immune cell activation through several mechanisms, including the adenosinergic (CD39/CD73/adenosine) pathway. The IFN-γ preconditioning of bone marrow MSCs improves their inhibitory properties for therapy applications; however, isolating human gingival tissue-derived MSCs (hGMSCs) is more accessible. These cells have shown better immunomodulatory effects, yet the outcome of IFN-γ preconditioning and its impact on the adenosinergic pathway has not been evaluated. This study first validated the immunoregulatory properties of primary-cultured hGMSCs, and the results showed that IFN-γ preconditioning strengthens CD39/CD73 coexpression, adenosine production, and the regulatory properties of hGMSC, which were confirmed by describing for the first time their ability to reduce pDC activation and their IFN-α secretion and to increase the frequency of CD73+ pDC. In addition, when CD73's enzymatic activity was neutralized in hGMSCs, adenosine production and the IFN-γ preconditioning effect were restrained. This evidence might be applied to design hGMSCs- and adenosine-based immunotherapeutic strategies for treating inflammatory disorders that are associated with pDC overactivation.
Topics: Humans; Mesenchymal Stem Cells; Dendritic Cells; Adenosine; Interferon-gamma; Gingiva; 5'-Nucleotidase; Cells, Cultured; Apyrase; GPI-Linked Proteins
PubMed: 38927060
DOI: 10.3390/biom14060658 -
BMC Pulmonary Medicine Jun 2024Sedation during flexible bronchoscopy (FB) should maintain an adequate respiratory drive, ensure maximum comfort for the patient, and warrant that the objectives of the... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Dexmedetomidine-ketamine combination versus fentanyl-midazolam for patient sedation during flexible bronchoscopy: a prospective, single-blind, randomized controlled trial.
BACKGROUND
Sedation during flexible bronchoscopy (FB) should maintain an adequate respiratory drive, ensure maximum comfort for the patient, and warrant that the objectives of the procedure are achieved. Nevertheless, the optimal sedation method for FB has yet to be established. This study aimed to compare the standard recommended combination of midazolam-fentanyl (MF) with that of dexmedetomidine-ketamine (DK) for patient sedation during FB.
METHODS
Patients subjected to FB were randomly assigned to a DK (n = 25) and an MF group (n = 25). The primary outcome was the rate of critical desaturation events (arterial oxygen saturation < 80% with nasal oxygen supply 2 L/min). Secondary outcomes included sedation depth, hemodynamic complications, adverse events, and patient and bronchoscopist satisfaction.
RESULTS
The incidence rates of critical desaturation events were similar between the two groups (DK: 12% vs. MF: 28%, p = 0.289). DK achieved deeper maximum sedation levels (higher Ramsay - lower Riker scale; p < 0.001) and was associated with longer recovery times (p < 0.001). Both groups had comparable rates of hemodynamic and other complications. Patient satisfaction was similar between the two groups, but bronchoscopist satisfaction was higher with the DK combination (p = 0.033).
CONCLUSION
DK demonstrated a good safety profile in patients subjected to FB and achieved more profound sedation and better bronchoscopist satisfaction than the standard MF combination without increasing the rate of adverse events.
Topics: Humans; Dexmedetomidine; Bronchoscopy; Fentanyl; Male; Midazolam; Ketamine; Female; Middle Aged; Prospective Studies; Hypnotics and Sedatives; Single-Blind Method; Aged; Patient Satisfaction; Adult; Conscious Sedation
PubMed: 38926768
DOI: 10.1186/s12890-024-02988-w -
Scientific Reports Jun 2024Opioids are the gold standard for the treatment of chronic pain but are limited by adverse side effects. In our earlier work, we showed that Heat shock protein 90...
Opioids are the gold standard for the treatment of chronic pain but are limited by adverse side effects. In our earlier work, we showed that Heat shock protein 90 (Hsp90) has a crucial role in regulating opioid signaling in spinal cord; Hsp90 inhibition in spinal cord enhances opioid anti-nociception. Building on these findings, we injected the non-selective Hsp90 inhibitor KU-32 by the intrathecal route into male and female CD-1 mice, showing that morphine anti-nociceptive potency was boosted by 1.9-3.5-fold in acute and chronic pain models. At the same time, tolerance was reduced from 21-fold to 2.9 fold and established tolerance was rescued, while the potency of constipation and reward was unchanged. These results demonstrate that spinal Hsp90 inhibition can improve the therapeutic index of morphine. However, we also found that systemic non-selective Hsp90 inhibition blocked opioid pain relief. To avoid this effect, we used selective small molecule inhibitors and CRISPR gene editing to identify 3 Hsp90 isoforms active in spinal cord (Hsp90α, Hsp90β, and Grp94) while only Hsp90α was active in brain. We thus hypothesized that a systemically delivered selective inhibitor to Hsp90β or Grp94 could selectively inhibit spinal cord Hsp90 activity, resulting in enhanced opioid therapy. We tested this hypothesis using intravenous delivery of KUNB106 (Hsp90β) and KUNG65 (Grp94), showing that both drugs enhanced morphine anti-nociceptive potency while rescuing tolerance. Together, these results suggest that selective inhibition of spinal cord Hsp90 isoforms is a novel, translationally feasible strategy to improve the therapeutic index of opioids.
Topics: Animals; HSP90 Heat-Shock Proteins; Spinal Cord; Mice; Analgesics, Opioid; Male; Female; Morphine; Protein Isoforms; Drug Tolerance; Chronic Pain; Disease Models, Animal; Injections, Spinal
PubMed: 38926482
DOI: 10.1038/s41598-024-65637-6 -
Nature Communications Jun 2024Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples,...
Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.
Topics: Humans; RNA Editing; Adenosine; Adenosine Deaminase; Brain; Inosine; RNA-Binding Proteins; Autopsy; Prefrontal Cortex; Postmortem Changes; Male
PubMed: 38926387
DOI: 10.1038/s41467-024-49268-z -
Nature Communications Jun 2024METTL3 is the catalytic subunit of the methyltransferase complex, which mediates mA modification to regulate gene expression. In addition, METTL3 regulates transcription...
METTL3 is the catalytic subunit of the methyltransferase complex, which mediates mA modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated mA sites. In summary, our results report a coordination of mA-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.
Topics: Methyltransferases; Chromatin; Cellular Senescence; Humans; Stress Granules; Hexokinase; RNA, Messenger; Adenosine; HEK293 Cells; Metabolic Reprogramming; Phase Separation
PubMed: 38926365
DOI: 10.1038/s41467-024-49745-5 -
BMJ Open Gastroenterology Jun 2024To estimate the strength of association between exposure to selected classes of prescribed medications and the risk of developing iron deficiency anaemia (IDA),...
OBJECTIVE
To estimate the strength of association between exposure to selected classes of prescribed medications and the risk of developing iron deficiency anaemia (IDA), specifically considering oral anticoagulants (OACs), antidepressants, antiplatelet agents, proton pump inhibitors (PPIs) and non-steroidal anti-inflammatories.
DESIGN
A case-control study involving the analysis of community repeat prescriptions among subjects referred with IDA, and unmatched controls referred as gastroenterology fast-tracks for other indications. Multivariable logistic regression modelling was used to calculate ORs for the association between IDA presentation and each medication class, adjusted for age, sex and coprescribing. For those classes showing significance, it was also used to calculate risk differences between those in the IDA group with or without haemorrhagic lesions on investigation.
RESULTS
A total of 1210 cases were analysed-409 in the IDA group, and 801 in the control group. Significant associations were identified between presentation with IDA and long-term exposure to PPIs (OR 3.29, 95% CI: 2.47 to 4.41, p<0.001) and to OACs (OR 2.04, 95% CI: 1.29 to 3.24, p=0.002). IDA was not associated with long-term exposure to any of the other three drug classes. In contrast to the relationship with PPIs, the association with OACs was primarily in the IDA sub-group with haemorrhagic lesions.
CONCLUSION
Long-term exposure to PPIs and OACs are independently associated with the risk of developing IDA. There are grounds for considering that these associations may be causal, though the underlying mechanisms probably differ.
Topics: Humans; Anemia, Iron-Deficiency; Case-Control Studies; Female; Male; Proton Pump Inhibitors; Middle Aged; Aged; Anticoagulants; Risk Factors; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Platelet Aggregation Inhibitors; Adult; Logistic Models; Aged, 80 and over
PubMed: 38926132
DOI: 10.1136/bmjgast-2023-001305 -
Biological & Pharmaceutical Bulletin 2024We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel...
We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel adjusted to pH 7 with 1 M NaOH aq or 1 M HCl aq provided a translucent hydrogel with a lamellar liquid crystal structure in the concentration region of decanoic acid ≥12% and arginine ≤9%. Rheological measurements showed that C10/Arg gel is a viscoelastic material with both solid and liquid properties, with elasticity being dominant over viscosity in the low shear stress region. The skin permeability of hydrocortisone (HC) and indomethacin (IM) from C10/Arg gels was investigated in vitro using hairless mouse skin and compared to control formulation drug suspensions (IM or HC) in water. The cumulative permeation amount of HC and IM from the C10/Arg gel at 10 h after application was approximately 16 and 11 times higher than that of the control, respectively. On the other hand, the flux of IM decreased with increasing arginine concentration, likely due to the acid-base interaction between Arg and IM in C10/Arg gel. Adequate drug skin permeation enhancement by C10/Arg gel requires optimizing the gel composition for each specific drug.
Topics: Animals; Arginine; Hydrogels; Mice, Hairless; Skin Absorption; Administration, Cutaneous; Skin; Indomethacin; Decanoic Acids; Hydrocortisone; Mice; Rheology; Permeability; Male
PubMed: 38925923
DOI: 10.1248/bpb.b24-00078 -
JAMA Network Open Jun 2024Opioid medications are commonly prescribed for the management of acute postoperative pain. In light of increasing awareness of the potential risks of opioid prescribing,...
IMPORTANCE
Opioid medications are commonly prescribed for the management of acute postoperative pain. In light of increasing awareness of the potential risks of opioid prescribing, data are needed to define the procedures and populations for which most opioid prescribing occurs.
OBJECTIVE
To identify the surgical procedures accounting for the highest proportion of opioids dispensed to adults after surgery in the United States.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional analysis of the 2020-2021 Merative MarketScan Commercial and Multi-State Databases, which capture medical and pharmacy claims for 23 million and 14 million annual privately insured patients and Medicaid beneficiaries, respectively, included surgical procedures for individuals aged 18 to 64 years with a discharge date between December 1, 2020, and November 30, 2021. Procedures were identified using a novel crosswalk between 3664 Current Procedural Terminology codes and 1082 procedure types. Data analysis was conducted from November to December 2023.
MAIN OUTCOMES AND MEASURES
The total amount of opioids dispensed within 3 days of discharge from surgery across all procedures in the sample, as measured in morphine milligram equivalents (MMEs), was calculated. The primary outcome was the proportion of total MMEs attributable to each procedure type, calculated separately among procedures for individuals aged 18 to 44 years and those aged 45 to 64 years.
RESULTS
Among 1 040 934 surgical procedures performed (mean [SD] age of patients, 45.5 [13.3] years; 663 609 [63.7%] female patients), 457 016 (43.9%) occurred among individuals aged 18 to 44 years and 583 918 (56.1%) among individuals aged 45 to 64 years. Opioid prescriptions were dispensed for 503 058 procedures (48.3%). Among individuals aged 18 to 44 years, cesarean delivery accounted for the highest proportion of total MMEs dispensed after surgery (19.4% [11 418 658 of 58 825 364 MMEs]). Among individuals aged 45 to 64 years, 4 of the top 5 procedures were common orthopedic procedures (eg, arthroplasty of knee, 9.7% of total MMEs [5 885 305 of 60 591 564 MMEs]; arthroscopy of knee, 6.5% [3 912 616 MMEs]).
CONCLUSIONS AND RELEVANCE
In this cross-sectional study of the distribution of postoperative opioid prescribing in the United States, a small number of common procedures accounted for a large proportion of MMEs dispensed after surgery. These findings suggest that the optimal design and targeting of surgical opioid stewardship initiatives in adults undergoing surgery should focus on the procedures that account for the most opioid dispensed following surgery over the life span, such as childbirth and orthopedic procedures. Going forward, systems that provide periodic surveillance of opioid prescribing and associated harms can direct quality improvement initiatives to reduce opioid-related morbidity and mortality.
Topics: Humans; Analgesics, Opioid; Adult; Female; Middle Aged; Male; Cross-Sectional Studies; Pain, Postoperative; Practice Patterns, Physicians'; Patient Discharge; United States; Adolescent; Young Adult; Drug Prescriptions; Surgical Procedures, Operative
PubMed: 38922619
DOI: 10.1001/jamanetworkopen.2024.17651 -
Brazilian Dental Journal 2024The aim of this clinical, prospective, randomized, and parallel study was to evaluate different in-office treatments for dentin hypersensitivity (DH). One hundred... (Randomized Controlled Trial)
Randomized Controlled Trial
The aim of this clinical, prospective, randomized, and parallel study was to evaluate different in-office treatments for dentin hypersensitivity (DH). One hundred ninety-two teeth with non-cavitated root exposures were treated using different desensitizers: fluoride varnish (Duraphat - FLU); bioactive ceramic solution (Biosilicate - BIOS); universal self-etching adhesive (Single Bond Universal - SBU); bioactive photoactivated varnish (PRG filler - SPRG). The degree of DH was analyzed using a visual analog scale (VAS) and computerized visual scale (CoVAS), before treatments and after 7, 15, and 30 days from the first session. Comparisons among desensitizers were performed using the Kruskal-Wallis and Dunn's tests. Friedman test was used to compare between times (p ≤ 0.05). Comparing desensitizers FLU presented a higher value of DH than BIOS using VAS at 7 days, however, no differences were found using CoVAS analysis. Comparing times, BIOS and SBU showed a reduction in DH after 7 days and SBU showed a reduction at 30 days compared to 7 days using VAS. FLU and SPRG groups reduced DH from 15 days to 30 days using VAS. There was a reduction in DH for FLU, BIOS, and SBU after 7 days and for BIOS this reduction also occurred at 30 days when compared to 15 days using CoVAS. SPRG group showed a reduction from 15 to 30 days. All desensitizers tested were able to reduce the initial sensitivity. The bioactive ceramic solution reduced the DH gradually after 30 days using computerized analysis.
Topics: Humans; Dentin Sensitivity; Dentin Desensitizing Agents; Male; Female; Prospective Studies; Adult; Treatment Outcome; Middle Aged; Fluorides, Topical
PubMed: 38922247
DOI: 10.1590/0103-6440202405487 -
Critical Care Science 2024Boswellia serrata is an herbal extract from the Boswellia serrata tree that has anti-inflammatory and analgesic properties and alleviates pain caused by rheumatoid...
Boswellia serrata is an herbal extract from the Boswellia serrata tree that has anti-inflammatory and analgesic properties and alleviates pain caused by rheumatoid arthritis, gout, osteoarthritis, and sciatica. Syndrome of inappropriate antidiuretic hormone secretion accompanied by hyponatremia, seizures, and rhabdomyolysis as a manifestation of Boswellia serrata intoxication has not been reported previously. A 38-year-old female suffered clinically isolated syndrome and has since been regularly taking B. serrata capsules (200mg/d) to strengthen her immune system. She experienced hypersensitivity to light, ocular pain, nausea, dizziness, and lower limb weakness four days after receiving her first BNT162b2 vaccine dose, and she increased the dosage of B. serrata to five capsules (1000mg/d) one week after vaccination. After taking B. serrata at a dosage of 1000mg/d for 3 weeks, she was admitted to the intensive care unit because of a first, unprovoked generalized tonic-clonic seizure. The patient's workup revealed syndrome of inappropriate antidiuretic hormone secretion, which resolved completely upon treatment and discontinuation of B. serrata. In summary, B. serrata potentially causes syndrome of inappropriate antidiuretic hormone secretion when it is taken at high doses. Patients should not self-medicate.
Topics: Humans; Female; Adult; Inappropriate ADH Syndrome; Hyponatremia; Rhabdomyolysis; Seizures; Boswellia; Plant Extracts
PubMed: 38922237
DOI: 10.62675/2965-2774.20240049-en