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Stem Cell Research & Therapy Jul 2024Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation...
BACKGROUND
Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation.
METHODS
MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography.
RESULT
Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p < 0.05). Western blotting revealed the significant reduction of Rab8 and p-FAK in 3-MA-treated MSCs (p < 0.05), indicating the inhibition of TNT assembly and vesicle transport. Likewise, the stimulation of autophagy increased autophagic flux and mitochondrial membrane integrity compared to 3-MA-treated MSCs. Despite these findings, protein levels of mitochondrial membrane Miro1 and 2 were unchanged after autophagy inhibition/stimulation (p > 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator.
CONCLUSIONS
In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies.
Topics: Mesenchymal Stem Cells; Autophagy; Mitochondria; Adenine; Humans; Nanotubes; Apoptosis; Animals; Metformin; Cells, Cultured; Wnt Signaling Pathway; Cell Membrane Structures
PubMed: 38956646
DOI: 10.1186/s13287-024-03813-1 -
Molecular Brain Jul 2024Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol... (Review)
Review
Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol for GBM patients, there is still a poor prognosis in these patients. Temozolomide (TMZ) as a first-line therapeutic agent in GBM can easily cross from the blood-brain barrier to inhibit tumor cell proliferation. However, there is a high rate of TMZ resistance in GBM patients. Since, there are limited therapeutic choices for GBM patients who develop TMZ resistance; it is required to clarify the molecular mechanisms of chemo resistance to introduce the novel therapeutic targets. MicroRNAs (miRNAs) regulate chemo resistance through regulation of drug metabolism, absorption, DNA repair, apoptosis, and cell cycle. In the present review we discussed the role of miRNAs in TMZ response of GBM cells. It has been reported that miRNAs mainly induced TMZ sensitivity by regulation of signaling pathways and autophagy in GBM cells. Therefore, miRNAs can be used as the reliable diagnostic/prognostic markers in GBM patients. They can also be used as the therapeutic targets to improve the TMZ response in GBM cells.
Topics: Humans; Temozolomide; Glioblastoma; MicroRNAs; Drug Resistance, Neoplasm; Brain Neoplasms; Animals; Dacarbazine; Autophagy; Gene Expression Regulation, Neoplastic
PubMed: 38956588
DOI: 10.1186/s13041-024-01113-6 -
BMC Pediatrics Jul 2024Although recent discoveries regarding the biomarkers of newborn screening (NBS) programs by tandem mass spectrometry (MS/MS) highlight the critical need to establish...
OBJECTIVES
Although recent discoveries regarding the biomarkers of newborn screening (NBS) programs by tandem mass spectrometry (MS/MS) highlight the critical need to establish reference intervals (RIs) specifically for preterm infants, no such RIs has been formally published yet. This study addressed the gap by offering a comprehensive set of reference intervals (RIs) for preterm neonates, and illustrating the dynamic changes of each biomarker with age.
DESIGN AND METHODS
The NBS data of 199,693 preterm newborns (< 37 weeks of gestation) who met the inclusion and exclusion criteria from the NNSCP database were included in study analysis. The birth weight stratified dynamic trend of each biomarker were captured by their concentrations over age. Reference partitions were determined by the method of Harris and Boyd. RIs, corresponding to the 2.5th and 97.5th percentiles, as well as the 0.5th, 25th, 50th, 75th and 99.5th percentiles were calculated using a non-parametric rank approach.
RESULTS
Increasing birth weight is associated with an elevation in the levels of arginine, citrulline, glycine, leucine and isobarics, methionine, ornithine, phenylalanine, and valine, whereas the levels of alanine, proline and tyrosine decrease. Additionally, two short-chain acylcarnitines (butyrylcarnitine + isobutyrylcarnitine and isovalerylcarnitine + methylbutyrylcarnitine) and a median-chain acylcarnitine (octenoylcarnitine) decrease, while four long-chain acylcarnitines (tetradecanoylcarnitine, palmitoylcarnitine, palmitoleylcarnitine and oleoylcarnitine) increase with increasing birth weight. Age impacts the levels of all MS/MS NBS biomarkers, while sex only affects the level of malonylcarnitine + 3-hydroxybutyrylcarnitine (C3-DC + C4-OH) in very low birth weight preterm neonates.
CONCLUSION
The current study developed reference intervals (RIs) specific to birth weight, age, and/or sex for 35 MS/MS biomarkers, which can help in the timely evaluation of the health and disease of preterm neonates.
Topics: Humans; Infant, Newborn; Neonatal Screening; Reference Values; Male; Female; Tandem Mass Spectrometry; Biomarkers; Infant, Premature; Retrospective Studies; Dried Blood Spot Testing; China; Carnitine; Birth Weight; East Asian People
PubMed: 38956494
DOI: 10.1186/s12887-024-04865-1 -
BMC Infectious Diseases Jul 2024Severe COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a...
BACKGROUND
Severe COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a biomarker indicated severity of disease and, in particular, if variable expression of angiotensin converting enzyme 2 (ACE2) in blood might clarify this difference in risk and of post COVID -19 conditions (PCC).
METHODS
The IRB-approved study compared patients hospitalized with severe COVID-19 to healthy controls. Severe infection was defined requiring oxygen or increased oxygen need from baseline at admission with positive COVID-19 PCR. A single blood sample was obtained from patients within a day of admission. ACE2 RNA expression in blood cells was measured by an RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-9 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10.
RESULTS
Forty-eight patients and 72 healthy controls were recruited during the pandemic. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID-19 but common in controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculopathy (MMP-9) were additionally elevated. ACE2 RNA expression during severe COVID-19 often responded within hours to convalescent plasma. Analogous to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID-19 (the renin-angiotensin system (RAS), fibrosis and vasculopathy) initiate or promote post-COVID-19 conditions (PCC) in susceptible individuals.
CONCLUSIONS
This work elucidates biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.
Topics: Humans; COVID-19; Angiotensin-Converting Enzyme 2; Male; Female; Middle Aged; Leukocytes, Mononuclear; Aged; SARS-CoV-2; Adult; Biomarkers; Tissue Inhibitor of Metalloproteinase-1; Matrix Metalloproteinase 9; Severity of Illness Index; Case-Control Studies; Peptidyl-Dipeptidase A
PubMed: 38956476
DOI: 10.1186/s12879-024-09321-0 -
BMC Anesthesiology Jul 2024Nefopam and propacetamol are the most commonly used analgesics in postoperative multimodal analgesic regimens. Distinct mechanisms are involved in each drug's... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Comparison of analgesic effectiveness between nefopam and propacetamol in living kidney donors following rectus sheath block after hand-assisted living donor nephrectomy: a prospective, randomized controlled trial.
BACKGROUND
Nefopam and propacetamol are the most commonly used analgesics in postoperative multimodal analgesic regimens. Distinct mechanisms are involved in each drug's anti-nociceptive effects. No studies have compared pain relief efficacy between the two drugs in patients undergoing transplantation surgery. Here, we investigated whether the administration of nefopam or propacetamol to healthy living kidney donors who underwent rectus sheath block (RSB) for parietal pain could reduce the subsequent opioid dose necessary to produce adequate analgesia.
METHODS
This prospective, randomized controlled trial included 72 donors undergoing elective hand-assisted living donor nephrectomy into two groups: propacetamol (n = 36) and nefopam (n = 36). Intraoperative RSB was performed in all enrolled donors. The primary outcome was the total volume of intravenous opioid-based patient-controlled analgesia (PCA) used on postoperative day 1 (POD 1). Additionally, the Numeric Rating Scale scores for flank (visceral) and umbilicus (parietal) pain at rest and during coughing were compared, and the Korean adaptation of the Quality of Recovery-15 Questionnaire (QoR-15 K) was evaluated on POD 1.
RESULTS
Both groups had similar preoperative and intraoperative characteristics. On POD 1, the total amount of PCA infusion was significantly lower in the nefopam group than in the propacetamol group (44.5 ± 19.3 mL vs. 70.2 ± 29.0 mL; p < 0.001). This group also reported lower pain scores at the flank and umbilical sites and required fewer rescue doses of fentanyl in the post-anesthesia care unit. However, pain scores and fentanyl consumption in the ward were comparable between groups. The QoR-15 K scores were similar between groups; there were substantial improvements in breathing, pain severity, and anxiety/depression levels in the nefopam group. The incidences of postoperative complications, including sweating and tachycardia, were similar between groups.
CONCLUSION
Compared with propacetamol, nefopam provides a greater analgesic effect for visceral pain and enhances the effects of blocks that reduce the opioid requirement in living kidney donors with parietal pain managed by RSB.
TRIAL REGISTRATION
The trial was registered prior to patient enrollment in the clinical trial database using the Clinical Research Information Service (registration no. KCT0007351 , Date of registration 03/06/2022).
Topics: Humans; Nefopam; Nephrectomy; Male; Female; Prospective Studies; Living Donors; Pain, Postoperative; Acetaminophen; Nerve Block; Adult; Analgesics, Non-Narcotic; Middle Aged; Analgesics, Opioid; Analgesia, Patient-Controlled; Rectus Abdominis
PubMed: 38956473
DOI: 10.1186/s12871-024-02607-5 -
BMC Anesthesiology Jul 2024As a novel regional analgesic technique, ultrasound-guided pericapsular nerve group (PENG) block has some potential advantages, and we designed a randomized clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of pericapsular nerve group block and suprainguinal fascia iliaca block on postoperative analgesia and stress response in elderly patients undergoing hip arthroplasty: a prospective randomized controlled double-blind trial.
BACKGROUND
As a novel regional analgesic technique, ultrasound-guided pericapsular nerve group (PENG) block has some potential advantages, and we designed a randomized clinical trial (RCT) to investigate whether the ultrasound-guided PENG block combined with general anesthesia can better reduce stress response, maintain intraoperative hemodynamic stability, and reduce postoperative analgesia in elderly hip arthroplasty compared with ultrasound-guided suprainguinal fascia iliaca block (SIFIB) combined with general anesthesia.
METHODS
Seventy-four subjects were enrolled over an 8-month period (20 April 2023 to 31 December 2023). All patients were divided into the test group (group P) and the control group (group S) using the envelope as the randomization method. The test group was treated with preoperative ultrasound-guided PENG block analgesia combined with general anesthesia and the control group was treated with preoperative ultrasound-guided SIFIB analgesia combined with general anesthesia. The primary outcome selected was the patient Visual Analogue Scale (VAS) score at 12 h postoperatively.
RESULTS
After generalized estimating equations (GEE) analysis, there was a statistically significant difference in the main effect of postoperative VAS score in group P compared with group S (P = 0.009), the time effect of VAS score in each group was significantly different (P < 0.001), and there was no statistically significant difference in the group-time interaction effect (P = 0.069). There was no statistically significant difference in the main effect of intraoperative mean arterial pressure (MAP) change (P = 0.911), there were statistically significant differences in the time effect of MAP in each group (P < 0.001), and there were statistically significant differences in the interaction effect (P < 0.001).
CONCLUSIONS
In summary, we can conclude that in elderly patients undergoing hip fracture surgery, postoperative analgesia is more pronounced, intraoperative hemodynamic parameters are more stable, and intraoperative stress is less induced in patients receiving SIFIB than in patients receiving PENG block.
Topics: Humans; Male; Female; Aged; Double-Blind Method; Nerve Block; Prospective Studies; Arthroplasty, Replacement, Hip; Pain, Postoperative; Ultrasonography, Interventional; Anesthesia, General; Fascia; Stress, Physiological; Aged, 80 and over
PubMed: 38956469
DOI: 10.1186/s12871-024-02604-8 -
Scientific Reports Jul 20242K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown...
2K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L displayed improved and broad-spectrum antibacterial activity than temporin-1CEc in vitro. Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, C. elegans and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant Acinetobacter baumannii strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-κB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against A. baumannii uptake into C. elegans, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by A. baumannii. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-κB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.
Topics: Animals; Caenorhabditis elegans; Mice; Acinetobacter baumannii; Macrophages; Lipopolysaccharides; Shock, Septic; NF-kappa B; Antimicrobial Peptides; Humans; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Inflammation; Anti-Bacterial Agents; Anti-Inflammatory Agents; Oxidative Stress; Mitogen-Activated Protein Kinases; Caenorhabditis elegans Proteins
PubMed: 38956179
DOI: 10.1038/s41598-024-64511-9 -
Scientific Reports Jul 2024Bovine pain assessment relies on validated behavioral scales related to normal and pain-related behaviors. This study investigated the reliability and applicability of...
Bovine pain assessment relies on validated behavioral scales related to normal and pain-related behaviors. This study investigated the reliability and applicability of real-time and video-recorded pain assessment, and their agreement, in young, adult bulls undergoing surgical castration. Ten Nelore and nine Angus bulls underwent general anesthesia and surgical castration. Three-minute real-time observations and simultaneous videos were recorded at - 48 h (M0), before sedation, under fasting (M1), after surgery, 3 h after sternal recumbency (M2), after rescue analgesia (M3) and at 24 h (M4). Animals received morphine (after M2), dipyrone (after M3), and flunixin meglumine after surgical castration (M4). Two trained evaluators assessed real-time (n = 95) and video-recorded time-points (n = 95) using the Unesp-Botucatu Cattle Pain Scale (UCAPS). Both assessment methods inferred 'very good' reliability (≥ 0.81) with minimal bias, however, video-recorded assessment (4.33 ± 2.84) demonstrated slightly higher scores compared to real-time (3.08 ± 2.84). The results from this study suggest that UCAPS can be used in real-time or video-recorded to assess pain and guide analgesic therapy in cattle.
Topics: Animals; Male; Cattle; Pain Measurement; Video Recording; Orchiectomy; Reproducibility of Results; Clonixin; Pain; Morphine; Dipyrone; Pain, Postoperative
PubMed: 38956118
DOI: 10.1038/s41598-024-65890-9 -
Cell Death Discovery Jul 2024The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is...
The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.
PubMed: 38956056
DOI: 10.1038/s41420-024-02083-3 -
Nutrition & Diabetes Jul 2024Vitamin D status has been shown to be associated with prediabetes risk. However, epidemiologic evidence on whether sex modulates the association between vitamin D and...
BACKGROUND/OBJECTIVES
Vitamin D status has been shown to be associated with prediabetes risk. However, epidemiologic evidence on whether sex modulates the association between vitamin D and prediabetes is limited. The present study investigated sex-specific associations between vitamin D and prediabetes.
SUBJECTS/METHODS
The Kuwait Wellbeing Study, a population-based cross-sectional study, enrolled nondiabetic adults. Prediabetes was defined as 5.7 ≤ HbA1c% ≤6.4; 25-hydroxyvitamin D (25(OH)D) was measured in venous blood and analyzed as a continuous, dichotomous (deficiency: <50 nmol/L vs. insufficiency/sufficiency ≥50 nmol/L), and categorical (tertiles) variable. Associations were evaluated by estimating adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs), while stratifying by sex.
RESULTS
A total of 384 participants (214 males and 170 females) were included in the current analysis, with a median age of 40.5 (interquartile range: 33.0-48.0) years. The prevalence of prediabetes was 35.2%, and 63.0% of participants had vitamin D deficiency. Assessments of statistical interaction between sex and 25(OH)D status were statistically significant (P < 0.05). In the sex-stratified analysis, after adjustment for confounding factors, decreased 25(OH)D levels were associated with increased prevalence of prediabetes in males (aPR: 2.35, 95% CI: 1.36-4.07), but not in females (aPR: 1.03, 95% CI: 0.60-1.77). Moreover, the prevalence of prediabetes differed between males and females at 25(OH)D levels of ≤35 nmol/L, with a higher prevalence of prediabetes in males compared to females. Such a sex-specific difference was not observed at 25(OH)D levels of >35 nmol/L.
CONCLUSIONS
Sex modified the association between vitamin D levels and prediabetes, with an inverse association observed among males, but not among females. Moreover, the observed sex-disparity in the prevalence of prediabetes was only pronounced at 25(OH)D levels of ≤35 nmol/L.
Topics: Humans; Prediabetic State; Female; Male; Cross-Sectional Studies; Middle Aged; Adult; Vitamin D; Vitamin D Deficiency; Sex Factors; Prevalence; Kuwait
PubMed: 38956028
DOI: 10.1038/s41387-024-00311-4