-
Future Medicinal Chemistry Jul 2024PD-L1 is overexpressed on the surface of tumor cells and binds to PD-1, resulting in tumor immune escape. Therapeutic strategies to target the PD-1/PD-L1 pathway involve... (Review)
Review
PD-L1 is overexpressed on the surface of tumor cells and binds to PD-1, resulting in tumor immune escape. Therapeutic strategies to target the PD-1/PD-L1 pathway involve blocking the binding. Immune checkpoint inhibitors have limited efficacy against tumors because PD-L1 is also present in the cytoplasm. PD-L1 of post-translational modifications (PTMs) have uncovered numerous mechanisms contributing to carcinogenesis and have identified potential therapeutic targets. Therefore, small molecule inhibitors can block crucial carcinogenic signaling pathways, making them a potential therapeutic option. To better develop small molecule inhibitors, we have summarized the PTMs of PD-L1. This review discusses the regulatory mechanisms of small molecule inhibitors in carcinogenesis and explore their potential applications, proposing a novel approach for tumor immunotherapy based on PD-L1 PTM.
PubMed: 38949857
DOI: 10.1080/17568919.2024.2366146 -
Clinical Science (London, England :... Jul 2024Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and...
Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and functional impairment across multiple organs, including kidneys and gonads. However, it remains unclear whether promoting M2 macrophage polarization can alleviate the hypertension, inflammation, and end organ damage in mice with salt sensitive hypertension (SSHTN). Male and female mice were made hypertensive by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/mL) for 2 weeks in the drinking water, followed by a 2-week interval without any treatments, and a subsequent high salt diet for 3 weeks (SSHTN). AVE0991 (AVE) was intraperitoneally administered concurrently with the high salt diet. Control mice were provided standard diet and tap water. AVE treatment significantly attenuated BP and inflammation in mice with SSHTN. Notably, AVE promoted M2 macrophage polarization, decreased pro-inflammatory immune cell populations, and improved function in renal and gonadal tissues of mice with SSHTN. Additionally, AVE decreased lymphangiogenesis in the kidneys and testes of male SSHTN mice and the ovaries of female SSHTN mice. These findings highlight the effectiveness of AVE in mitigating SSHTN-induced elevated BP, inflammation, and end organ damage by promoting M2 macrophage polarization and suppressing pro-inflammatory immune responses. Targeting macrophage polarization emerges as a promising therapeutic approach for alleviating inflammation and organ damage in SSHTN. Further studies are warranted to elucidate the precise mechanisms underlying AVE-mediated effects and to assess its clinical potential in managing SSHTN.
PubMed: 38949840
DOI: 10.1042/CS20240699 -
Clinical Science (London, England :... Jul 2024We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated...
We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice. However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both. We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN. SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/mL) in their drinking water for 2 weeks, followed by a 2-week washout period. Subsequently, the mice received a 3-week 4% high salt diet (SSHTN). The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks. In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice. Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN. These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.
PubMed: 38949825
DOI: 10.1042/CS20240698 -
Chemistry (Weinheim An Der Bergstrasse,... Jul 2024A series of fluorescent carbazole-coumarins exhibiting good photoluminescence quantum yields and thermally activated delayed fluorescence (TADF) properties have been...
A series of fluorescent carbazole-coumarins exhibiting good photoluminescence quantum yields and thermally activated delayed fluorescence (TADF) properties have been designed and synthetized using computer-aided density functional theory calculations. The TADF characteristics of the carbazole-coumarins were systematically explored both in solution and in the solid state, utilizing poly(methyl methacrylate) (PMMA) as a matrix. The study revealed that the introduction of carbazole units onto the coumarin benzene ring led to compounds with thermally induced reverse intersystem crossing and delayed fluorescence. The study further demonstrated the potential utility of these compounds in practical applications by incorporating them into a Cmr-PMMA-based sensor for molecular oxygen detection. The resulting sensor exhibited promising performance, highlighting the adaptability and efficacy of the synthesized TADF-carbazole-coumarin compounds for reversible molecular oxygen sensing.
PubMed: 38949777
DOI: 10.1002/chem.202401263 -
Journal of Chemical Ecology Jun 2024Plant responses to damage by insectivorous herbivores are well-documented in mature leaves. The resulting herbivore-induced plant volatiles (HIPVs) protect the plant by...
Plant responses to damage by insectivorous herbivores are well-documented in mature leaves. The resulting herbivore-induced plant volatiles (HIPVs) protect the plant by attracting carnivorous arthropods and even some insectivorous vertebrates, to parasitize or consume the plant invaders. However, very little is known about plant production of HIPVs in developing buds, particularly when herbivorous insects are too small to be considered a prey item. It is additionally unclear whether plants respond differently to generalist and specialist chewing insects that overlap in distribution. Therefore, we compared HIPV production of Downy oak (Quercus pubescens Willd.) buds infested with freshly hatched caterpillars of Tortrix viridana (specialist) and Operophtera brumata (generalist), against uninfested buds. Of the compounds identified in both years of the experiment, we found that (Z)-hex-3-enyl acetate, (E)-β-ocimene, acetophenone, linalool, (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), methyl salicylate, α-copaene, α-humulene, (E)-caryophyllene, and (E,E)-α-farnesene appeared to be higher in infested buds compared to controls. We found no difference in HIPV production between the specialist and the generalist herbivores. Production of HIPVs was also associated with leaf damage, with higher HIPV production in more severely attacked buds. Thus, our study shows that oak trees already start responding to insect herbivory before leaves are developed, by producing compounds similar to those found in damaged mature leaves. Future work should focus on how Downy oak may benefit from initiating alarm cues at a time when carnivorous arthropods and insectivorous vertebrates are unable to use herbivorous insects as host or food.
PubMed: 38949747
DOI: 10.1007/s10886-024-01520-y -
Neurological Sciences : Official... Jun 2024Here we described an 18-year-old woman who were initially misdiagnosed as psychiatric disorders in a psychiatric institution. She was transferred to our neurological...
Here we described an 18-year-old woman who were initially misdiagnosed as psychiatric disorders in a psychiatric institution. She was transferred to our neurological ward because of impaired consciousness. Neuronal antibody testing confirmed the diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Cerebral magnetic resonance imaging (MRI) revealed a concomitant disorder named reversible splenial lesion syndrome (RESLES). After administration of combined immunotherapy, the patient recovered completely 3 months after discharge. To our knowledge, co-occurrence of RESLES and anti-NMDAR encephalitis was only described in two patients with teratoma and we provide another case without teratoma. We highlight that anti-NMDAR antibodies can be added to the multiple causes of RESLES. It is therefore imperative for clinicians to detect anti-neuronal antibodies in patients with RESLES to avoid missed diagnosis.
PubMed: 38949742
DOI: 10.1007/s10072-024-07646-x -
Neurotoxicity Research Jun 2024Nonketotic hyperglycinemia (NKH) is an inherited disorder of amino acid metabolism biochemically characterized by the accumulation of glycine (Gly) predominantly in the... (Review)
Review
Nonketotic hyperglycinemia (NKH) is an inherited disorder of amino acid metabolism biochemically characterized by the accumulation of glycine (Gly) predominantly in the brain. Affected patients usually manifest with neurological symptoms including hypotonia, seizures, epilepsy, lethargy, and coma, the pathophysiology of which is still not completely understood. Treatment is limited and based on lowering Gly levels aiming to reduce overstimulation of N-methyl-D-aspartate (NMDA) receptors. Mounting in vitro and in vivo animal and human evidence have recently suggested that excitotoxicity, oxidative stress, and bioenergetics disruption induced by Gly are relevant mechanisms involved in the neuropathology of NKH. This brief review gives emphasis to the deleterious effects of Gly in the brain of patients and animal models of NKH that may offer perspectives for the development of novel adjuvant treatments for this disorder.
Topics: Hyperglycinemia, Nonketotic; Animals; Humans; Oxidative Stress; Energy Metabolism; Glycine; Brain
PubMed: 38949693
DOI: 10.1007/s12640-024-00711-5 -
Addiction Biology Jul 2024Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding...
Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.
Topics: Humans; Receptors, Opioid, mu; DNA Methylation; Male; Female; Epigenesis, Genetic; Chronic Pain; Opioid-Related Disorders; Middle Aged; Adult; Sex Factors; Analgesics, Opioid; Case-Control Studies; CpG Islands; Quality of Life
PubMed: 38949208
DOI: 10.1111/adb.13422 -
Medicine and Science in Sports and... Jul 2024Epigenetic aging, a marker of biological aging measured by DNA methylation, may be affected by behaviors, including sleep and physical activity. However, investigations...
INTRODUCTION
Epigenetic aging, a marker of biological aging measured by DNA methylation, may be affected by behaviors, including sleep and physical activity. However, investigations of physical activity and sleep with epigenetic aging among pediatric populations are scant and have not accounted for correlated behaviors.
METHODS
The study population included 472 Mexico City adolescents (52% female). Blood collection and 7-day wrist actigraphy (Actigraph GTX-BT) occurred during a follow-up visit when participants were 14.5 (2.09) years. Leukocyte DNA methylation was measured with the Infinium MethylationEPIC array after bisulfite conversion, and 9 epigenetic clocks were calculated. Sleep vs wake time was identified through a pruned dynamic programing algorithm, and physical activity was processed with Chandler cut-offs. Kmeans clustering was used to select actigraphy-assessed physical activity and sleep behavior clusters. Linear regression analyses were used to evaluate adjusted associations between the clusters and epigenetic aging.
RESULTS
There were 3 unique clusters: "Short sleep/high sedentary behavior", "Adequate sleep duration and late timing/low moderate or vigorous physical activity (MVPA)", and "Adequate sleep duration/high MVPA". Compared to the "Adequate duration/high MVPA", adolescents with "Adequate duration and late sleep timing/low MVPA" had more accelerated aging for the GrimAge clock (β = 0.63;95% CI 0.07, 1.19). In pubertal-stratified analyses, more mature adolescents in the "Adequate duration and late sleep timing/low MVPA group" had accelerated epigenetic aging. In contrast, females in the "Short sleep/high sedentary" group had decelerated epigenetic aging for the Wu pediatric clock.
CONCLUSIONS
Associations between behavior clusters and epigenetic aging varied by pubertal status and sex. Contrary results in the Wu clock suggest the need for future research on pediatric-specific clocks.
PubMed: 38949160
DOI: 10.1249/MSS.0000000000003498 -
JPMA. the Journal of the Pakistan... Jun 2024To compare the effects of magnesium sulphate on the total dose of intravenous morphine consumption postoperatively following limb amputations along with rescue analgesia... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare the effects of magnesium sulphate on the total dose of intravenous morphine consumption postoperatively following limb amputations along with rescue analgesia requirement, pain scores and side effects.
METHODS
This prospective, triple-blinded, randomised controlled study was conducted from October 2021 to May 2022 at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised of patients scheduled for limb amputations. They were randomised into 2 equal groups. The anaesthesia protocol was uniform for all patients. Intervention group A was administered 30mg/kg loading dose and 10mg/kg/hr maintenance dose of magnesium sulphate intravenously, while patients in control group B received the same amount of plain isotonic saline. Morphine consumption, including that used for rescue analgesia and patient-controlled analgesia, was measured for 24 hours postoperatively. Numeric rating scale was used for the evaluation of postoperative pain in both groups at 15min, 1h, 2h, at discharge from the post-anaesthesia care unit and at 12h and 24h in the ward. Data was analysed using SPSS 23.
RESULTS
Of the 24 patients enrolled, the study was completed by 20(83.33%). There were 10(50%) patients in group A; 8(40%) males and 2(20%) females with mean age 24.8±14.14 years and mean surgery time 130.5±47.86 minutes. There were 10(50%) patients in group B; 8(40%) males and 2(20%) females with mean age 23.2±7.4 years and mean surgery time 117±23.85 minutes (p>0.05). Total morphine used over 24 hours in group A was 16±3.1 mg compared to 29.6±11.2 mg in group B (p<0.05). The time for first use of patient-controlled analgesia after arriving in the postanaesthesia care unit was significantly delayed in group A (72.2±24.95 minutes) compared to that in group B (25±26.68 minutes) (p<0.05). Pain scores were significantly higher in the group B at 15min compared to group A (p<0.05), but not at the rest of the time points (p>0.05).
CONCLUSIONS
Intravenous magnesium sulphate proved to be effective in lowering postoperative opioid requirement following limb amputations.
Topics: Humans; Pain, Postoperative; Magnesium Sulfate; Female; Male; Analgesics, Opioid; Adult; Morphine; Prospective Studies; Amputation, Surgical; Pain Measurement; Middle Aged; Analgesia, Patient-Controlled; Young Adult; Acute Pain
PubMed: 38948969
DOI: 10.47391/JPMA.9022