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Immunity, Inflammation and Disease Jun 2024Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as...
BACKGROUND
Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown.
METHODS
C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF).
RESULTS
The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF.
CONCLUSION
These results highlight OAW's robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.
Topics: Animals; Asthma; Mast Cells; Mice; Disease Models, Animal; Administration, Oral; Mice, Inbred C57BL; beta-Glucans; Cytokines; Inflammation; Ovalbumin; Respiratory Hypersensitivity; Bronchoalveolar Lavage Fluid; Lung
PubMed: 38934407
DOI: 10.1002/iid3.1333 -
Haematologica Jun 2024The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical...
The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.
PubMed: 38934082
DOI: 10.3324/haematol.2023.284716 -
Frontiers in Endocrinology 2024Our understanding of type 2 diabetes (T2D) has evolved dramatically. Advances have upended entrenched dogmas pertaining to the onset and progression of T2D, beliefs that... (Review)
Review
Our understanding of type 2 diabetes (T2D) has evolved dramatically. Advances have upended entrenched dogmas pertaining to the onset and progression of T2D, beliefs that have prevailed from the early era of diabetes research-and continue to populate our medical textbooks and continuing medical education materials. This review article highlights key insights that lend new governing principles for gold standard management of T2D. From the historical context upon which old beliefs arose to new findings, this article outlines evidence and perspectives on beta cell function, the underlying defects in glucoregulation, the remediable nature of T2D, and, the rationale supporting the shift to complication-centric prescribing. Practical approaches translate this rectified understanding of T2D into strategies that fill gaps in current management practices of prediabetes through late type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Humans; Blood Glucose; Hypoglycemic Agents; Insulin-Secreting Cells; Glycemic Control; Disease Management
PubMed: 38933821
DOI: 10.3389/fendo.2024.1394805 -
Frontiers in Pharmacology 2024Polypharmacy, the use of multiple medications, is a growing concern among middle-aged and older patients, posing potential risks and challenges in healthcare management.
INTRODUCTION
Polypharmacy, the use of multiple medications, is a growing concern among middle-aged and older patients, posing potential risks and challenges in healthcare management.
AIM
This study aimed to identify the prevalence of polypharmacy and hyper-polypharmacy among populations of middle-aged vs older patients and identify its associated common comorbidities and prescribed medications in Qatif Central Hospital (QCH), Saudi Arabia.
METHODS
Patients aged 40 years or older who presented to an outpatient medical care clinic at QCH, Saudi Arabia, between 1 January and 31 December 2021 were included, and their comorbidities, prescribed medications, and recent clinical laboratory test results were collected. The Charlson comorbidity index (CCI) score was calculated to predict the risk of mortality. Logistic regression was used to compute the association between the prevalence of polypharmacy and patient characteristics. The results were presented as odds ratios (ORs) and 95% confidence intervals (95% CIs).
RESULTS
A total of 14,081 patients were included; 31% of the cohort comprised older patients, and 66% of the cohort was identified with polypharmacy. The majority of the polymedicated patients were presented to an internal medicine care unit (34%). The prevalence of polypharmacy was positively associated with CCI (OR = 3.4, 95% CI 3.3-3.6), having a disease related to the musculoskeletal system (MSD) (OR = 4.2, 95% CI 3.8-4.7), and alimentary tract and metabolism (ATM) (OR = 3.8, 95% CI 3.4-4.2). Conversely, the prevalence of polypharmacy was negatively associated with age (OR = 0.9, 95% CI 0.89-0.91) and patients with cardiovascular diseases (OR = 0.6, 95% CI 0.5-0.7).
CONCLUSION
Polypharmacy is still an ongoing concern. Patients, particularly those with diseases related to MSD or ATM, should be considered for reviewing prescriptions by pharmacists to reduce the risk of adverse drug reactions and future consequences of polypharmacy.
PubMed: 38933679
DOI: 10.3389/fphar.2024.1357171 -
Clinical, Cosmetic and Investigational... 2024The topical application of antioxidants has been shown to augment the skin's innate antioxidant system and enhance photoprotection. A challenge of topical antioxidant...
PURPOSE
The topical application of antioxidants has been shown to augment the skin's innate antioxidant system and enhance photoprotection. A challenge of topical antioxidant formulation is stability and penetrability. The use of a targeted drug delivery system may improve the bioavailability and delivery of antioxidants. In this ex vivo study, we assessed the effects of the topical application of a liposome-encapsulated antioxidant complex versus a free antioxidant complex alone on skin photoaging parameters and penetrability in human skin explants.
PATIENTS AND METHODS
Human organotypic skin explant cultures (hOSEC) were irradiated to mimic photoaging. The encapsulated antioxidant complex and free antioxidant complex were applied topically onto the irradiated hOSEC daily for 7 days. The two control groups were healthy untreated hOSEC and irradiated hOSEC. Photoprotective efficacy was measured with pro-inflammatory cytokine (IL-6 and IL-8) and matrix metalloproteinase 9 (MMP-9) secretion. Cell viability and metabolic activity were measured via resazurin assay. Tissue damage was evaluated via lactate dehydrogenase (LDH) cytotoxicity assay. Skin penetration of the encapsulated antioxidant complex was assessed via fluorescent dye and confocal microscopy.
RESULTS
Compared to healthy skin, irradiated skin experienced increases in IL-6, IL-8 (p < 0.05), and MMP-9 (p < 0.05) secretion. After treatment with the encapsulated antioxidant complex, there was a 39.3% reduction in IL-6 secretion, 49.8% reduction in IL-8 (p < 0.05), and 38.5% reduction in MMP-9 (p < 0.05). After treatment with the free antioxidant complex, there were no significant differences in IL-6, IL-8, or MMP-9 secretion. Neither treatment group experienced significant LDH leakage or reductions in metabolic activity. Liposomes passed through the stratum corneum and into the epidermis.
CONCLUSION
The topical application of a liposome-encapsulated antioxidant complex containing ectoin, astaxanthin-rich microalgae extract, and THDA improves penetrability and restored IL-6, IL-8, and MMP-9 levels in irradiated human skin explants, which was not seen in the comparator free antioxidant complex group.
PubMed: 38933604
DOI: 10.2147/CCID.S461753 -
IBRO Neuroscience Reports Dec 2024First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve...
First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. and ). Some, e.g. were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.
PubMed: 38933596
DOI: 10.1016/j.ibneur.2024.05.006 -
Frontiers in Bioengineering and... 2024Stem cell-derived islets (SC-islets) are not only an unlimited source for cell-based therapy of type 1 diabetes but have also emerged as an attractive material for...
Stem cell-derived islets (SC-islets) are not only an unlimited source for cell-based therapy of type 1 diabetes but have also emerged as an attractive material for modeling diabetes and conducting screening for treatment options. Prior to SC-islets becoming the established standard for disease modeling and drug development, it is essential to understand their response to various nutrient sources . This study demonstrates an enhanced efficiency of pancreatic endocrine cell differentiation through the incorporation of WNT signaling inhibition following the definitive endoderm stage. We have identified a tri-hormonal cell population within SC-islets, which undergoes reduction concurrent with the emergence of elevated numbers of glucagon-positive cells during extended culture. Over a 6-week period of culture, the SC-islets consistently demonstrated robust insulin secretion in response to glucose stimulation. Moreover, they manifested diverse reactivity patterns when exposed to distinct nutrient sources and exhibited deviant glycolytic metabolic characteristics in comparison to human primary islets. Although the SC-islets demonstrated an aberrant glucose metabolism trafficking, the evaluation of a potential antidiabetic drug, pyruvate kinase agonist known as TEPP46, significantly improved insulin secretion of SC-islets. Overall, this study provided cell identity dynamics investigation of SC-islets during prolonged culturing , and insights into insulin secretagogues. Associated advantages and limitations were discussed when employing SC-islets for disease modeling.
PubMed: 38933536
DOI: 10.3389/fbioe.2024.1392575 -
Frontiers in Plant Science 2024, widely used in clinical practice as a medicinal herb, belongs to the genus in the family Ephedraceae. However, the presence of numerous varieties and variants...
OBJECTIVE
, widely used in clinical practice as a medicinal herb, belongs to the genus in the family Ephedraceae. However, the presence of numerous varieties and variants requires differentiation for accurate identification.
METHODS
In this study, we employed headspace gas chromatography mass spectrometry (HS-GC-MS), ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), and global natural products social molecular networking (GNPS) for chemical component identification. Chemometric analysis was used to analyze the differential components. Metabolic analysis and Kyoto encyclopedia of genes and genomes (KEGG) enrichment were utilized to explore the synthesis pathways of different components.
RESULT
A total of 83 volatile and 79 non-volatile components were identified in species. Differential analysis revealed that among the eight stems, 18 volatile and 19 non-volatile differential compounds were discovered, whereas roots exhibited 21 volatile and 17 non-volatile markers. Volatile compounds were enriched in four synthetic pathways, while non-volatile components were enriched in five pathways among the differentiated components.
CONCLUSION
This study is the first to conduct a comparative analysis of chemical components in different species and parts. It provides a foundational reference for authenticating herbs, evaluating medicinal resources, and comparing quality in future studies.
PubMed: 38933459
DOI: 10.3389/fpls.2024.1421008 -
Frontiers in Cell and Developmental... 2024Lipids, the primary constituents of the cell membrane, play essential roles in nearly all cellular functions, such as cell-cell recognition, signaling transduction, and... (Review)
Review
Lipids, the primary constituents of the cell membrane, play essential roles in nearly all cellular functions, such as cell-cell recognition, signaling transduction, and energy provision. Lipid metabolism is necessary for the maintenance of life since it regulates the balance between the processes of synthesis and breakdown. Increasing evidence suggests that cancer cells exhibit abnormal lipid metabolism, significantly affecting their malignant characteristics, including self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance. Prominent oncogenic signaling pathways that modulate metabolic gene expression and elevate metabolic enzyme activity include phosphoinositide 3-kinase (PI3K)/AKT, MAPK, NF-kB, Wnt, Notch, and Hippo pathway. Conversely, when metabolic processes are not regulated, they can lead to malfunctions in cellular signal transduction pathways. This, in turn, enables uncontrolled cancer cell growth by providing the necessary energy, building blocks, and redox potentials. Therefore, targeting lipid metabolism-associated oncogenic signaling pathways could be an effective therapeutic approach to decrease cancer incidence and promote survival. This review sheds light on the interactions between lipid reprogramming and signaling pathways in cancer. Exploring lipid metabolism as a target could provide a promising approach for creating anticancer treatments by identifying metabolic inhibitors. Additionally, we have also provided an overview of the drugs targeting lipid metabolism in cancer in this review.
PubMed: 38933330
DOI: 10.3389/fcell.2024.1399065 -
Frontiers in Immunology 2024Targeted therapy for Sjögren's syndrome (SS) has become an important focus for clinicians. Multi-omics-wide Mendelian randomization (MR) analyses have provided new...
BACKGROUND
Targeted therapy for Sjögren's syndrome (SS) has become an important focus for clinicians. Multi-omics-wide Mendelian randomization (MR) analyses have provided new ideas for identifying potential drug targets.
METHODS
We conducted summary-data-based Mendelian randomization (SMR) analysis to evaluate therapeutic targets associated with SS by integrating DNA methylation, gene expression and protein quantitative trait loci (mQTL, eQTL, and pQTL, respectively). Genetic associations with SS were derived from the FinnGen study (discovery) and the GWAS catalog (replication). Colocalization analyses were employed to determine whether two potentially relevant phenotypes share the same genetic factors in a given region. Moreover, to delve deeper into potential regulation among DNA methylation, gene expression, and protein abundance, we conducted MR analysis to explore the causal relationship between candidate gene methylation and expression, as well as between gene expression and protein abundance. Drug prediction and molecular docking were further employed to validate the pharmacological activity of the candidate drug targets.
RESULTS
Upon integrating the multi-omics data, we identified three genes associated with SS risk: TNFAIP3, BTN3A1, and PLAU. The methylation of cg22068371 in BTN3A1 was positively associated with protein levels, consistent with the negative effect of cg22068371 methylation on the risk of SS. Additionally, positive correlations were observed between the gene methylation of PLAU (cg04939496) and expression, as well as between expression and protein levels. This consistency elucidates the promotional effects of PLAU on SS risk at the DNA methylation, gene expression, and protein levels. At the protein level, genetically predicted TNFAIP3 (OR 2.47, 95% CI 1.56-3.92) was positively associated with SS risk, while BTN3A1 (OR 2.96E-03, 95% CI 2.63E-04-3.33E-02) was negatively associated with SS risk. Molecular docking showed stable binding for candidate drugs and target proteins.
CONCLUSION
Our study reveals promising therapeutic targets for the treatment of SS, providing valuable insights into targeted therapy for SS. However, further validation through future experiments is warranted.
Topics: Humans; Sjogren's Syndrome; Mendelian Randomization Analysis; Quantitative Trait Loci; DNA Methylation; Genome-Wide Association Study; Molecular Docking Simulation; Genetic Predisposition to Disease; Molecular Targeted Therapy; Polymorphism, Single Nucleotide; Multiomics
PubMed: 38933282
DOI: 10.3389/fimmu.2024.1419363