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European Review For Medical and... May 2024This study aimed to quantitatively analyze the calculi components of upper urinary tract calculi and to explore the relationship between calculus components, demographic...
OBJECTIVE
This study aimed to quantitatively analyze the calculi components of upper urinary tract calculi and to explore the relationship between calculus components, demographic characteristics, and underlying diseases.
PATIENTS AND METHODS
Clinical data of 1,495 patients with upper urinary tract calculi were retrospectively collected. The calculi were divided into simple calcium oxalate, calcium oxalate mixed, calcium phosphate mixed, uric acid, magnesium ammonium phosphate, and other components. Statistical software SPSS 22.0 was used to analyze the differences between the stone compositions and various factors. The influencing factors (p < 0.05) were analyzed using multiple logistic regression analysis.
RESULTS
Among 1,495 patients with upper urinary tract calculi, simple calcium oxalate calculi were the most common component (39.7%), followed by calcium oxalate mixed calculi (30.4%), uric acid calculi (13.6%), calcium phosphate mixed calculi (10.4%), magnesium ammonium phosphate calculi (5.8%) and other component calculi (0.1%). Univariate analysis revealed statistically significant differences in stone composition according to gender, age, and hyperuricemia (p < 0.05). Multiple logistic regression analysis showed that compared to men, the odds ratio (OR) values of calcium oxalate mixed stones, calcium phosphate mixed stones, and magnesium ammonium phosphate stones in women were 1.61, 2.50, and 4.17, respectively (p < 0.001). Compared with elderly patients, the OR values of calcium phosphate mixed stones in young and middle-aged patients were 3.14 and 2.70, respectively (p < 0.05).
CONCLUSIONS
Patients with different stone components had different demographic characteristics, and stone components were significantly different between gender and age. Calcium oxalate mixed stones were more common in females, and calcium phosphate mixed stones and magnesium ammonium phosphate stones were more common in females, young patients, and middle-aged patients.
Topics: Humans; Male; Female; Urinary Calculi; Middle Aged; Calcium Phosphates; Age Factors; Adult; Retrospective Studies; Calcium Oxalate; Sex Factors; Uric Acid; Aged; Struvite; Phosphates; Adolescent; Young Adult
PubMed: 38766801
DOI: 10.26355/eurrev_202405_36190 -
Frontiers in Immunology 2024Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS....
Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients.
Topics: Animals; Dimethyl Fumarate; Encephalomyelitis, Autoimmune, Experimental; Lymph Nodes; Mice; Female; T-Lymphocytes, Regulatory; Mice, Inbred C57BL; Mesentery; Cytokines; Immunosuppressive Agents; Disease Models, Animal
PubMed: 38765015
DOI: 10.3389/fimmu.2024.1391949 -
Fitoterapia Jul 2024The uncontrolled hyperglycemia that characterizes diabetes mellitus (DM) causes several complications in the organism. DM is among the major causes of deaths, and the...
The uncontrolled hyperglycemia that characterizes diabetes mellitus (DM) causes several complications in the organism. DM is among the major causes of deaths, and the limited efficacy of current treatments push the search for novel drug candidates, also among natural compounds. We focused our attention on caffeoylmalic acid, a phenolic derivative extracted from Urtica dioica, a plant investigated for its potential against type 2 DM. This compound was tested for its antidiabetic activity in vitro through a glucose uptake assay, in vivo in a mouse DM model and through molecular docking towards α-amylase and α-glucosidase. The effects on glucose blood level, liver enzymes, insulin and creatinine levels as well as on lipid and blood parameters, considered biochemical markers of diabetes, were also evaluated. The results showed an antidiabetic activity in vitro and in vivo, as the compound stimulates glucose absorbtion and reduces blood glucose levels. Moreover, it ameliorates lipid profile, liver and blood parameters, with moderate effect on insulin secretion. Taken together, these findings pave the way for the compounds from this class of caffeoylmalic acid as potential antidiabetic compounds.
Topics: Animals; Hypoglycemic Agents; Mice; Urtica dioica; Male; Molecular Docking Simulation; Blood Glucose; Molecular Structure; Diabetes Mellitus, Experimental; Malates; Phytochemicals; Insulin; Caffeic Acids
PubMed: 38763410
DOI: 10.1016/j.fitote.2024.106024 -
Journal of Neuroinflammation May 2024Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising...
BACKGROUND
Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI).
METHODS
We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes.
RESULTS
We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression.
CONCLUSION
Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.
Topics: Animals; NF-E2-Related Factor 2; Hypoxia-Ischemia, Brain; Mice; Astrocytes; Succinates; Animals, Newborn; Neuroprotective Agents; Signal Transduction; Mice, Inbred C57BL; Oxidative Stress; Disease Models, Animal
PubMed: 38760862
DOI: 10.1186/s12974-024-03121-8 -
Biological Research May 2024Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its...
BACKGROUND
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood.
RESULTS
miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models.
CONCLUSIONS
These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma.
Topics: MicroRNAs; Glioma; Humans; Isocitrate Dehydrogenase; Cell Line, Tumor; Cell Cycle; Glutarates; Mutation; Apoptosis; Cell Proliferation; Animals; Mice; Brain Neoplasms; Gene Expression Regulation, Neoplastic; Mice, Nude
PubMed: 38760850
DOI: 10.1186/s40659-024-00512-2 -
Scientific Reports May 2024Oxalate, a uremic toxin that accumulates in dialysis patients, is associated with cardiovascular disease. As oxalate crystals can activate immune cells, we tested the...
Oxalate, a uremic toxin that accumulates in dialysis patients, is associated with cardiovascular disease. As oxalate crystals can activate immune cells, we tested the hypothesis that plasma oxalate would be associated with cytokine concentrations and cardiovascular outcomes in dialysis patients. In a cohort of 104 US patients with kidney failure requiring dialysis (cohort 1), we measured 21 inflammatory markers. As IL-16 was the only cytokine to correlate with oxalate, we focused further investigations on IL-16. We searched for associations between concentrations of IL-16 and mortality and cardiovascular events in the 4D cohort (1255 patients, cohort 2) and assessed further associations of IL-16 with other uremic toxins in this cohort. IL-16 levels were positively correlated with pOx concentrations (ρ = 0.39 in cohort 1, r = 0.35 in cohort 2) and were elevated in dialysis patients when compared to healthy individuals. No significant association could be found between IL-16 levels and cardiovascular events or mortality in the 4D cohort. We conclude that the cytokine IL-16 correlates with plasma oxalate concentrations and is substantially increased in patients with kidney failure on dialysis. However, no association could be detected between IL-16 concentrations and cardiovascular disease in the 4D cohort.
Topics: Humans; Male; Female; Renal Dialysis; Middle Aged; Interleukin-16; Cardiovascular Diseases; Aged; Heart Disease Risk Factors; Oxalates; Biomarkers; Cohort Studies; Adult; Risk Factors; Kidney Failure, Chronic
PubMed: 38760468
DOI: 10.1038/s41598-024-61808-7 -
Nature Communications May 2024The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the...
The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.
Topics: Animals; Humans; Oncolytic Virotherapy; Succinates; Mice; Cell Line, Tumor; Oncolytic Viruses; Interferon Type I; NF-E2-Related Factor 2; Colonic Neoplasms; Antiviral Agents; NF-kappa B; I-kappa B Kinase; Kelch-Like ECH-Associated Protein 1; Inflammation; Female; Vesicular stomatitis Indiana virus; Signal Transduction
PubMed: 38750019
DOI: 10.1038/s41467-024-48422-x -
ESMO Open May 2024The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced... (Randomized Controlled Trial)
Randomized Controlled Trial
Evaluation of the inflammation-based modified Glasgow Prognostic Score (mGPS) as a prognostic and predictive biomarker in patients with metastatic colorectal cancer receiving first-line chemotherapy: a post hoc analysis of the randomized phase III XELAVIRI trial (AIO KRK0110).
BACKGROUND
The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial.
PATIENTS AND METHODS
In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed.
RESULTS
Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS = 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS = 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS = 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P = 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P = 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P = 0.022).
CONCLUSION
We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy.
Topics: Humans; Colorectal Neoplasms; Male; Female; Middle Aged; Aged; Prognosis; Antineoplastic Combined Chemotherapy Protocols; Inflammation; Irinotecan; Adult; Capecitabine; C-Reactive Protein; Oxaloacetates; Bevacizumab; Fluorouracil; Biomarkers, Tumor; Neoplasm Metastasis
PubMed: 38744100
DOI: 10.1016/j.esmoop.2024.103374 -
Scientific Reports May 2024Bulk composition of kidney stones, often analyzed with infrared spectroscopy, plays an essential role in determining the course of treatment for kidney stone disease....
Bulk composition of kidney stones, often analyzed with infrared spectroscopy, plays an essential role in determining the course of treatment for kidney stone disease. Though bulk analysis of kidney stones can hint at the general causes of stone formation, it is necessary to understand kidney stone microstructure to further advance potential treatments that rely on in vivo dissolution of stones rather than surgery. The utility of Raman microscopy is demonstrated for the purpose of studying kidney stone microstructure with chemical maps at ≤ 1 µm scales collected for calcium oxalate, calcium phosphate, uric acid, and struvite stones. Observed microstructures are discussed with respect to kidney stone growth and dissolution with emphasis placed on < 5 µm features that would be difficult to identify using alternative techniques including micro computed tomography. These features include thin concentric rings of calcium oxalate monohydrate within uric acid stones and increased frequency of calcium oxalate crystals within regions of elongated crystal growth in a brushite stone. We relate these observations to potential concerns of clinical significance including dissolution of uric acid by raising urine pH and the higher rates of brushite stone recurrence compared to other non-infectious kidney stones.
Topics: Kidney Calculi; Spectrum Analysis, Raman; Calcium Oxalate; Uric Acid; Calcium Phosphates; Humans; Struvite; Magnesium Compounds; Phosphates
PubMed: 38734821
DOI: 10.1038/s41598-024-61652-9 -
International Journal of Pharmaceutics Jun 2024The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between...
The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between the nasal cavity and the brain. Dimethyl fumarate is used to treat relapsing-remitting multiple sclerosis, with a role as an immunomodulator towards T- T-cells and a cytoprotector towards neurons and glial cells. Its use in therapy is hindered by its low aqueous solubility, and low stability, due to hydrolysis and sublimation at room temperature. To overcome this limitation, in this study we evaluated the feasibility of using two amorphous β-cyclodextrin derivatives, namely hydroxypropyl β-cyclodextrin and methyl β-cyclodextrin, to obtain a nasally administrable powder with a view to nose-to-brain administration. Initially, the interaction product was studied using different analytical methods (differential scanning calorimetry, Fourier transform infrared spectroscopy and powder X-ray diffraction) to detect the occurrence of binary product formation, while phase solubility analysis was used to probe the complexation in solution. The dimethyl fumarate-cyclodextrin binary product showing best solubility and stability properties was subsequently used in the development of a chitosan-based mucoadhesive nasally administrable powder comparing different preparative methods. The best performance in terms of both hydrolytic stability and DMF recovery was achieved by the powder obtained via freeze-drying.
Topics: Dimethyl Fumarate; Chitosan; Powders; Administration, Intranasal; Drug Stability; beta-Cyclodextrins; Solubility; Brain; 2-Hydroxypropyl-beta-cyclodextrin; Spectroscopy, Fourier Transform Infrared; Calorimetry, Differential Scanning; X-Ray Diffraction
PubMed: 38734272
DOI: 10.1016/j.ijpharm.2024.124216