Saved Queries

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median overall survival (OS) of 15–18 months despite standard treatments. Approximately 8% of GBM cases exhibit genomic alterations in fibroblast growth factor receptors (FGFRs), particularly FGFR1 and FGFR3. Next-generation sequencing techniques have identified various FGFR3 fusions in GBM. This report presents a novel FGFR3 fusion with fatty acid synthase (FASN) in a 41-year-old male diagnosed with GBM. The patient presented with a persistent headache, and imaging revealed a right frontal lobe lesion. Surgical resection and subsequent histopathology confirmed GBM. Initial NGS analysis showed no mutations in the IDH1, IDH2 or H3F3 genes, but revealed a TERT promoter mutation and CDKN2A/2B and PTEN deletions. Postoperative treatment included radiotherapy and temozolomide. Despite initial management, recurrence occurred four months post-diagnosis, confirmed by MRI and histology. A second surgery identified a novel FGFR3-FASN fusion, alongside increased Ki67 expression. The recurrence was managed with regorafenib and bevacizumab, though complications like hand–foot syndrome and radiation necrosis arose. Despite initial improvement, the patient died 15 months after diagnosis. This case underscores the importance of understanding GBM’s molecular landscape for effective treatment strategies. The novel FGFR3-FASN fusion suggests potential implications for GBM recurrence and lipid metabolism. Further studies are warranted to explore FGFR3-FASN’s role in GBM and its therapeutic targeting. Full article

►▼ Show Figures

Figure 1

Figure 1
MRI at time of diagnosis and progression. Diagnosis: Axial T1 contrast-enhanced image (A) shows a right parasagittal frontal tumor involving the genu of the corpus callosum. There is predominantly peripheral mural enhancement with central areas of necrotic appearance. It is surrounded by a diffuse hyperintense area on the FLAIR sequence (B), mostly due to edema. Progression: Five months after diagnosis, several enhancing nodules (white arrows in (C)) appear along the anterior and medial margins of the post-surgical cavity (*), suggestive of tumor recurrence. There is scarce edema in the anterior frontal subcortical white matter on the FLAIR image (black arrow in (D)). * refers to post-surgical cavity. Full article ">Figure 2
Urgent MRI in May 2023, showing an intermediate signal lesion on FLAIR imaging (black arrow in (A)) adjacent to the lateral edge of the resection cavity, with increased edema and a worsening mass effect, causing midline deviation. There is a markedly high signal intensity on diffusion-weighted imaging (DWI) (B), with very low apparent diffusion coefficient (ADC) values due to diffusion restriction (C), mild peripheral enhancement on the T1 CE sequence (D) and an irregular surrounding low signal (hemorrhage and hemoglobin degradation products) with very fine lineal hypointensities within the lesion (probably vascular structures) on susceptibility-weighted imaging (SWI) (E). On dynamic susceptibility contrast (DSC) perfusion imaging (F), relative cerebral blood volume is slightly increased (blue dynamic curve in (F)) with respect to the normal contralateral white matter (green dynamic curve in (F)). Full article ">Figure 3
Short-echo-time MR spectroscopy shows a mildly elevated choline/creatine (Cho/Cr) ratio, low N-acetylaspartate/creatine ratio and a very high peak of lipids. Radionecrosis was suspected, but a differential diagnosis with pseudoprogression was considered. Full article ">Figure 4
The last MRI, performed fifteen months after diagnosis, shows less edema and an improvement in the mass effect (A). Marked DWI restriction persists (B) with very low ADC values (C). There is a slight growth in the lesion from its posterior margin (white arrow in (B)). Peripheral enhancement has decreased on the T1 CE sequence (D). DSC perfusion imaging shows decreased rVSC compared to the normal contralateral white matter (E), with an almost flat dynamic curve (light blue in (F)). Persistent marked DWI restriction, but contrast enhancement improvement, and decreased perfusion suggest a mixture of mechanisms, partly radionecrosis with some degree of superimposed pseudoprogression, due to regorafenib. Full article ">Figure 5
Timeline describing the treatment of the patient. Full article ">

13 pages, 1635 KiB

Open AccessArticle

Modulation of Urea Transport Attenuates TLR2-Mediated Microglial Activation and Upregulates Microglial Metabolism In Vitro

by Najlaa A. Al-Thani, Dylan Zinck, Gavin S. Stewart and Derek A. Costello

Metabolites 2024, 14(11), 634; https://doi.org/10.3390/metabo14110634 (registering DOI) - 17 Nov 2024

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder traditionally characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain. However, emerging research has highlighted additional metabolic hallmarks of AD pathology. These include the metabolic reprogramming of microglia in favour of glycolysis over oxidative phosphorylation. This shift is attributed to an ‘M1′-like pro-inflammatory phenotype, which exacerbates neuroinflammation and contributes to neuronal damage. The urea cycle also presents as an altered metabolic pathway in AD, due to elevated urea levels and altered expression of urea cycle enzymes, metabolites, and transporters in the brain. However, to date, these changes remain largely unexplored. Methods: This study focuses on understanding the effects of extracellular urea and urea transporter-B (UT-B) inhibition on inflammatory changes in lipoteichoic acid (LTA)-stimulated BV2 microglia and on the viability of SH-SY5Y neuronal cells under oxidative stress and neurotoxic conditions. Results: In BV2 microglia, UT-B inhibition demonstrated a notable anti-inflammatory effect by reducing the formation of nitric oxide (NO) and the expression of tumour necrosis factor α (TNFα) and CCL2 in response to stimulation with the toll-like receptor (TLR)2 agonist, lipoteichoic acid (LTA). This was accompanied by a reduction in extracellular urea and upregulation of UT-B expression. The application of exogenous urea was also shown to mediate the inflammatory profile of BV2 cells in a similar manner but had only a modest impact on UT-B expression. While exposure to LTA alone did not alter the microglial metabolic profile, inhibition of UT-B upregulated the expression of genes associated with both glycolysis and fatty acid oxidation. Conversely, neither increased extracellular urea nor UT-B inhibition had a significant impact on cell viability or cytotoxicity in SH-SY5Y neurones exposed to oxidative stressors tert-butyl hydroperoxide (t-BHP) and 6-hydroxydopamine (6-OHDA). Conclusions: This study further highlights the involvement of urea transport in regulating the neuroinflammation associated with AD. Moreover, we reveal a novel role for UT-B in maintaining microglial metabolic homeostasis. Taken together, these findings contribute supporting evidence to the regulation of UT-B as a therapeutic target for intervention into neuroinflammatory and neurodegenerative disease. Full article

(This article belongs to the Section Cell Metabolism)

►▼ Show Figures

Figure 1

Figure 1
Inhibition of urea transport alleviates LTA-induced microglial activation. BV2 cells were exposed to LTA (5 μg/mL) for 24 h in the presence and absence of UT-Bi (100 nM) or urea (5, 7.5, 10, 20 mM). Supernatant expression of TNFa (a,e), formation of nitrite (b,f), CCL2 (c), and urea (d) was measured. Cellular expression of UT-B mRNA (Slc14a1; (g)) was assessed by quantitative PCR. Data are presented as mean ± SEM, relative to control values (n = 6–8 replicates from 3–4 independent experiments). Inset represents result of two-way ANOVA. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, two-way ANOVA followed by Tukey’s post hoc test. Full article ">Figure 2
UT-Bi promotes expression of markers of glycolytic metabolism in microglia. BV2 cells were incubated with LTA (5 μg/mL) for 24 h in the presence and absence of UT-Bi (100 nM) or urea (5, 7.5, 10, 20 mM). Expression of Pfkfb1 (a,d), Pfkfb3 (b,e), and Hk3 (c,f) mRNA was evaluated using qPCR with respect to expression of Gapdh. Data are presented as mean ± SEM, relative to control values (n = 5–6 independent experiments). Insets represent results of two-way ANOVA. * p < 0.05, ** p < 0.01, two-way ANOVA followed by Tukey’s post hoc test. Full article ">Figure 3
UT-Bi enhances markers of oxidative phosphorylation in microglia. BV2 cells were incubated with LTA (5 μg/mL) for 24 h in the presence and absence of UT-Bi (100 nM) or urea (5, 7.5, 10, 20 mM). mRNA expression of Cpt1a (a,c) and Acadm (b,d) was evaluated relative to Gapdh using qPCR. Data are presented as mean ± SEM, relative to control (n = 5–6 independent experiments). Insets represent results of two-way ANOVA. Full article ">Figure 4
Inhibition of urea transport does not prevent oxidative stress-induced cell death. SH-SY5Y cells were treated with either tBHP (200 µM) or 6-OHDA (180 µM) for 24 h in the presence of either UT-Bi (100 nM) or urea (0–10 mM). Cell viability was evaluated by CCK-8 assay (a,c), and cytotoxicity was determined by supernatant expression of LDH (b,d). Data are expressed as mean ± SEM, as a percentage of control values (n = 9 replicates from 3 independent experiments). Statistical comparisons were determined by two-way ANOVA followed by Tukey’s multiple comparisons tests. ** p < 0.01, **** p < 0.0001. Full article ">

14 pages, 3728 KiB

Open AccessArticle

Microsomal Prostaglandin E Synthase-1 Controls Colonic Prostaglandin E₂ Production and Exerts a Protective Effect on Colitis Induced by Trinitrobenzene Sulfonic Acid in Mice

by Fumiaki Kojima, Yuka Hioki, Hiroki Sekiya, Hitoshi Kashiwagi, Yoshiko Iizuka, Kei Eto, Shotaro Maehana, Fumitaka Kawakami, Makoto Kubo, Hitoshi Ishibashi and Takafumi Ichikawa

Int. J. Mol. Sci. 2024, 25(22), 12326; https://doi.org/10.3390/ijms252212326 (registering DOI) - 17 Nov 2024

Viewed by 120

Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) is an isozyme of the prostaglandin (PG) E synthase that acts downstream of cyclooxygenase and catalyzes the conversion of PGH₂ to PGE₂. The impact of genetic deletion of mPGES-1 on the development of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, a well-established model of inflammatory bowel disease (IBD), was investigated in this study. After administration of TNBS, mice deficient in mPGES-1 (mPGES-1^−/− mice) showed more severe colitis than did wild-type (WT) mice. Histological examination revealed that mPGES-1^−/− mice had markedly exacerbated symptoms of colitis. mPGES-1 expression was detectable in the colons of WT mice at both the mRNA and protein levels. Lack of mPGES-1 resulted in marked reduction of colonic PGE₂ production. Our study also showed a significant increase in colonic expression of interleukin-17A (IL-17A), as well as interferon γ (IFNγ) and tumor necrosis factor α, during colitis in mPGES-1^−/− mice compared with that in WT mice. Furthermore, loss of mPGES-1 increased the populations of IL-17A-producing T-helper (Th) 17 and IFNγ-producing Th1 cells in mesenteric lymph nodes. These results suggest that mPGES-1 is the main enzyme responsible for colonic PGE₂ production and deficiency of mPGES-1 facilitates the development of colitis and T-cell-mediated immunity. mPGES-1 might, therefore, impact T-cell-related immune response associated with IBD. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Insights)

►▼ Show Figures

Figure 1

Figure 1
Impact of mPGES-1 genetic deletion in TNBS-induced colitis. (A) On day 3 following TNBS administration, the length of each colon was assessed as an indirect indicator of inflammation (n = 11 to 13). Colon photographs are typical examples in WT and mPGES-1−/− mice. (B) Time course of body weight changes in WT and mPGES-1−/− mice before and after TNBS administration (n = 17); Mice were fasted overnight and then TNBS was administered on day 0; (C) The progression of DAI scores after the specified days of TNBS administration (n = 11 to 12). *, p < 0.05; ANOVA followed by the Bonferroni test. Full article ">Figure 2
Histological evaluation of TNBS-induced colitis in mPGES-1 deficiency. (A) On day 3 after TNBS administration, colon sections of mPGES-1 WT and mPGES-1−/− mice were stained with H&E. Results are typical pictures using the Swiss roll method (n = 11 to 17). Stars and arrows in the panel indicate epithelial damage and inflammatory infiltration in mPGES-1−/− mice relative to WT mice. Scale bar represents 100 µm. (B) A blinded researcher evaluated the histology scores by calculating the sum of the inflammatory infiltration score and the epithelial damage score, with a maximum possible score of 8 (n = 11 to 17). (C) On day 3 following the injection of TNBS, intestinal permeability was assessed using FITC-dextran. (n = 3 to 6). *, p < 0.05; ANOVA followed by the Bonferroni test. Full article ">Figure 3
Expression of mRNA for PGE2 biosynthetic enzymes in the colon following exposure to TNBS. On day 3 after TNBS administration, the expression levels of mRNA for PGES and COX isozymes in the colons were assessed using real-time RT-PCR. mRNA expression levels are presented as fold induction relative to the expression in WT mice that did not receive TNBS treatment (assigned the value “1”). *, p < 0.05; ANOVA followed by the Bonferroni test (n = 6). Full article ">Figure 4
Western blot analysis was conducted to examine the colonic protein expression of PGES, PGDS, and COX on day 3 following TNBS administration (n = 3). Full article ">Figure 5
Levels of PGE2 (A) and PGD2 (B) in the colons of mice treated or not treated with TNBS were measured using ELISA. *, p < 0.05; ANOVA followed by the Bonferroni test (n = 6 to 11). Full article ">Figure 6
Expression of Th17/Th1-related cytokines in the colon of mPGES-1−/− mice. On day 3 following TNBS administration, the expression of IL-17A, IFNγ, TNFα, and IL-1β mRNA in the colons of mice was examined using real-time RT-PCR. The expression levels are presented as fold changes compared to the expression in WT mice that did not receive TNBS treatment (assigned the value “1”). *, p < 0.05; ANOVA followed by the Bonferroni test (n = 6). Full article ">Figure 7
Population of IL-17A- and IFNγ-producing T cells in MLNs of mPGES-1−/− mice. (A) Typical FCM data showing IL-17A-producing Th17 cells and IFNγ-producing Th1 cells in MLNs of WT and mPGES-1−/− mice. On day 3 following the administration of TNBS, MLNs were isolated and assessed using FCM, as mentioned in the Materials and Methods. (B) Proportion of IL-17A+ and IFNγ+ cells in MLNs on day 3 following TNBS treatment (n = 6). *, p < 0.05 vs. WT; t test. Full article ">

19 pages, 2635 KiB

Open AccessArticle

Association of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) Genetic Variants with Risk and Outcome of Cutaneous Melanoma

by Ana Maria Castro Ferreira, Juliana Carron, Gabriela Vilas Bôas Gomez, Vinicius de Lima Vazquez, Sergio Vicente Serrano, Gustavo Jacob Lourenço and Carmen Silvia Passos Lima

Int. J. Mol. Sci. 2024, 25(22), 12327; https://doi.org/10.3390/ijms252212327 (registering DOI) - 17 Nov 2024

Viewed by 143

Abstract

This study aimed to verify whether germline single nucleotide variants (SNV) in CTLA-4 gene, c.-1765C>T, c.-1661A>G, c.-1577G>A, and c.-1478G>A, influence the risk, clinicopathological aspects, and survival of patients with CM, as well as its functional consequences. A total of 432 patients with CM and 504 controls were evaluated. CTLA-4 genotypes were identified by real-time polymerase chain reaction (RT-PCR) and expression of CTLA-4 by quantitative PCR (qPCR) and luciferase assay. Cell cycle, proliferation, apoptosis/necrosis, and migration analyses were performed in SK-MEL-28 and A-375 cell lines modified to present homozygous ancestral or variant genotypes by CRISPR technique. Individuals with the CTLA-4 c.-1577 AA genotype and the combined CTLA-4 c.-1577 and c.-1478 AA + AA genotypes were at 1.60- and 3.12-fold higher risk of developing CM, respectively. The CTLA-4 c.-1577 AA genotype was seen as an independent predictor of worse event-free survival and was also associated with higher gene expression, higher cell proliferation, lower cell apoptosis, and higher cell migration. Our data present, for the first time, evidence that CTLA-4 c.-1577G>A alters the risk and clinical aspects of CM treated with conventional procedures and may be used for selecting individuals for tumor prevention and patients for distinct treatment. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases: 2nd Edition)

►▼ Show Figures

Figure 1

Figure 1
Signaling pathway of CTLA-4. The dendritic cell identifies antigens in the microenvironment and, with the help of the major histocompatibility complex (MHC), presents these antigens to inactive T lymphocytes, initiating the activation process (A). The first step occurs when the MHC binds to the T-cell receptor (TCR). After this binding, surface proteins of the CD80/86 family on dendritic cells bind to the CD28 receptor on T lymphocytes, promoting increased cell proliferation, enhancing cytokine production, and combating tumor melanocytes. During activation, CTLA-4, initially stored in vesicles within the cytoplasm, is released, becomes a receptor, and binds with higher affinity than CD28 to the CD80/86 family proteins (B). This binding leads to the inactivation and apoptosis of T lymphocytes, allowing tumor melanocytes to survive, as lymphocytes do not target them, blocking T-lymphocyte activation from the binding of melanocytes to antigen-presenting cells (C). By binding to tumor melanocytes, the dendritic cell prevents the antigen from being presented to T lymphocytes, thus inhibiting T-lymphocyte activation. As a result, the tumor melanocyte evades the immune system’s response. Full article ">Figure 2
Functional analyses of the ancestral and variant genotypes of the CTLA-4 c.-1577G>A. Analysis of CTLA-4 gene expression in peripheral blood of patients with cutaneous melanoma (A). Gene expression was higher in patients with AA genotype than in those with GG genotype. Relative luciferase activity in SK-MEL-28 and A-375 melanoma cell lines transfected with the ancestral plasmid (GG genotype) or with the variant plasmid (AA genotype) (B). Luciferase activity was higher in cells with AA genotype than in cells with GG genotype. Assessment of the cell cycle in strains modified to present ancestral and variant genotypes (C). Cells were identified in the G1, S, and G2 phases using flow cytometry. A higher percentage of SK-MEL-28 cells with the GG genotype was found in the G1 phase compared to those with the AA genotype *, and a higher percentage of SK-MEL-28 cells with the AA genotype was found in S phase compared to those with GG genotype **; a similar percentage of A-375 cells were seen in the G1, S, and G2 phases. Cell proliferation in SK-MEL-28 and A-375 melanoma cell lines (D). A higher percentage of SK-MEL-28 and A-375 cells with AA genotype was found in proliferation when compared to those with the GG genotype. Analysis of the assessment of apoptosis and necrosis by flow cytometry with stimulation of the immunotherapy drug ipilimumab (E). A higher percentage of SK-MEL-28 cells with GG genotype was found in necrosis compared to those with the AA genotype *; a higher percentage of cells with the AA genotype were alive compared to those with the GG genotype **; the A-375 cells with the GG genotype were in initial apoptosis when compared to cells with the AA genotype. Full article ">Figure 3
Transcription factor binding sites for the CTLA-4 1577G>A (rs11571316) single-nucleotide polymorphism (SNP). Binding of the transcription factor POUPF2 in the 3′-5′ direction of the CTLA-4 gene (A). Binding of the transcription factor HMGA1 in the 3′-5′ direction of the CTLA-4 gene (B). The gray square represents the SNP alleles. Full article ">Figure 4
Cell migration by wound healing assay in melanoma cell lines SK-MEL-28 (A) and A-375 (B). Cells with the AA genotype of the CTLA-4 c.-1577G>A single nucleotide variant showed a higher percentage of wound closure after 16 h. Full article ">

16 pages, 4022 KiB

Open AccessArticle

Berberine Mitigates Sepsis-Associated Acute Kidney Injury in Aged Rats by Preserving Mitochondrial Integrity and Inhibiting TLR4/NF-κB and NLRP3 Inflammasome Activations

by Ruedeemars Yubolphan, Anongporn Kobroob, Apisek Kongkaew, Natthakarn Chiranthanut, Natthanicha Jinadang and Orawan Wongmekiat

Antioxidants 2024, 13(11), 1398; https://doi.org/10.3390/antiox13111398 - 15 Nov 2024

Viewed by 260

Abstract

Sepsis-associated acute kidney injury (SA-AKI) presents a severe challenge in the elderly due to increasing incidence, high mortality, and the lack of specific effective treatments. Exploring novel and secure preventive and/or therapeutic approaches is critical and urgent. Berberine (BBR), an isoquinoline alkaloid with anti-inflammatory, antioxidant, and immunomodulatory properties, has shown beneficial effects in various kidney diseases. This study examined whether BBR could protect against SA-AKI in aged rats. Sepsis was induced in 26-month-old male Wistar rats by cecal ligation and puncture (CLP), either with or without BBR pretreatment. CLP induction led to SA-AKI, as indicated by elevated serum levels of malondialdehyde, tumor necrosis factor-alpha, urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL), along with histopathological features of kidney damage. Key indicators of kidney oxidative stress, mitochondrial dysfunction, apoptosis, and activations of the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling, including the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome pathway, were also elevated following CLP induction. BBR pretreatment substantially mitigated these adverse effects, suggesting that it protects against SA-AKI in aged rats by reducing oxidative stress, preserving mitochondrial integrity, and inhibiting key inflammatory pathways. These findings highlight the potential of BBR as a therapeutic agent for managing SA-AKI in elderly populations. Full article

(This article belongs to the Special Issue Oxidative Stress in Renal Health)

►▼ Show Figures

Figure 1

11 pages, 2222 KiB

Open AccessArticle

First Report of Bacterial Kidney Disease (BKD) Caused by Renibacterium salmoninarum in Chum Salmon (Oncorhynchus keta) Farmed in South Korea

by Kyoung-Hui Kong, In-Ha Gong, Sung-Ju Jung, Myung-Joo Oh, Myung-Hwa Jung, Hyun-Ja Han, Hyoung Jun Kim and Wi-Sik Kim

Microorganisms 2024, 12(11), 2329; https://doi.org/10.3390/microorganisms12112329 - 15 Nov 2024

Viewed by 240

Abstract

In 2021, a prominent increase in mortality was observed in juvenile and subadult cultured chum salmon (Oncorhynchus keta) on a mariculture farm in Jeollanam-do Province, South Korea. The affected fish displayed distinct symptoms: pale gills, petechial hemorrhages in the muscles, and white nodules on the kidneys. Infectious pancreatic necrosis virus (IPNV) was cultured from some fish samples using fish cell lines. Bacteria were isolated from various fish tissues using kidney disease medium-two (KDM-2) culture medium. By detecting and sequencing the 16S rRNA gene using DNA extracted from the kidneys of the infected fish via PCR, the isolated bacteria were identified as Renibacterium salmoninarum. Histopathological examination primarily focused on hematopoietic tissues of kidneys and revealed clear evidence of severe necrosis and granulomatous changes. Additionally, nuclei with peripherally displaced chromatin were abundant in the kidneys of affected fish. These findings suggest that mass mortality of chum salmon was caused by R. salmoninarum, which induced typical bacterial kidney disease (BKD) symptoms, without IPNV infection. This represents the first outbreak of BKD attributed to R. salmoninarum infection in farmed chum salmon in South Korea. Full article

(This article belongs to the Section Veterinary Microbiology)

►▼ Show Figures

Figure 1

Figure 1
Geographical location of the aquaculture farm in Goheung, Korea. Full article ">Figure 2
Cumulative mortality of subadult and juvenile chum salmon relative to changes in salinity. Full article ">Figure 3
Affected chum salmon, showing petechial hemorrhages in the muscle (black arrowhead) and grayish-white nodules in the kidney (white arrowhead) of (a,b) subadult and (c,d) juvenile fish. Scale bars = 1 cm. Full article ">Figure 4
Morphology of CHSE-214 cell lines: (a) normal CHSE-214 cell (×100) and (b) CHSE-214 infected with IPNV (×100). Full article ">Figure 5
Appearance of Renibacterium salmoninarum colonies on KDM-2 after incubation for 19 d at 15 °C. Full article ">Figure 6
PCR result using DNA extracted from 12 diseased fish (M = marker; S1–S6 = subadult fish; J1–J6 = juvenile fish; DW = negative control). Full article ">Figure 7
Histopathology and immunohistochemical analysis of kidney tissues of chum salmon. (a) Histopathology of the kidney showing tissue necrosis and granuloma by hematoxylin and eosin staining. g: necrosis in the central part of a granuloma; n: necrotic cells. Scale bars = 100 μm. Immunohistochemical analysis showing a positive reaction of necrotic cells in the kidney (b) and no reaction in the negative control (c). Bar = 50 μm. Full article ">

16 pages, 5276 KiB

Open AccessArticle

Multimodal MRI and ¹H-MRS for Preoperative Stratification of High-Risk Molecular Subtype in Adult-Type Diffuse Gliomas

by Xin Han, Kai Xiao, Jie Bai, Fengqi Li, Bixiao Cui, Ye Cheng, Huawei Liu and Jie Lu

Diagnostics 2024, 14(22), 2569; https://doi.org/10.3390/diagnostics14222569 - 15 Nov 2024

Viewed by 264

Abstract

Isocitrate dehydrogenase (IDH) and O⁶-methylguanine-DNA methyltransferase (MGMT) genes are critical molecular markers in determining treatment options and predicting the prognosis of adult-type diffuse gliomas. Objectives: this study aimed to investigate whether multimodal MRI enables the differentiation of genotypes in adult-type diffuse gliomas. Methods: a total of 116 adult-type diffuse glioma patients (61 males, 51.5 (37, 62) years old) who underwent multimodal MRI before surgery were retrospectively analysed. Multimodal MRI included conventional MRI, proton magnetic resonance spectroscopy (¹H-MRS), and diffusion tensor imaging (DTI). Conventional visual features, N-acetyl-aspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, Cho/NAA, fractional anisotropy (FA), mean diffusivity (MD), and diffusion histogram parameters were extracted on the whole tumour. Multimodal MRI parameters of IDH-mutant and IDH-wildtype gliomas were compared using the Mann–Whitney U test, Student’s t-test, or Pearson chi-square tests. Logistic regression was used to select the MRI parameters to predict IDH-mutant gliomas. Furthermore, multimodal MRI parameters were selected to establish models for predicting MGMT methylation in the IDH-wildtype gliomas. The performance of models was evaluated by the receiver operating characteristics curve. Results: a total of 56 patients with IDH-mutant gliomas and 60 patients with IDH-wildtype glioblastomas (GBM) (37 with methylated MGMT and 17 with unmethylated MGMT) were diagnosed by 2021 WHO classification criteria. The enhancement degree (OR = 4.298, p < 0.001), necrosis/cyst (OR = 5.381, p = 0.011), NAA/Cr (OR = 0.497, p = 0.037), FA-Skewness (OR = 0.497, p = 0.033), MD-Skewness (OR = 1.849, p = 0.035), FA_mean (OR = 1.924, p = 0.049) were independent factors for the multimodal combined prediction model in predicting IDH-mutant gliomas. The combined modal based on conventional MRI, ¹H-MRS, DTI parameters, and histogram performed best in predicting IDH-wildtype status (AUC = 0.890). However, only NAA/Cr (OR = 0.17, p = 0.043) and FA (OR = 0.38, p = 0.015) were associated with MGMT methylated in IDH-wildtype GBM. The combination of NAA/Cr and FA-Median is more accurate for predicting MGMT methylation levels than using these elements alone (AUC, 0.847 vs. 0.695/0.684). Conclusions: multimodal MRI based on conventional MRI, ¹H-MRS, and DTI can provide compound imaging markers for stratified individual diagnosis of IDH mutant and MGMT promoter methylation in adult-type diffuse gliomas. Full article

(This article belongs to the Special Issue Clinical Applications and Potential of Magnetic Resonance Spectroscopy)

►▼ Show Figures

Figure 1

Figure 1
Flow chart of the inclusion and exclusion criteria. Full article ">Figure 2
Delineation of tumour regions of interest and volume of interest; (A) Delineation of the ROI within the solid part of a glioma; (B) Delineation of the ROI within the contralateral frontal part of the centrum semiovale; (C) Delineation of the VOI for the whole tumor area. ROI, region of interest; VOI, volume of interest; three-dimensional T1CE, three-dimensional contrast-enhanced T1-weighted sequence; T2 FLAIR, T2-weighted fluid-attenuated inversion recovery; FA, fractional anisotropy; MD, mean diffusivity. Full article ">Figure 3
Forest plot of univariate logistic regression and the results of LASSO regression for different modalities MRI. (A) Conventional MRI results. (B) 1H-MRS results. (C) DIT histogram results. (D) Conventional DTI results. Full article ">Figure 4
Multimodal MRI of IDH-wildtype and IDH-mutant adult-type diffuse glioma cases. (A) A 59-year-old male patient, IDH-wildtype GBM: the mass in the left frontal lobe is isointense or hypointense on T1WI and heterogeneously hyperintense on T2WI. The tumour parenchyma show marked circular enhancement on the enhanced scan, with severe oedema and necrosis, with relatively high FAmean (0.163) and low MDmin (558.04 × 10−6 mm2/s). 1H-MRS analysis (voxel size = 1.3 cm × 1.3 cm × 2.0 cm) showed relatively low level of NAA/Cr (0.905). (B) A 38-year-old male patient, IDH-mutant adult-type diffuse glioma: the mass located in the right frontal lobe with circular hypointense on T1WI and hyperintense on T2WI, and no enhancement on enhanced scans, with the absence of peritumoral oedema and necrosis, with relatively low FAmean (0.101) and high MDmin (1386.08 × 10−6 mm2/s). 1H-MRS analysis (voxel size = 1.3 cm × 1.3 cm × 2.0 cm) showed moderate level of NAA/Cr (1.13). Full article ">Figure 5
Multimodal MRI of MGMT-methylated and MGMT-unmethylated IDH-wildtype GBM cases. (A) A 54-year-old female patient, IDH-wildtype with MGMT methylated: the mass located in the right parietal lobe with long T1 and long T2 signals. The tumour parenchyma show obvious-heterogeneous enhancement, with peritumoral oedema and necrosis, with FA-Median = 0.215. 1H-MRS analysis (voxel size = 1.3 cm × 1.3 cm × 2.0 cm) showed the level of NAA/Cr is 0.674. (B) A 50-year-old male patient, IDH-wildtype with MGMT unmethylated: the mass located in the left frontal lobe with circular long T1 and long T2 signals and obvious heterogeneous enhancement on enhanced scans like the previous case, with the presence of peritumoral oedema and necrosis, with FA-Median = 0.176. 1H-MRS analysis (voxel size = 1.3 cm × 1.3 cm × 2.0 cm) showed the level of NAA/Cr is 0.401. Full article ">Figure 6
ROC curves for diagnostic performance of prediction models. (A) ROC curve for IDH status prediction in the 5-fold cross-validation. (B) ROC curve for MGMT status prediction in the 5-fold cross-validation. ROC is the receiver operating characteristic. AUC is the area under the curve. Full article ">

20 pages, 2243 KiB

Open AccessArticle

New Pharmacological Insight into Etanercept and Pregabalin in Allodynia and Nociception: Behavioral Studies in a Murine Neuropathic Pain Model

by Loulwah Alothman, Emad Alhadlaq, Asma Alhussain, Alwaleed Alabdulkarim, Youssef Sari and Shakir D. AlSharari

Brain Sci. 2024, 14(11), 1145; https://doi.org/10.3390/brainsci14111145 - 15 Nov 2024

Viewed by 270

Abstract

Background/Objectives: Neuropathic pain is challenging to treat, often resistant to current therapies, and associated with significant side effects. Pregabalin, an anticonvulsant that modulates calcium channels, is effective but can impair mental and motor functions, especially in older patients. To improve patient outcomes, reducing the doses of pregabalin and combining it with other drugs targeting different neuropathic pain mechanisms may be beneficial. TNF-α blockers such as etanercept have shown potential in addressing neuropathic pain by affecting sodium channels, synaptic transmission, and neuroinflammation. This study evaluates the efficacy and safety of combining low doses of etanercept and pregabalin in allodynia and nociceptive tests. Materials and Methods: Male C57/BL6 mice underwent chronic constriction injury (CCI) of the sciatic nerve to induce neuropathic pain. They were divided into seven groups: sham control, CCI control, low and high doses of pregabalin, low and high doses of etanercept, and a combination of low doses of both drugs. Behavioral tests, including von Frey, hot-plate, and rotarod tests, were used to assess pain responses and motor activity. Results: The results indicated that a high dose of pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia but impaired motor function. Conversely, low doses of etanercept alone had no significant effect. However, the combination of low doses of etanercept (20 mg/kg) and pregabalin (5 mg/kg) effectively alleviated pain without compromising locomotor activity. Conclusions: These results suggest a novel therapeutic strategy for neuropathic pain, enhancing analgesic efficacy while minimizing adverse effects. Full article

(This article belongs to the Section Neuroscience of Pain)

►▼ Show Figures

Figure 1

15 pages, 964 KiB

Open AccessSystematic Review

Purslane Ameliorates Inflammation and Oxidative Stress in Diabetes Mellitus: A Systematic Review

by Zikho Nkhumeleni, Wendy N. Phoswa and Kabelo Mokgalaboni

Int. J. Mol. Sci. 2024, 25(22), 12276; https://doi.org/10.3390/ijms252212276 - 15 Nov 2024

Viewed by 263

Abstract

Type 2 diabetes (T2D) is characterised by insulin resistance and leads to hyperglycaemia. Its prevalence and associated complications continue to rise exponentially, despite the existence of pharmaceutical drugs, and this has prompted research into exploring safer herbal remedies. Portulaca oleracea (purslane) has been investigated in animal and clinical trials to explore its effects on diabetes, yielding conflicting results. This study aimed to evaluate the effects of purslane on inflammation and oxidative stress in diabetes mellitus. We conducted a comprehensive literature search on Scopus PubMed, and through a manual bibliographical search to find relevant studies from inception to 13 September 2024. The search terms included purslane, portulaca oleracea, and type 2 diabetes mellitus. Of the 38 retrieved studies, 12 were considered relevant and underwent critical review. Evidence from rodent studies showed decreased inflammatory markers such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), nuclear factor kappa-beta (NF-κβ), and C-reactive (CRP), while interleukin-10 (IL-10) was increased after intervention with purslane. The markers of oxidative stress such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) levels increased, thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS) and malondialdehyde (MDA) decreased. Notably, the evidence from clinical trials showed a significant reduction in NF-κβ and CRP after purslane treatment; however, no effect was observed on MDA and TAC. The evidence gathered in this study suggests that purslane exerts anti-inflammatory properties by downregulating NF-κβ, thus suppressing the production of associated pro-inflammatory cytokines. Therefore, purslane may be used as an antioxidant and inflammatory agent for diabetes. However, further clinical evidence with a broader population is required to validate the therapeutic properties of purslane in diabetes. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Health and Disease)

►▼ Show Figures

Figure 1

Figure 1
Purslane and its active compounds [<a href="#B26-ijms-25-12276" class="html-bibr">26</a>,<a href="#B29-ijms-25-12276" class="html-bibr">29</a>,<a href="#B31-ijms-25-12276" class="html-bibr">31</a>]. An active compound is found in purslane leaves and stems. Full article ">Figure 2
PRISMA flow chart depicting study selection, screening and inclusion. Full article ">

13 pages, 635 KiB

Open AccessArticle

Carnosine Supplementation Has No Effect on Inflammatory Markers in Adults with Prediabetes and Type 2 Diabetes: A Randomised Controlled Trial

by Saeede Saadati, Maximilian de Courten, Cyril Deceneux, Magdalena Plebanski, David Scott, Jakub Mesinovic, Paul Jansons, Giancarlo Aldini, James Cameron, Jack Feehan, Aya Mousa and Barbora de Courten

Nutrients 2024, 16(22), 3900; https://doi.org/10.3390/nu16223900 - 15 Nov 2024

Viewed by 250

Abstract

Background/Objectives: In vitro studies suggest that carnosine reduces inflammation by upregulating anti-inflammatory mediators and downregulating pro-inflammatory cytokines. However, human clinical trials examining the effects of carnosine on inflammatory biomarkers are scant. We conducted a secondary analysis of a double-blind randomised controlled trial (RCT) to examine the effects of carnosine supplementation on inflammatory markers and adipokines in participants with prediabetes or well-controlled type 2 diabetes (T2D). Methods: Out of 88 participants who were recruited, 49 adults with prediabetes or well-controlled T2D (HbA1c: 6.6 ± 0.7% [mean ± SD]) who were treated with diet and/or metformin were eligible for inclusion. Participants were randomised to receive 2 g/day of carnosine or a matching placebo for 14 weeks. We measured serum concentrations of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-10, C-reactive protein (CRP), tumour necrosis factor-α (TNF-α), adiponectin, leptin, adipsin, serpin, and resistin levels at baseline and after 14 weeks. The trial was registered at clinicaltrials.gov (NCT02917928). Results: Forty-one participants (M = 29/F = 12) aged 53 (42.6, 59.3) years [median (IQR)] completed the trial. After 14 weeks of supplementation, changes in pro- and anti-inflammatory cytokine and adipokine levels did not differ between the carnosine and placebo groups (p > 0.05 for all). The results remained unchanged after adjustment for confounders including age, sex, and anthropometric measures (e.g., body fat percentage and visceral adipose tissue). Conclusions: In individuals with prediabetes and well-controlled T2D, carnosine supplementation did not result in any significant changes in inflammatory markers. Larger RCTs with longer follow-up durations are needed to evaluate whether carnosine may be beneficial in individuals with poorly controlled T2D. Full article

(This article belongs to the Section Nutrition and Diabetes)

►▼ Show Figures

Figure 1

Figure 1
Study design and flow of participants. Full article ">

12 pages, 11436 KiB

Open AccessCase Report

The Management of a Giant Convexity en Plaque Anaplastic Meningioma with Gerstmann Syndrome: A Case Report of Surgical Outcomes in a 76-Year-Old Male

by Corneliu Toader, Felix Mircea Brehar, Mugurel Petrinel Radoi, Matei Serban, Razvan-Adrian Covache-Busuioc, Ghaith S. Aljboor and Radu M. Gorgan

Diagnostics 2024, 14(22), 2566; https://doi.org/10.3390/diagnostics14222566 - 15 Nov 2024

Viewed by 231

Abstract

Background: This case report highlights a rare presentation of a giant convexity en plaque anaplastic meningioma, located in the left frontoparietal parasagittal region, infiltrating the superior sagittal sinus, and associated with Gerstmann syndrome. This study aims to explore the clinical challenges, surgical management, and potential reversibility of neurological deficits induced by the tumor, including those characteristic of Gerstmann syndrome. Methods: A 76-year-old male patient presented with a history of worsening expressive aphasia and cognitive impairments, culminating in a generalized seizure. Preoperative imaging confirmed a 4 × 6 cm highly vascularized tumor with significant peritumoral edema. The patient underwent near-total resection of the tumor, aiming for a Simpson grade 2 resection, while managing hypervascularity and brain edema. Histological analysis confirmed the diagnosis of anaplastic meningioma (WHO Grade III), showing features such as necrosis, brain invasion, and high mitotic activity. Results: Post-surgical follow-up demonstrated significant improvement in the patient’s neurological deficits, particularly in expressive language and cognitive function, suggesting a potential reversal of Gerstmann syndrome. Postoperative imaging revealed a moderate degree of cerebral collapse and absence of contrast leakage. Two-month follow-up confirmed no recurrence of neurological deficits. Conclusions: This case emphasizes the complexity of managing giant convexity en plaque anaplastic meningiomas, particularly when associated with Gerstmann syndrome. Surgical resection, despite the challenges posed by tumor size, hypervascularity, and peritumoral edema, can lead to significant neurological recovery, highlighting the potential reversibility of tumor-induced Gerstmann syndrome. Full article

(This article belongs to the Special Issue Meningioma: Radiomics, Diagnosis and Management)

►▼ Show Figures

Figure 1

Figure 1
Preoperative MRI. The preoperative MRI scans display a large, convexity en plaque meningioma in the left frontoparietal region, extending toward the parasagittal area. The tumor exhibits homogenous enhancement on T2-weighted images, indicating a highly vascular lesion consistent with meningiomas. The tumor’s dimensions are approximately 4 × 6 cm, and it infiltrates the dura mater, extending deeply toward the paraventricular area. This infiltration reaches the superior sagittal sinus, posing challenges for surgical resection due to the involvement of this critical venous structure. The dashed frames indicate the area of interest, while the yellow lines mark intersecting planes across axial, sagittal, and coronal views, facilitating anatomical correlation and spatial orientation for surgical planning. Full article ">Figure 2
Preoperative MRI. The preoperative MRI scans illustrate a large, homogeneously enhancing convexity en plaque meningioma located in the left frontoparietal region. In these images, the tumor’s infiltration of the dura mater and partial involvement of the superior sagittal sinus are evident, posing additional complexity for surgical resection. Full article ">Figure 3
Left frontoparietal parasagittal region. Full article ">Figure 4
Macroscopic view of the tumor. Full article ">Figure 5
CT scan conducted 7 days post-surgery. Full article ">Figure 6
CT scan conducted 14 days after the surgery. Full article ">Figure 7
CT scan shows left paramedian frontal hypodensity, without contrast outlet. Full article ">Figure 8
The histological images illustrate key features of anaplastic meningioma (WHO Grade III), including extensive necrosis, brain and vascular invasion, and high cellular atypia. Tumor cells show pleomorphism, hyperchromatic nuclei, and high mitotic activity, indicative of aggressive malignancy. Hemorrhagic areas highlight rapid tumor growth, while classic meningioma structures like meningothelial whorls and psammoma bodies are also present. These findings emphasize the highly invasive and malignant nature of anaplastic meningiomas. Anaplastic meningiomas, classified as WHO Grade III, exhibit aggressive features such as necrosis, brain invasion, and overtly malignant cytomorphology. The histological sections (Images 1–3,6,7) highlight key pathological characteristics, including extensive necrosis, brain parenchyma invasion, and cellular pleomorphism. In particular, Image 1 shows marked necrosis and brain invasion, a hallmark of aggressive meningioma behavior, while Image 2 reveals cytomorphology resembling high-grade sarcoma, with pleomorphic, hyperchromatic nuclei and abundant mitotic figures. Vascular invasion, visible in Image 3, is another critical feature of high-grade meningiomas, increasing metastatic potential. Poor differentiation and hemorrhagic areas (Images 4,8) underscore the malignancy, with irregular tumor cells and compromised vascular support leading to hemorrhage. Classic meningioma features, such as whorls of meningothelial cells and psammoma bodies, are also observed (Image 5), which, while typical of benign forms, can still be present in more aggressive variants. These images, stained with HE, provide a comprehensive view of the aggressive, infiltrative, and poorly differentiated nature of anaplastic meningiomas. Full article ">

13 pages, 2313 KiB

Open AccessArticle

Lactobacillus helveticus HY7801 Improves Premenstrual Syndrome Symptoms by Regulating Sex Hormones and Inflammatory Cytokines in a Mouse Model of Metoclopramide-Induced Hyperprolactinemia

by Hyeon-Ji Kim, Ji-Woong Jeong, Joo-Yun Kim, Jae-Jung Shim and Jae-Hwan Lee

Nutrients 2024, 16(22), 3889; https://doi.org/10.3390/nu16223889 - 14 Nov 2024

Viewed by 348

Abstract

Background/Objectives: Premenstrual syndrome (PMS), a clinical condition that manifests in the form of various physical and psychological symptoms, occurs periodically during the luteal phase of the menstrual cycle and reduces quality of life. Methods: Here, we conducted in vitro and in vivo experiments to investigate the effects of Lactobacillus helveticus HY7801 (HY7801) on PMS symptoms. Results: Data from the in vitro experiments showed that HY7801 inhibits prolactin secretion by estradiol-induced GH3 cells, as well as the secretion of pro-inflammatory cytokines by LPS-induced Raw 264.7 cells. Additionally, the oral administration of HY7801 (10⁹ colony-forming units/kg/day) to mice with metoclopramide-induced hyperprolactinemia reduced uterine tissue mass and endometrial thickness, both of which were increased excessively in the presence of prolactin. HY7801 also regulated the serum levels of follicle-stimulating hormone and prostaglandin E1/E2, as well as recovering the progesterone/estradiol ratio. HY7801 also downregulated the serum levels of prolactin and pro-inflammatory cytokines such as interleukin (Il)-6, tumor necrosis factor-alpha (Tnf), and IL-1β. Finally, HY7801 reduced the expression of genes encoding inflammatory cytokines (i.e., Tnf and Il-6), cyclooxygenase-2 (Cox-2), and inducible nitric oxide synthase (iNOS) in mice with hyperprolactinemia. Conclusion: In summary, HY7801 may be a functional bacterium that alleviates PMS symptoms by modulating hormones and inflammatory markers. Full article

(This article belongs to the Special Issue Eating Behavior and Women's Health)

►▼ Show Figures

Figure 1

Figure 1
Effect of HY7801 on (A) the viability of GH3 cells and (B) the secretion of prolactin by estradiol (E2)-treated GH3 cells. Data are presented as the mean ± SE. ### p < 0.001 vs. untreated group; * p < 0.05 vs. E2-treated group. E2: estradiol; HY7801: Lactobacillus helveticus HY7801 + E2. Full article ">Figure 2
Effects of HY7801 on pro-inflammatory cytokines secreted by LPS-induced Raw 264.7 cells. (A) IL-6; (B) TNF-α. Data are presented as the mean ± SE. ### p < 0.001 vs. untreated group; *** p < 0.001 vs. LPS-treated group. IL-6: interleukin-6; TNF-α: tumor necrosis factor-alpha; LPS: lipopolysaccharide; HY7801: Lactobacillus helveticus HY7801 + LPS. Full article ">Figure 3
Effect of HY7801 on physiological indicators in mice with MCP-induced hyperprolactinemia. (A) Dietary intake; (B) water intake; (C) change in body weight; (D) mass of uterine tissue; and (E) mass of spleen tissue. Data are presented as the mean ± SE. # p < 0.05 vs. CON group; * p < 0.05 vs. MCP group. CON: non-treatment group; MCP: metoclopramide-induced mice; PFM: prefemin (100 mg/kg/day) + MCP; HY7801: Lactobacillus helveticus HY7801 (109 CFU/kg/day) + MCP. Full article ">Figure 4
Histological analysis of uterine tissue from mice with MCP-induced hyperprolactinemia. (A) Hematoxylin and eosin-stained sections; 200× magnification; arrows point to the endometrium. (B) Endometrial thickness. Data are presented as the mean ± SE. ### p < 0.001 vs. CON group; *** p < 0.001 vs. MCP group. CON: non-treatment group; MCP: metoclopramide-induced mice; PFM: prefemin (100 mg/kg/day) + MCP; HY7801: Lactobacillus helveticus HY7801 (109 CFU/kg/day) + MCP. Full article ">Figure 5
Effect of HY7801 on serum levels of sex hormones in mice with MCP-induced hyperprolactinemia. (A) Prolactin; (B) FSH; and (C) the progesterone/estradiol ratio. Data are presented as the mean ± SE. # p < 0.05 and ## p < 0.01 vs. CON group; * p < 0.05 and ** p < 0.01 vs. MCP group. FSH: follicle-stimulating hormone; CON: non-treatment group; MCP: metoclopramide-induced mice; PFM: prefemin (100 mg/kg/day) + MCP; HY7801: Lactobacillus helveticus HY7801 (109 CFU/kg/day) + MCP. Full article ">Figure 6
Effect of HY7801 on serum levels of pro-inflammatory cytokines and prostaglandin in mice with MCP-induced hyperprolactinemia. (A) IL-6; (B) TNF-α; (C) IL-1β; (D) PGE1; (E) PGE2 levels; and (F) the PGE1/PGE2 ratio. Data are presented as the mean ± SE. # p < 0.05 vs. CON group; * p < 0.05 vs. MCP group. IL-6: interleukin-6; TNF: tumor necrosis factor-alpha; IL-1β: interleukin-1β; PGE1: prostaglandin E1; PGE2: prostaglandin E2; CON: non-treatment group; MCP: metoclopramide-induced mice; PFM: prefemin (100 mg/kg/day) + MCP; HY7801: Lactobacillus helveticus HY7801 (109 CFU/kg/day) + MCP. Full article ">Figure 7
Effect of HY7801 on the expression of mRNA encoding inflammation-related genes in uterine tissues from MCP-induced hyperprolactinemia mice. (A) Il-6; (B) Tnf; (C) Cox-2; and (D) iNOS. Data are presented as the mean ± SE. # p < 0.05 and ## p < 0.01 vs. CON group; * p < 0.05 and ** p < 0.01 vs. MCP group. Il-6: interleukin-6; Tnf: tumor necrosis factor-alpha; Cox-2: cyclooxygenase-2; iNOS: inducible nitric oxide synthase; CON: non-treatment group; MCP: metoclopramide-induced mice; PFM: prefemin (100 mg/kg/day) + MCP; HY7801: Lactobacillus helveticus HY7801 (109 CFU/kg/day) + MCP. Full article ">

15 pages, 2164 KiB

Open AccessArticle

Rhabdomyolysis After Prolonged Tourniquet Application Is Associated with Reversible Acute Kidney Injury (AKI) in Rats

by Thomas J. Walters, Luciana N. Torres, Kathy L. Ryan, Robert V. Hainline, Stephanie M. Lipiec, Ijeoma E. Obi, Jennifer Ybarra, Casey E. Niland and Lusha Xiang

Biomedicines 2024, 12(11), 2607; https://doi.org/10.3390/biomedicines12112607 - 14 Nov 2024

Viewed by 305

Abstract

Extremity trauma, including ischemia (e.g., prolonged tourniquet application or crush), is common among battlefield injuries. Injured muscle releases toxins leading to rhabdomyolysis and, potentially, acute kidney injury (AKI). The goal of this study was to characterize sequelae of ischemic extremity injury over 72 h, focusing on time courses of rhabdomyolysis and AKI. Male Sprague Dawley rats were placed into two groups. Ischemic injury was produced in anesthetized rats using bilateral tourniquets (TK; n = 10) for 5 h; control (CON; n = 9) rats were treated identically without TK application. Indicators of rhabdomyolysis and renal function were measured in conscious rats 1 day preinjury (baseline, BL) and then at 1.5, 24, 48, and 72 h post-TK release. Prolonged TK application produced necrosis in both muscle and bone marrow but not in kidney. The wet/dry weights indicated edema in injured limbs at 72 h (4.1 (0.5) (TK) vs. 2.9 (0.1) (CON); p < 0.001). TK rats exhibited a 100-fold increase in creatine kinase activity compared to CON at 1.5 h (20,040 (7265) U/L vs. 195 (86) U/L (mean (SD); p < 0.0001). TK decreased the mean glomerular filtration rate (GFR; p < 0.001) at 1.5 h, but these values recovered by 24 h in concert with elevated urinary flow and alkalinization. Prolonged ischemic extremity injury therefore produced severe rhabdomyolysis without irreversible renal damage. Full article

(This article belongs to the Section Molecular and Translational Medicine)

►▼ Show Figures

Figure 1

Figure 1
Timeline of the 5-day experimental protocol. The blue boxes represent the anesthetized periods (isoflurane), the yellow box represents the 1.5 h recovery from anesthesia after tourniquet (TK) treatment, and the green boxes represent conscious periods in the metabolic cages. The red arrows represent the time points for blood sample collections and measurements of mean arterial pressure (MAP), heart rate, and glomerular filtration rate (GFR), while the yellow arrows represent the time points for urine collection and measurements of water and food intake from the previous day. “Cath. Surg” represents the catheterization of the carotid artery on Day 1. Full article ">Figure 2
Parameters defining injury to hindlimb muscle following 5 h of tourniquet (TK) application. Panel (A), plasma creatine kinase (n = 4/group); Panel (B), limb wet/dry ratio (n= 7 and 6 for CON and TK, respectively); Panels (C,D), muscle from two rats (H&E, 40X). Panel (C) represents normal control muscle tissue. Panel (D) represents muscle from a rat following TK placement. Myocytes exhibit polyphasic degenerative and necrotic changes characterized by pale, swollen, and vacuolated sarcoplasm with disrupted myofibrils (degeneration); hypereosinophilic, shrunken, and fragmented or hyalinized sarcoplasm with loss of cross striations and a pyknotic or karyorrhectic nucleus (necrosis); or lightly basophilic sarcoplasm with multiple internalized, linearly arranged, vesiculate nuclei with prominent nucleoli (regeneration). Occasionally, multifocal random foci of inflammatory cells expand the epimysium, perimysium, and endomysium and surround and separate individual myocytes, composed primarily of neutrophils and histiocytes with rare lymphocytes and plasma cells. CON, control group; TK, tourniquet group; BL, baseline. * p < 0.05 between CON and TK groups at the time point; # p < 0.05 compared to BL within treatment group. Full article ">Figure 3
Systemic hemodynamics following 5 h of tourniquet application. Panel (A): MAP, mean arterial pressure; Panel (B): HR, heart rate. BL, baseline; CON, control group; TK, tourniquet group. The respective N for each group for both panels at BL, 1.5 h, 24 h, 46 h, and 72 h was 7, 7, 5, 7, 6 for CON and 8, 7, 6, 5, 5 for TK. * p < 0.05 between CON and TK groups; # p < 0.05 compared to BL within treatment group. Full article ">Figure 4
Parameters defining renal function and injury following 5 h of tourniquet (TK) application. Panel (A): Glomerular filtration rate (GFR) measured noninvasively using the FITC-sinistrin technique. The respective N for each group at BL, 1.5 h, 24 h, 46 h, and 72 h was 7, 7, 5, 7, 7 for CON and 8, 7, 6, 6, 6 for TK. Panel (B): Creatinine clearance normalized to body weight. The respective N for each group at BL, 24 h, 46 h, and 72 h was 7, 4, 6, 6 for CON and 8, 5, 5, 6 for TK. GFR, glomerular filtration rate; BL, baseline; CON, control group. * p < 0.05 between CON and TK groups; # p < 0.05 compared to BL within treatment group. Full article ">Figure 5
Blood parameters. Panel (A): hematocrit (HCT); Panel (B): hemoglobin; Panel (C): potassium; Panel (D): bicarbonate (HCO3−). BL, baseline; CON, control group; TK, tourniquet group; PCV, packed cell volume. * p < 0.05 between CON and TK groups; # p < 0.05 compared to BL within treatment group. The respective N for each group at BL, 1.5 h, 24 h, 46 h, and 72 h was 7, 7, 5, 7, 7 for CON and 8, 7, 6, 5, 6 for TK. Full article ">Figure 6
Water consumption (Panel (A)) and urinary parameters (Panels (B–D)). Panel (B): daily urine output, normalized to body weight (BW); Panel (C): urinary protein excretion, normalized to BW; Panel (D): urinary pH. BL, baseline; CON, control group (solid circle); TK, tourniquet group (hollow circle). * p < 0.05 between CON and TK groups; # p < 0.05 compared to BL within treatment group. The respective N for each group at BL, 24 h, 46 h, and 72 h was 7, 7, 6, and 7 for CON and 8, 6, 6, and 6 for TK, respectively. * p < 0.05 between CON and TK groups; # p < 0.05 compared to BL within treatment group. Full article ">

11 pages, 6415 KiB

Open AccessArticle

Pathological and Ileal Microbiota Findings in Seven-Day-Old Chicks with Gizzard Lesions and Growth Delay

by Dayse Helena Lages da Silva, Luana Ferreira Marques Cordeiro, Diego Lisboa Rios, Oliveiro Caetano de Freitas Neto, Leonardo José Camargos Lara, Juan Carlos Ariute Oliveira, Flávia Figueira Aburjaile and Roselene Ecco

Poultry 2024, 3(4), 409-419; https://doi.org/10.3390/poultry3040031 - 14 Nov 2024

Viewed by 407

Abstract

Gizzard erosion and ulceration (GEU) is characterized by defects and necrosis in the koilin layer, particularly in broilers. This condition has been associated with growth retardation, runting, and economic implications for poultry producers; nevertheless, its influence on gut microbiota remains unknown. This study investigated the compositional changes in the bacterial community of the ileum of seven-day-old broiler chicks with GEU using next-generation sequencing (NGS) technology. Twenty-two samples were obtained from the ileal mucosa and contents of sixteen chicks with GEU and six without GEU raised in a conventional system located on a farm in southeast Brazil. The results revealed that bacterial phyla in both groups exhibited a similar composition, with Firmicutes representing the most abundant. Porphyromonas, Candidatus Arthromitus, and Limosilactobacillus were statistically more abundant in the group without GEU. The most prevalent genera in the group with GEU were Lactobacillus and Enterococcus, and the relative abundance of Enterococcus in the ilea of some chicks with GEU was considerable. Based on the results of the current study, necrosis in the koilin layer can change the composition of ileal microbiota. Therefore, further studies should be carried out to clarify whether GEU and consequently poor digestibility of the feed cause significant changes in the intestinal microbiota. Full article

►▼ Show Figures

Figure 1

16 pages, 1091 KiB

Open AccessReview

Beyond Suppression: Peripheral T Cell Responses to Vaccination in Inflammatory Bowel Disease Patients Undergoing Anti-Tumor-Necrosis-Factor Therapy

by Martin Qui and Ennaliza Salazar

Vaccines 2024, 12(11), 1280; https://doi.org/10.3390/vaccines12111280 - 14 Nov 2024

Viewed by 455

Abstract

Alimentary tract inflammation in inflammatory bowel disease (IBD) is treated by systemically administered drugs that alter fundamental host immune responses. Biologics that target tumor necrosis factor (TNF) are first-line biologics in IBD, used widely for their effectiveness, steroid-sparing quality, and lower cost. While they enable a significant proportion of patients to achieve clinical remission, they carry an increased risk of infection and poor serological responses to vaccination. Conversely, our understanding of adaptive T cell responses in anti-TNF-treated IBD patients remains limited. The introduction of COVID-19 vaccines has prompted research that both challenges and refines our view on immunomodulatory therapy and its potential implications for immunity and protection. Here, we review these emergent findings, evaluate how they shape our understanding of vaccine-induced T cell responses in the context of anti-TNF therapy in IBD, and provide a perspective highlighting the need for a holistic evaluation of both cellular and humoral immunity in this population. Full article

(This article belongs to the Special Issue Immune Responses in Patients with Inflammatory Bowel Disease after Vaccination)

►▼ Show Figures

Figure 1

Figure 1
Magnitude of vaccine-induced adaptive immune responses in patients treated with anti-TNF therapy compared to healthy controls. Despite the defective induction of vaccine-induced humoral (IgG) responses, cellular TH1/IL-10 responses persist. The line styles represent the different types of vaccine-induced responses measured, as labelled within the figure. Full article ">Figure 2
Impact of anti-inflammatory drugs on the magnitude of peripheral adaptive immune responses in patients with IBD induced by primary vaccination. Most vaccines induce humoral (IgG) and cellular responses (TH1 or potentially IL-10) to vaccine antigens. The vaccination of patients undergoing anti-TNF therapy induces poor IgG titers but intact or higher TH1/IL-10 cellular responses. Corticosteroids are associated with lower-magnitude induction of responses; however, their effects remain unknown for vaccine-induced IL-10 responses. The other anti-inflammatory drugs (non-anti-TNF biologics and antimetabolites) variably preserve humoral responses but mostly preserve vaccine-induced cellular responses. Full article ">Figure 3
Impact of anti-TNF drugs on the magnitude and profile of global adaptive immune responses. Anti-TNF drugs are associated with increased magnitudes in cellular responses; however, their effects on total IgG are unknown. The negative effects of anti-TNF therapy on germinal center B cells and long-lived plasma cells may cause an overall decrease in total IgG over time [<a href="#B108-vaccines-12-01280" class="html-bibr">108</a>]. The line styles represent the different types of peripheral immune responses measured, as labelled within the figure. Full article ">

Show export options Show export options

Select all

Export citation of selected articles as:

Error

Oops... you haven't selected anything for export.

Displaying article 1-50 on page 1 of 175.

Go to page 1 2 3 4 5

Search Results (8,708)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI