Increase In Levels Of Pro-inflammatory Cytokines Research Articles

Chronic hyperglycemia aggravates lung function in a Scnn1b-Tg murine model.

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel β subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model utilizing Scnn1b-Tg mice made diabetic by injection of streptozotocin. In Ussing chamber recordings of trachea, Scnn1b-Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in ATP-activated currents compared to wildtype (WT) littermates. Both diabetic WT (WT-D) and diabetic Scnn1b-Tg (Scnn1b-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 weeks; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF) Bulk lung RNA-seq data showed significant differences between WT-D and Scnn1b-Tg-D mice. Neutrophil counts in BALF were substantially increased in Scnn1b-Tg-D lungs compared to controls (Scnn1b-Tg-con) and compared to WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Scnn1b-Tg-D mice compared to WT-D mice, consistent with development of a spontaneous lung infection. We intranasally administered Pseudomonas aeruginosa to induce lung infection in these mice for 24 hours, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b-Tg mice. The model can be utilized for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.

Free Fatty Acid 4 Receptor Activation Attenuates Collagen-Induced Arthritis by Rebalancing Th1/Th17 and Treg Cells.

Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) has been found to be beneficial in rodent rheumatoid arthritis models and human trials. However, the molecular targets of n-3 PUFAs and their beneficial effects on rheumatoid arthritis are under-researched. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor for n-3 PUFA. We aim to investigate whether FFA4 activation reduces collagen-induced rheumatoid arthritis (CIA) by using an FFA4 agonist, compound A (CpdA), in combination with DBA-1J Ffa4 gene wild-type (WT) and Ffa4 gene knock-out (KO) mice. CIA induced an increase in the arthritis score, foot edema, synovial hyperplasia, pannus formation, proteoglycan loss, cartilage damage, and bone erosion, whereas the administration of CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA increased mRNA expression levels of pro-inflammatory Th1/Th17 cytokines, whereas CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA induced an imbalance between Th1/Th17 and Treg cells, whereas CpdA rebalanced them in spleens from Ffa4 WT mice but not Ffa4 gene KO mice. In SW982 synovial cells, CpdA reduced the LPS-induced increase in pro-inflammatory cytokine levels. In summary, the present results suggest that the activation of FFA4 in immune and synovial cells could suppress the characteristics of rheumatoid arthritis and be an adjuvant therapy.

Rhodium-Rhenium Alloy Nanozymes for Non-inflammatory Photothermal Therapy.

Analogous to thermal ablation techniques in clinical settings, cell necrosis induced during tumor photothermal therapy (PTT) can provoke an inflammatory response that is detrimental to the treatment of tumors. In this study, we employed a straightforward one-step liquid-phase reduction process to synthesize uniform RhRe nanozymes with an average hydrodynamic size of 41.7 nm for non-inflammatory photothermal therapy. The obtained RhRe nanozymes showed efficient near-infrared (NIR) light absorption for effective PTT, coupled with a remarkable capability to scavenge reactive oxygen species (ROS) for anti-inflammatory treatment. After laser irradiation, the 4T1 tumors were effectively ablated without obvious tumor recurrence within 14 days, along with no obvious increase in pro-inflammatory cytokine levels. Notably, these RhRe nanozymes demonstrated high biocompatibility with normal cells and tissues, both in vitro and in vivo, as evidenced by the lack of significant toxicity in female BALB/c mice treated with 10 mg/kg of RhRe nanozymes over a 14 day period. This research highlights RhRe alloy nanoparticles as bioactive nanozymes for non-inflammatory PTT in tumor therapy.

Microglia-neuron interactions in schizophrenia.

Multiple lines of evidence implicate increased neuroinflammation mediated by glial cells to play a key role in neurodevelopmental disorders such as schizophrenia. Microglia, which are the primary innate immune cells of the brain, are crucial for the refinement of the synaptic circuitry during early brain development by synaptic pruning and the regulation of synaptic plasticity during adulthood. Schizophrenia risk factors as genetics or environmental influences may further be linked to increased activation of microglia, an increase of pro-inflammatory cytokine levels and activation of the inflammasome resulting in an overall elevated neuroinflammatory state in patients. Synaptic loss, one of the central pathological hallmarks of schizophrenia, is believed to be due to excess removal of synapses by activated microglia, primarily affecting glutamatergic neurons. Therefore, it is crucial to investigate microglia-neuron interactions, which has been done by multiple studies focusing on post-mortem brain tissues, brain imaging, animal models and patient iPSC-derived 2D culture systems. In this review, we summarize the major findings in patients and in vivo and in vitro models in the context of neuron-microglia interactions in schizophrenia and secondly discuss the potential of anti-inflammatory treatments for the alleviation of positive, negative, and cognitive symptoms.

Therapeutic potential of flavonoids in ovalbumin induced asthma in mice model.

Desmodium triquetrum DC (Fabaceae) is a plant commonly used in Indian traditional medicine to treat allergies. Asthma is a severe condition, with an estimated 300 million deaths annually, which could increase to 400 million by 2025. Flavonoids, a class of compounds found in many plants, have been found to have beneficial effects in treating asthma. In this study, researchers focused on three flavonoids, Baicalein, Naringin, and Neohesperidin, derived from Desmodium triquetrum DC, to investigate their potential as a treatment for asthma. The study used an aerosolized ovalbumin-induced asthma model to evaluate the effects of the flavonoids on various substances in bronchoalveolar lavage fluid, including total differential leukocyte, nitrite, nitrate, TNF, IL-4, and IL-13. The researchers also measured the levels of myeloperoxidase and malondialdehyde in the lungs. The results showed that ovalbumin-induced airway hyper-responsiveness led to a significant increase in pro-inflammatory cytokine levels. However, the flavonoids significantly decreased the severity of airway inflammation. Histopathology results also supported the effectiveness of the flavonoids. These findings suggest that these flavonoids could be a supplementary and alternative treatment for asthma by inhibiting the pro-inflammatory pathway. The findings suggest that the isolated compounds have the potential to act cumulatively to decrease the levels of the tested cytokines, normalize eosinophil and activated lymphocyte counts, and significantly reduce MPO and MDA. This indicates a possible respiratory mechanism of action for the drugs.

2A2 protein of DHAV-1 induces duck embryo fibroblasts gasdermin E-mediated pyroptosis

The duck hepatitis A virus type 1 (DHAV-1) causes rapid death in ducklings by triggering a severe cytokine storm. Pyroptosis is an inflammatory form of programmed cell death that is directly related to an increase in pro-inflammatory cytokine levels. Only a few studies have explored the mechanisms underlying pyroptosis in virus-infected avian cells. In this study, we established an avian infection model in vitro by infecting duck embryo fibroblasts (DEFs) with the virulent DHAV-1 LY0801 strain. DHAV-1 infection induced pyroptosis in the DEFs by activating gasdermin E (GSDME) protein via caspase-3-mediated cleavage. The genes encoding the different structural and non-structural DHAV-1 proteins were cloned into eukaryotic expression plasmids, and the 2A2 protein was identified as the key protein involved in pyroptosis. The HPLC-tandem mass spectrometry (HPLC-MS/MS) and co-immunoprecipitation (Co-IP) analysis established that DHAV-1 2A2 directly interacted with the mitochondrial anti-viral signaling protein (MAVS) both intracellularly and in vitro. Furthermore, we got the results that N-terminal 1–130 aa of 2A2 was involved in the interaction with MAVS and the C-terminal TM domain of MAVS is necessary for the interaction with 2A2 by Co-IP analysis. To our knowledge, this is the first study to reveal that DHAV-1 protein interacts with host proteins to induce pyroptosis. Our findings provide new insights into the molecular pathogenesis of DHAV-1 infection, and a scientific basis for the prevention and treatment of duck viral hepatitis.

Pre-Leukemic Transformation of the Bone Marrow Microenvironment Induced By AML1-ETO Fusion Protein

Objective: The bone marrow (BM) microenvironment, especially stromal cells (SCs) and cytokines, plays a critical role in supporting normal hematopoiesis. However, in cases of hematological malignancies such as acute myeloid leukemia (AML), leukemia cells can reshape the BM microenvironment to promote their survival. Despite this, there is still limited understanding of the changes in AML1-ETO fusion protein induced pre-leukemia microenvironment niche. In this study, the alterations of the BM microenvironment in the Aml1 Eto/+; Mx1-Cre (AE KI) mouse model are thoroughly explored and analyzed. This investigation will encompass the study of SCs, cytokines, their sources, and their potential impacts on the occurrence and progression of AML induced by AML1-ETO. Methods: After 4 weeks of PIPC induction, proportion changes of endothelial cells (ECs), osteoblasts, mesenchymal stem cells (MSCs) in the BM of Aml1 Eto/+; Mx1-Cre mice (experimental group) and Aml1 Eto/+; w/o Mx1-Cre mice (control group) were analyzed by flow cytometry. Bulk RNA sequencing (RNAseq) and single cell RNA sequencing (scRNAseq) techniques were applied for analysis of abnormal hematopoietic Lin -Sca-1 +c-Kit + (LSK) stem cells. Cytokine levels were detected using ELISA and Luminex bead assay. Additionally, CRISPR-Cas9 technology was used to knock out the target genes and their functions were validated. Results: Following 4 weeks of PIPC induction, the experimental group exhibited a considerable reduction in the proportion and absolute number of ECs, osteoblasts and MSCs, with ECs being the most significantly reduced. The Luminex assay revealed a substantial increase in cytokine release in the BM of the experimental group, including IL4, IL10, TNFa, Cxcl10, Cxcl11, Ccl1, Ccl2, Ccl4, Ccl7, etc. Bulk RNAseq studies of LSK cells showed that the inflammatory pathway in the experimental group was significantly upregulated. To further explore the release sources of cytokines in the BM and heterogeneity in LSK cell cytokine secretion, scRNAseq analysis of LSK cells was conducted in the AE KI group, which were classified into 9 subgroups. Subgroups 1 and 5 exhibited a significant upregulation of Ccl2, Ccl4, Cxcl2, and IL15. Subgroups 4 and 8 showed upregulation of Ccl2 and IL4. Subgroups 0 and 2 exhibited upregulation of Ccl4, while subgroups 6, 7, and 9 showed upregulation of Cxcl2. Notably, subgroups 1 and 5 also displayed increased expression of Ccr5, which is the receptor for Ccl2. To further validate the origins of cytokines, LSK cells were sorted from experimental group and the control group for in vitro culture, respectively. Subsequently, the cell culture supernatants were collected for Luminex assay, revealing a notable upregulation of Ccl2 and Ccl7 in the experimental group. Furthermore, when comparing m-cherry + LSK cells (AML1-ETO positive) with m-cherry - LSK cells (AML1-ETO negative) from the same mouse, a significant increase in the Ccl2 levels in the m-cherry + LSK cell culture supernatant was observed. Flow cytometry analysis of LSK cells further revealed high expression of Ccl2 and its receptor Ccr5 in Ccl2 + LSK cells. In order to gain a deeper understanding of the functions of Ccl2 and Ccl7, CRISPR-Cas9 technology was used to knockout Ccl2 and Ccl7 in c-kit + cells, which were then transplanted into mice for further investigation, respectively. After 3 months, partial restoration of ECs was observed compared to that of the scramble control group. Conclusion: Our findings suggested that significant changes occurred in the BM microenvironment in AML1-ETO-induced pre-leukemia stage. These changes were characterized by a decrease in SCs and an increase in pro-inflammatory cytokine levels. Moreover, our study identified the heterogeneity in cytokine transcriptional profiles among AE KI LSK cells. The secretion of Ccl2 and Ccl7 by AE KI LSK cells with a blockage in hematopoietic differentiation seemed to be involved in the reduction of stromal cell population. These results provided valuable insights for further exploration of the intricate interactions between abnormal hematopoietic stem cells and the BM microenvironment in AML1-ETO-induced pre-leukemic and leukemic states. Understanding these interactions is crucial for advancing our knowledge of the underlying mechanisms involved in the development and progression of AML.

Evaluation of Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio in Covid-19 Patients Treated with Tocilizumab Due to Cytokine Storm

Background/Aims: There is a significant increase in proinflammatory cytokine levels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients entering cytokine storm. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), also increase in inflammatory diseases. The aim was to evaluate the NLR and PLR of coronavirus disease 2019 (COVID-19) patients receiving tocilizumab (TCZ) due to cytokine storm. Materials and Methods: In this retrospective, cross-sectional study conducted in between March and December 2020, adult patients with laboratory-confirmed COVID-19 were analyzed Results; The mean age of 519 patients included in the study was 61.6 ± 17.0 years, with male predominance (64.7%). 70.7% of patients had at least one type of comorbidity and the most common comorbid conditions were chronic obstructive pulmonary disease (45.9%) and asthma (28.7%). 399 patients who were given TCZ (group 1) and 120 patients who were not given TCZ (group 2) were evaluated. Compared with group 2, group 1 had more male predominance and they were older (p<0.001). The mortality rate, which was found to be 48.6% in group 1, was approximately twice as high in the intensive care unit (ICU). NLR and PLR were significantly higher and lymphopenia was more prominent in group 1, especially in ICU patients than group 2 (p<0.001). Conclusion: High NLR, PLR and lymphopenia was more common in critically ill Covid-19 patients. Therefore, they may be used as a marker to predict poor prognosis. It can be suggested to treat these patients more aggressively in the initial period.

Guanosine treatment prevents lipopolysaccharide-induced depressive-like behavior in mice

Guanosine is a purinergic nucleoside that has been shown to have neuroprotective effects, mainly through its ability to modulate the glutamatergic system. An increase in pro-inflammatory cytokine levels triggers the activation of the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), leading to glutamatergic excitotoxicity, which has important roles in the pathophysiology of depression. The aim of this study was to investigate the possible antidepressant-like effects and underlying mechanisms of action of guanosine against lipopolysaccharide (LPS)-induced depression in a mouse model. Mice were orally pre-treated with saline (0.9% NaCl), guanosine (8 or 16 mg/kg), or fluoxetine (30 mg/kg) for 7 days before LPS (0.5 mg/kg, intraperitoneal) injection. One day after LPS injection, mice were subjected to the forced swim test (FST), tail suspension test (TST), and open field test (OFT). After the behavioral tests, mice were euthanized and the levels of tumor necrosis factor-α (TNF-α), IDO-1, glutathione, and malondialdehyde in the hippocampus were measured. Pretreatment with guanosine was able to prevent LPS- induced depressive-like behaviors in the TST and FST. In the OFT, no locomotor changes were observed with any treatment. Both guanosine (8 and 16 mg/kg/day) and fluoxetine treatment prevented the LPS-induced increase in TNF-α and IDO expression and lipid peroxidation as well as decrease of reduced glutathione levels in the hippocampus. Taken together, our findings suggest that guanosine may have neuroprotective effects against LPS-induced depressive-like behavior through preventing oxidative stress and the expression of IDO-1 and TNF-α in the hippocampus.

Impact of the LPS from Cyanobacteria Brasilonema sp.on Lung Inflammation and Glucocorticoid Expression

Abstract Inhaled glucocorticoids (GCs) are the first-line treatment for asthma. However, patients with asthma characterized by recruitment of neutrophils show poor sensitivity to GC therapy. A potential etiology of this GC-resistant asthma is aerosolized cyanobacterial lipopolysaccharide (LPS) from cyanobacterial blooms. Previously, we demonstrated that inhalation of LPS from Geitlerinema sp. of cyanobacteria induces neutrophilic lung infiltration in mice. Our current data shows that the LPS from another cyanobacteria, Brasilonema sp., also induces lung inflammation after inhalation. Flow cytometric data demonstrate that Brasilonema sp. LPS induces neutrophil infiltration and ELISA identified increases in pro-inflammatory cytokine levels in bronchoalveolar lung fluid after Brasilonema sp. LPS exposure. Furthermore, IHC data demonstrate that mice exposed to Brasilonema sp. LPS show an increased level of lung epithelial GCRβ, a glucocorticoid receptor (GR) analog that inhibits GC activity. Conversely, expression of GCRα, the GR isoform responsible for glucocorticoid sensitivity, remains unchanged. These data help to elucidate the mechanisms of Brasilonema sp. LPS-induced lung-inflammation and potential glucocorticoid resistance, while highlighting the importance of the toxin in promoting human disease near cyanobacterial blooms. This work is supported by the Kenneth A. Suarez Fellowship and Intramural Funds at Midwestern University.

Ferroptosis mediates decabromodiphenyl ether-induced liver damage and inflammation

Decabromodiphenyl ether (BDE-209) is an environmental toxin. Increasing evidence showed that BDE-209 exposure induced liver injury, but the mechanism still remains unknown. The present study explored the effect and mechanism of ferroptosis on hepatotoxicity triggered by BDE-209 in vivo and in vitro. In vivo experiment, ICR mice were exposed to BDE-209 for 50 days, and then recovered for 50 days; HepG2 and L02 cells were treated with BDE-209 or/and ferrostatin-1 (Fer-1) for establishing in vitro model. In vivo, the results showed that BDE-209 accumulated in liver and induced liver damage, increased Fe2+ and MDA contents, and blocked the activation of SLC7A11/GSH/GPX4 pathway in liver; BDE-209 also activated IKK/IκB/NF-κB pathway and elevated inflammatory cytokines levels in liver after exposure for 50 days. After BDE-209 stopping exposure 50 days, the severity of liver damage, ferroptosis and inflammatory response were still higher than the corresponding control group. In vitro, ferroptosis inhibitor Fer-1 rescued ferroptotic damage and attenuated cell death in BDE-209-treated HepG2 and L02 cells. In addition, Fer-1 reversed the activation of IKK/IκB/NF-κB pathway and the increase of pro-inflammatory cytokines levels in BDE-209-treated HepG2 and L02 cells. Together, the above results suggested that BDE-209 induced tissue damage and inflammatory response by activating ferroptosis through increasing iron-dependent lipid peroxidation and blocking the activation of SLC7A11/GSH/GPX4 pathway in liver, indicating that ferroptosis is a potential mechanism for BDE-209-induced hepatotoxicity.

Extracts from sojae semen germinatum ameliorated carbon tetrachloride-induced liver injury in mice

Sojae semen germinatum (SSG) prepared from the germinating black soybean Glycine max L. Merr. is a traditional Chinese herbal medicine with heat-clearing, dampness-removing, and detoxifying properties. In the present study, we explored the effects and possible underlying mechanisms of petroleum ether extract (PEE), ethyl acetate extract (EAE), n-butanol extract (NBE) and aqueous fraction (AF) of SSG on the carbon tetrachloride (CCl4)-induced liver injury in mice, an animal model representing pathological features of “dampness-heat” syndrome from the perspective of Traditional Chinese Medicine. Results showed that the EAE and NBE of SSG significantly protected mice against the CCl4-induced increases of liver tissue index and serum transaminase levels, ameliorated the CCl4-induced liver morphological changes. Compared with CCl4 model controls, EAE and NBE of SSG decreased malondiadehyde (MDA) levels, enhanced glutathione (GSH) content and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in liver tissues, as well as reduced the number of apoptotic hepatocytes. Moreover, the CCl4-induced increase of pro-inflammatory cytokine levels in livers was markedly suppressed by pre-treatment with EAE of SSG. Data suggested that SSG extracts showed protective effect on the CCl4-induced liver injury via multiple pharmacological mechanisms including anti-oxidation, anti-inflammation and anti-apoptosis. EAE and NBE appeared to be superior to other fractions.

A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation.

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism and neuroinflammation, from a protective perspective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized that WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulatisng TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of the hippocampal TH regulatory system over TH circulating levels in the hippocampal glial reactivity.

Abstract P339: A Possible Role Of Neuronal Adam17 In The Development Of Hypertension And Related Cognitive Impairment By Altering The Microenvironment

Hypertension is one of the most prevalent cardiovascular diseases worldwide and is known to be dominated by the sympathetic nervous system (SNS). Previously, we found that targeting A Disintegrin and Metalloproteinase 17 (ADAM17) in glutamatergic neurons was able to blunt Ang-II-induced excitation of pre-autonomic neurons, and blocked DOCA-salt treatment-induced sympatho-excitation in mice, thereby alleviating their development of hypertension. However, how ADAM17 support the activation of pre-autonomic neurons remains unknown. Beyond the glutamatergic neurons, we found in the current study that microglial activation and increase of pro-inflammatory cytokine levels in the hypothalamus, induced by DOCA-salt treatment, were blunted in those mice with ADAM17 knockout in glutamatergic neurons (A17G; number of CD11b+cells per line: NT+DOCA vs. A17G+DOCA= 11±2 vs. 6±1, P= 0.0017; normalized TNFα level: NT+DOCA vs. A17G+DOCA= 1.00±0.37 vs. 0.67±0.11, P< 0.05; normalized IL-6 level: 1.00±0.32 vs. 0.59±0.20, P< 0.05). Especially, it also reversed DOCA-salt-induced downregulation of Gad67 mRNA expression (NT= 1.00±0.11, NT+DOCA= 0.66±0.12, A17G= 1.02±0.15, A17G+DOCA= 1.67±0.24 fold of change, NT vs. NT+DOCA and A17G vs. A17G+DOCA: P< 0.05), and normalized the decreased level of GABA in hypothalamus (normalized GABA levels: NT= 1.00±0.15, NT+DOCA= 0.84±0.09, A17G+DOCA= 1.09±0.17, NT vs. NT+DOCA: P< 0.05), suggesting that in addition to the effect of ADAM17 on the neuron itself, it might also regulate the SNS through altering the neuronal microenvironment. In L-NAME hypertensive model, though A17G mice showed no improvement in NOS-blockade-induced dysfunction of neuro-vascular coupling (increase of CBF induced by whisker-stimulation: NT vs. A17G= 24.34±11.20 vs. 24.87±15.78 PU%), it did exhibit improved performance in Barnes maze test (latency time: NT vs. A17G= 32.77±19.36 vs. 95.54±59.03 s, P= 0.002), suggesting that ADAM17 in glutamatergic is critical for the process of neuronal damage induced by hypoxia and ischemia, possibly through modulating the homeostasis of neuronal microenvironment.

Иммунологическая реактивность у больных хроническими диффузными заболеваниями печени

Цель: оценить состояние основных показателей клеточного иммунитета и уровень цитокинов у больных хроническими диффузными заболеваниями печени (ХДЗП). Материалы и методы. Обследовано 68 пациентов с ХДЗП, которые были распределены на 4 группы в зависимости от этиологических факторов формирования и прогрессирования стеатоза и фиброза печени: І группа — 36 больных неалкогольной жировой болезнью печени; ІІ группа — 13 больных хроническим вирусным гепатитом, ассоциированным с вирусом С; ІІІ группа — 14 больных алкогольной болезнью печени, ІV группа — 5 больных токсическим гепатитом. Проводили изучение основных показателей клеточного иммунитета и уровня интерлейкина (ИЛ) 6, ИЛ-10 и фактора некроза опухоли альфа. Результаты. У 83,3 % больных I группы, 76,9 % больных II группы и половины больных III группы наблюдали значительное снижение Т-хелперной субпопуляции. Недостаточность клеточного иммунитета у больных с ХДЗП способствует формированию стеатоза. У 69,2 % больных II группы установленные нарушения иммунорегуляции указывают на персистенцию вируса гепатита С и, как следствие, развитие фиброза. Согласно полученным результатам, у больных I, II и IV групп концентрация фактора некроза опухоли альфа достоверно превышает контрольные значения в 6,9, 7,9 и 11,0 раза соответственно (р < 0,05). Уровень ИЛ-6 достоверно выше в 3,9 раза (р < 0,05) у больных I группы по сравнению с IV группой больных. Это указывает на прогрессирование иммунопатологического процесса и является патогенетическим признаком неадекватности функционирования иммунной системы при ХДЗП. Выводы. Установлено, что прогрессирование стеатоза печени сопровождается недостаточностью клеточного звена иммунитета и повышением уровня провоспалительных цитокинов.

Direct and Indirect Neurological Signs of COVID-19.

Objective. To systematize the neurological manifestations of COVID-19. Materials and methods. A systematic computerized analysis of all currently available publications on the neurological manifestations of COVID-19 was undertaken (2374 reports in PubMed) by topological data analysis. Results. A set of interactions between infection with SARS-CoV-2, metabolic impairments affecting neurotransmitters (acetylcholine, dopamine, serotonin, and GABA), enkephalins, and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia, and neurodegeneration (including demyelination) was described. The most typical neurological manifestations of COVID-19 were anosmia/ageusia due to ischemia, neurodegeneration, and/or systematic increases in proinflammatory cytokine levels. COVID-19 provoked ischemic stroke, Guillain–Barré syndrome, polyneuropathy, encephalitis, meningitis, and parkinsonism. Coronavirus infection increased the severity of multiple sclerosis and myopathies. The possible roles of the human virome in the pathophysiology of COVID-19 are considered. A clinical case of a patient with neurological complications of COVID-19 is described. Conclusions. In the long-term perspective, COVID-19 promotes increases in neurodegenerative changes, which requires special neurological rehabilitation programs. Use of cholinergic drugs and antihypoxic agents compatible with COVID-19 therapy is advised.

Gastrodia elata Blume Polysaccharides Attenuate Vincristine-Evoked Neuropathic Pain through the Inhibition of Neuroinflammation.

Vincristine (Vin) is a well-known antitumor agent that frequently evokes neuropathic pain and decreases the quality of life of patients. Polysaccharides (GBP) extracted from Gastrodia elata Blume have been demonstrated to possess anti-inflammatory and neuroprotective effects in vivo; however, the effects of GBP on Vin-induced neuropathic pain remain unknown. The present study is aimed at exploring the alleviative potential of GBP against chemotherapy-evoked peripheral neuropathy to better understand and extend its pharmacological application. Vin was administered intraperitoneally to evoke neuropathic pain. GBP was orally administered for 21 days. The mechanical allodynia and thermal hyperalgesia were assessed using the Von Frey test and hot-plate test. Histopathological changes were assessed by hematoxylin and eosin staining. ELISA kits were used to measure the levels of inflammatory cytokines in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). qRT-PCR was employed to examine the expression of inflammatory cytokines and Sirtuin1 (SIRT1) in the sciatic nerve, spinal cord, and DRG. Our findings revealed that GBP treatment enhanced the paw withdrawal latency and paw withdrawal threshold and restored Vin-induced sciatic nerve damage in rats. GBP also attenuated the Vin-induced increase of proinflammatory cytokine levels, including IL-6, IL-8, TNF-α, IL-1β, and NF-κB. On the molecular level, treatment with GBP downregulated the mRNA levels of IL-6, IL-8, TNF-α, and IL-1β in the sciatic nerve, spinal cord, and DRG. Meanwhile, GBP increased SIRT1 activity and mRNA expression levels. Our data indicated that GBP exerted a potential protective effect against chemotherapy-induced neuropathic pain which might be mediated via the inhibition of neuroinflammation.

Transcriptome and 16S rRNA analyses revealed differences in the responses of largemouth bass (Micropterus salmoides) to early Aeromonas hydrophila infection and immunization

The largemouth bass (Micropterus salmoides) is an economically important fish species, but disease caused by Aeromonas hydrophila has led to the high mortality of this fish in farming environments. However, few studies have focused on the differences in the responses of largemouth bass to infection and immunization with A. hydrophila. In the present study, we found high fish mortality after A. hydrophila infection but not after immunization. Then, the immune response difference of largemouth bass in early infection and immunization with A. hydrophila was analyzed using transcriptome profiling and 16S rRNA sequencing. The results from the transcriptome analysis revealed that many upregulated genes were enriched in metabolic pathways after infection and immunization, but the number of upregulated genes associated with metabolic pathways and the magnitude of their upregulated expression in the infection group were much greater than they were in the immunization group, suggesting that A. hydrophila infection might cause metabolic disorders in largemouth bass. Increases in pro-inflammatory cytokine levels and reduced expression of genes associated with adaptive immunity were also observed in the infection group. Moreover, the results of the 16S rRNA analysis revealed that the intestinal microbiota homeostasis of the largemouth bass was severely disrupted by A. hydrophila infection but not by immunization. These results collectively demonstrated that metabolic disorders, higher inflammation, a reduced adaptive immune response and disrupted microbiota homeostasis in early infection might be important factors for the high mortality of largemouth bass caused by A. hydrophila infection.

Effect of exercise in the recovery process after the inflammation process caused by coronavirus

Coronavirus (SARS-CoV-2 - COVID-19) disease causes severe acute respiratory syndrome. During infection, activation of macrophages and pro-inflammatory granulocytes produces cell damage, inducing lung inflammation that leads to the characteristic symptoms of fever, cough, fibrosis, and high increase in pro-inflammatory cytokine levels. In general, during the inflammatory process and infection by coronavirus, cytokines are elevated, particularly IL-1, 6 and 12, TNF-α, and TGF-β. In addition, patients with complications and lethal prognosis present increased serum levels of IF-I and γ compared to healthy individuals or patients with moderate symptoms. On the other hand, it is known that physical activity favours an adaptation of the immune system function. In this context, we suggest that appropriate exercise programs could improve recovery of people who have suffered from COVID-19 disease, improving the quality of life and reinforcing the protection against future infections. The immunomodulatory properties of exercise and physical activity could act as prevention tools for different chronic diseases in healthy individuals and complement therapeutic tools in sick patients. Nevertheless, exercise must be adequate both in time and intensity, taking into account the patient's clinical situation as well as their previous physical activity.

Relationship between Gut Microbiota, Gut Hyperpermeability and Obesity.

Intestinal hyperpermeability is a complex metabolic process mediated by different pathways in close relation to the gut microbiota. Previous studies suggested that the gut microbiota is involved in different metabolic regulations, and its imbalance is associated with several metabolic diseases, including obesity. It is well known that intestinal hyperpermeability is associated with dysbiosis, and the combination of these two conditions can lead to an increase in the level of low-grade inflammation in obese patients due to an increase in pro-inflammatory cytokine levels. Inflammatory bowel syndrome often accompanies this condition causing an alteration of the intestinal mucosa and thus reinforcing the dysbiosis and gut hyperpermeability. The onset of metabolic disorders depends on violations of the integrity of the intestinal barrier as a result of increased intestinal permeability. Chronic inflammation due to endotoxemia is responsible for the development of obesity. Metabolic disorders are associated with dysregulation of the microbiota-gut-brain axis and with an altered composition of gut flora. In this review, we will discuss the mechanisms that illustrate the relationship between hyperpermeability, the composition of the gut microbiota, and obesity.