scholarly journals Development of Exhausted Memory Monocytes and Underlying Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Kisha Pradhan ◽  
Ziyue Yi ◽  
Shuo Geng ◽  
Liwu Li
Keyword(s):  
Inflammatory Mediator ◽  
Bacterial Endotoxin ◽  
High Dose ◽  
Murine Models ◽  
Inflammatory Genes ◽  
Underlying Mechanisms

Pathogenic inflammation and immuno-suppression are cardinal features of exhausted monocytes increasingly recognized in septic patients and murine models of sepsis. However, underlying mechanisms responsible for the generation of exhausted monocytes have not been addressed. In this report, we examined the generation of exhausted primary murine monocytes through prolonged and repetitive challenges with high dose bacterial endotoxin lipopolysaccharide (LPS). We demonstrated that repetitive LPS challenges skew monocytes into the classically exhausted Ly6Chi population, and deplete the homeostatic non-classical Ly6Clo population, reminiscent of monocyte exhaustion in septic patients. scRNAseq analyses confirmed the expansion of Ly6Chi monocyte cluster, with elevation of pathogenic inflammatory genes previously observed in human septic patients. Furthermore, we identified CD38 as an inflammatory mediator of exhausted monocytes, associated with a drastic depletion of cellular NAD+; elevation of ROS; and compromise of mitochondria respiration, representative of septic monocytes. Mechanistically, we revealed that STAT1 is robustly elevated and sustained in LPS-exhausted monocytes, dependent upon the TRAM adaptor of the TLR4 pathway. TRAM deficient monocytes are largely resistant to LPS-mediated exhaustion, and retain the non-classical homeostatic features. Together, our current study addresses an important yet less-examined area of monocyte exhaustion, by providing phenotypic and mechanistic insights regarding the generation of exhausted monocytes.

ACTH Response to a Low Dose but Not a High Dose of Bacterial Endotoxin in Rats Is Completely Mediated by Corticotropin-Releasing Hormone

1994 ◽  
Vol 1 (5) ◽  
pp. 300-307 ◽  
Author(s):  
Karel Schotanus ◽  
Gábor B. Makara ◽  
Fred J.H. Tilders ◽  
Frank BerkenboschTilders
Keyword(s):  
Low Dose ◽  
Bacterial Endotoxin ◽  
High Dose ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone

scholarly journals Targeting Pin1 Protects Mouse Cardiomyocytes from High-Dose Alcohol-Induced Apoptosis

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yuehong Wang ◽  
Zizhuo Li ◽  
Yu Zhang ◽  
Wei Yang ◽  
Jiantao Sun ◽  
...  
Keyword(s):  
Left Ventricular ◽  
High Dose ◽  
Enos Expression ◽  
Oxidation Stress ◽  
Ros Accumulation ◽  
Heavy Alcohol Consumption ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Long-term heavy alcohol consumption is considered to be one of the main causes of left ventricular dysfunction in alcoholic cardiomyopathy (ACM). As previously suggested, high-dose alcohol induces oxidation stress and apoptosis of cardiomyocytes. However, the underlying mechanisms are yet to be elucidated. In this study, we found that high-dose alcohol treatment stimulated expression and activity of Pin1 in mouse primary cardiomyocytes. While siRNA-mediated knockdown of Pin1 suppressed alcohol-induced mouse cardiomyocyte apoptosis, overexpression of Pin1 further upregulated the numbers of apoptotic mouse cardiomyocytes. We further demonstrated that Pin1 promotes mitochondria oxidative stress and loss of mitochondrial membrane potential but suppresses endothelial nitric oxide synthase (eNOS) expression in the presence of alcohol. Taken together, our results revealed a pivotal role of Pin1 in regulation of alcohol-induced mouse cardiomyocytes apoptosis by promoting reactive oxygen species (ROS) accumulation and repressing eNOS expression, which could be potential therapeutic targets for ACM.

scholarly journals Shengjing Capsule Improves Spermatogenesis through Upregulating Integrin α6/β1 in the NOA Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jiamin Wang ◽  
Shankun Zhao ◽  
Lianmin Luo ◽  
Yangzhou Liu ◽  
Ermao Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Sperm Quality ◽  
Sperm Count ◽  
Spermatogonial Stem Cells ◽  
Normal Group ◽  
Seminiferous Tubules ◽  
High Dose ◽  
Sprague Dawley ◽  
Underlying Mechanisms ◽  
Almost All

Objective. To evaluate the therapeutic effect of Shengjing capsules on nonobstructive azoospermia (NOA) in the rat model. Methods. Twenty-five male Sprague–Dawley rats were randomly divided into five groups as follows (n=5 per group): normal group, NOA group, and three Shengjing capsule treatment groups (low-dose, medium-dose, and high-dose groups, respectively). HE staining and semen smear were performed to assess sperm quality. The expression levels of PI3K/AKT and integrin α6/β1 were measured by qRT-PCR and western blot analyses. Results. In the NOA group, almost all of the seminiferous tubules were vacuolated with a thin layer of basal compartment containing some spermatogonial stem cells. The counts of sperms in the NOA group were strongly lower than those of the normal group (P=0.0001). The expression of PI3K/AKT and integrin α6/β1 was scarcely expressed in the NOA group. All indexes mentioned above were significantly different from those of the medium- and high-dose groups (P=0.001, all). The sperm count of rats treated with Shengjing capsules was significantly higher than that of the NOA group (P=0.0001). The rats of Shengjing capsule groups had more layers of spermatogonial stem cells and spermatocytes, and some had intracavitary sperms. Conclusions. Shengjing capsules may be a promising therapeutic medicine for NOA. The underlying mechanisms might involve activating SSCs by upregulating the integrin α6/β1 expression via the PI3K/AKT pathway.

scholarly journals Gingerol inhibits cisplatin-induced acute and delayed emesis in rats and minks by regulating the central and peripheral 5-HT, SP, and DA systems

2019 ◽  
Vol 74 (2) ◽  
pp. 353-370 ◽  
Author(s):  
Li Tian ◽  
Weibin Qian ◽  
Qiuhai Qian ◽  
Wei Zhang ◽  
Xinrui Cai
Keyword(s):  
Low Dose ◽  
Area Postrema ◽  
Biologically Active ◽  
Control Group ◽  
High Dose ◽  
Delayed Emesis ◽  
Blank Control Group ◽  
Qrt Pcr ◽  
Underlying Mechanisms ◽  
Different Doses

Abstract Gingerol, a biologically active component in ginger, has shown antiemetic properties. Our study aimed to explore the underlying mechanisms of gingerol on protecting rats and minks from chemotherapy-induced nausea and vomiting. The preventive impact of gingerol was evaluated in the pica model of rats and the vomiting model of minks induced by cisplatin at every 6 h continuously for a duration of 72 h. Animals were arbitrarily separated into blank control group, simple gingerol control group, cisplatin control group, cisplatin + metoclopramide group, cisplatin + three different doses gingerol group (low-dose; middle-dose; high-dose). The area postrema as well as ileum damage were assessed using H&E stain. The levels of 5-TH, 5-HT3 receptor, TPH, SERT, SP, NK1 receptor, PPT, NEP, DA, D2R, TH, and DAT were determined using immunohistochemistry or qRT-PCR in rats and minks. All indicators were measured in the area postrema along with ileum. The kaolin intake by rats and the incidence of CINV of minks were significantly decreased after pretreatment with gingerol in a dosage-dependent way for the duration of 0–24-h and 24–72-h. Gingerol markedly decreased the levels of 5-TH, 5-HT3 receptor, TPH, SP, NK1 receptor, PPT, DA, D2R, TH, alleviated area postrema as well as ileum damage, and increased the accumulation of SERT, NEP, DAT in the area postrema along with ileum of rats and minks. Gingerol alleviates cisplatin-induced kaolin intake of rats and emesis of minks possibly by regulating central and peripheral 5-HT system, SP system and DA system. Graphic abstract

scholarly journals Histomolecular characterization of intracranial meningiomas developed in patients exposed to high-dose cyproterone acetate: an antiandrogen treatment

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Sylvain Portet ◽  
Rania Naoufal ◽  
Gaëlle Tachon ◽  
Adrien Simonneau ◽  
Anaïs Chalant ◽  
...  
Keyword(s):  
Skull Base ◽  
Cyproterone Acetate ◽  
Comparative Genomic ◽  
High Dose ◽  
Low Grade ◽  
Pharmacological Interaction ◽  
Pik3ca Mutations ◽  
History Of ◽  
Underlying Mechanisms ◽  
Copy Number Changes

Abstract Background Meningiomas are the most common primary intracranial tumors in adults. The relationship between meningiomas and exogenous sex hormones such as cyproterone acetate (CPA) is well documented, yet the underlying mechanisms remain unknown. Defining the histomolecular status of meningiomas developed on CPA would help us to better understand the oncogenesis of these tumors. Methods We identified 30 patients operated for a meningioma after long-term high-dose CPA therapy and with a history of CPA discontinuation before establishing the indication for surgical intervention. We used array-comparative genomic hybridization (to characterize copy number changes in those 30 meningiomas and subsequently performed next-generation sequencing with the National Institute of Cancer (INCa) solid tumor panel, which is a targeted panel of clinically actionable genes. We also examined grade, type, and clinical features. Results We identified AKT1 mutations or PIK3CA mutations in 33.3% of CPA meningiomas. AKT1 and PIK3CA mutations were mutually exclusive. Enrichment in oncogenic PIK3CA mutations in the CPA cohort was detected. CPA meningiomas showed chromosomal stability and were located mainly in the skull base. Ninety percent of CPA meningiomas were low-grade meningiomas and 63.4% were meningotheliomas. Half of our CPA cohort had microcystic components. Conclusion Our study shows that low-grade meningothelial meningiomas of the skull base are predominant in CPA meningiomas. We identified PIK3CA/AKT1 pathway as a hypothetical actor in onco-pharmacological interaction between meningiomas and CPA. This signaling pathway could be an interesting target for precision medicine trials in meningioma patients who have been subjected to CPA. Our results could invite the scientific community to review the current classification of meningiomas and to evolve toward more specific histomolecular classification.

scholarly journals Laxative Effects of Yangyin Tongmi Capsule on a Model of Diphenoxylate-Induced Constipation in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Shan Liu ◽  
Dayun Sui ◽  
Wenwen Fu ◽  
Xiaofeng Yu ◽  
Yuangeng Li ◽  
...  
Keyword(s):  
Low Dose ◽  
High Dose ◽  
Water Control ◽  
Intestinal Hormones ◽  
Expression Levels ◽  
Laxative Effects ◽  
Bowel Movements ◽  
Difficult Defecation ◽  
Underlying Mechanisms ◽  
Related Proteins

Constipation is characterized by reduced number of bowel movements, dry stools, and difficult defecation. Yangyin Tongmi capsule (YTC), a traditional Chinese formula, is used in the treatment of constipation, while the underlying mechanisms remain unknown. Herein, this work attempted to prove the effects of YTC on constipation treatment and its possible mechanisms. KM mice were randomly divided into four groups (n = 10/group) and treated with double distilled water (Control), diphenoxylate (Model: 10 mg/kg), or diphenoxylate plus low-dose YTC (L-YTC: 0.6 g/kg) or high-dose YTC (H-YTC: 1.2 g/kg). The data indicated that YTC can significantly shorten the discharge time of the first black stool, improve intestinal propulsion rate, and increase the water content and quantity of feces in mice. ELISA suggested that YTC regulate the content of intestinal hormones and neurotransmitters, such as motilin (MTL), gastrin (GT), somatostatin (SST), substance P (SP), acetylcholine (Ach), and nitric oxide (NO). The expression levels of aquaporin 3 (AQP3) and aquaporin 8 (AQP8) in the colon were examined by immunohistochemistry. In the meantime, the expression levels of P2X2, C-kit, and stem cell factor (SCF) in the colon were examined by western blot analysis. The results of this study suggest that YTC has mitigative effects on diphenoxylate-induced constipation by regulating the content of intestinal hormones and neurotransmitters and regulating the expression of related proteins in the colon.

scholarly journals Immune Checkpoint Inhibitors: Cardiotoxicity in Pre-clinical Models and Clinical Studies

2021 ◽  
Vol 8 ◽  
Author(s):  
Shirley Xu ◽  
Umesh C. Sharma ◽  
Cheyanna Tuttle ◽  
Saraswati Pokharel
Keyword(s):  
Cancer Treatment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
High Dose ◽  
Cardiac Events ◽  
Cardiac Effects ◽  
Wide Range ◽  
Clinical Models ◽  
Underlying Mechanisms

Since the approval of the first immune checkpoint inhibitor (ICI) 9 years ago, ICI-therapy have revolutionized cancer treatment. Lately, antibodies blocking the interaction of programmed cell death protein (PD-1) and ligand (PD-L1) are gaining momentum as a cancer treatment, with multiple agents and cancer types being recently approved for treatment by the US Food and Drug Administration (FDA). Unfortunately, immunotherapy often leads to a wide range of immune related adverse events (IRAEs), including several severe cardiac effects and most notably myocarditis. While increased attention has been drawn to these side effects, including publication of multiple clinical observational data, the underlying mechanisms are unknown. In the event of IRAEs, the most widely utilized clinical solution is administration of high dose corticosteroids and in severe cases, discontinuation of these ICIs. This is detrimental as these therapies are often the last line of treatment options for many types of advanced cancer. In this review, we have systematically described the pathophysiology of the PD-1/PD-L1 axis (including a historical perspective) and cardiac effects in pre-clinical models, clinical trials, autoimmune mechanisms, and immunotherapy in combination with other cancer treatments. We have also reviewed the current challenges in the diagnosis of cardiac events and future directions in the field. In conclusion, this review will delve into this expanding field of cancer immunotherapy and the emerging adverse effects that should be quickly detected and prevented.

scholarly journals MicroRNA 322 Aggravates Dexamethasone-Induced Muscle Atrophy by Targeting IGF1R and INSR

2020 ◽  
Vol 21 (3) ◽  
pp. 1111 ◽  
Author(s):  
Hongwei Geng ◽  
Qinglong Song ◽  
Yunyun Cheng ◽  
Haoyang Li ◽  
Rui Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Immunosuppressive Agent ◽  
Skeletal Muscle Atrophy ◽  
Luciferase Reporter ◽  
C2c12 Myotubes ◽  
High Dose ◽  
Reporter Assays ◽  
Underlying Mechanisms

Dexamethasone (Dex) has been widely used as a potent anti-inflammatory, antishock, and immunosuppressive agent. However, high dose or long-term use of Dex is accompanied by side effects including skeletal muscle atrophy, whose underlying mechanisms remain incompletely understood. A number of microRNAs (miRNAs) have been shown to play key roles in skeletal muscle atrophy. Previous studies showed significantly increased miR-322 expression in Dex-treated C2C12 myotubes. In our study, the glucocorticoid receptor (GR) was required for Dex to increase miR-322 expression in C2C12 myotubes. miR-322 mimic or miR-322 inhibitor was used for regulating the expression of miR-322. Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (INSR) were identified as target genes of miR-322 using luciferase reporter assays and played key roles in Dex-induced muscle atrophy. miR-322 overexpression promoted atrophy in Dex-treated C2C12 myotubes and the gastrocnemius muscles of mice. Conversely, miR-322 inhibition showed the opposite effects. These data suggested that miR-322 contributes to Dex-induced muscle atrophy via targeting of IGF1R and INSR. Furthermore, miR-322 might be a potential target to counter Dex-induced muscle atrophy. miR-322 inhibition might also represent a therapeutic approach for Dex-induced muscle atrophy.

scholarly journals Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 687 ◽  
Author(s):  
Eun Seong Hwang ◽  
Seon Beom Song
Keyword(s):  
Adverse Effects ◽  
Inflammatory Diseases ◽  
Wide Spectrum ◽  
Public Awareness ◽  
High Dose ◽  
Negative Effects ◽  
Methylation Of Dna ◽  
Multiple Routes ◽  
Underlying Mechanisms ◽  
High Level

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD+) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM.

scholarly journals ELECTROCARDIOGRAM CHANGES IN ADDISON DISEASE: POTENTIAL CLINICAL MARKER FOR ADRENAL CRISIS

2019 ◽  
Vol 5 (5) ◽  
pp. e307-e310
Author(s):  
Pedro E. Perez ◽  
Wilson Sze ◽  
Joshua Miller
Keyword(s):  
Chest Pain ◽  
Cardiac Function ◽  
Adrenal Crisis ◽  
High Dose ◽  
Addison Disease ◽  
Cardiac Evaluation ◽  
History Of ◽  
Glucocorticoid Deficiency ◽  
Underlying Mechanisms ◽  
Ischemic Attack

Objective: To present a unique phenomenon of a patient in addisonian crisis with electrocardiogram (ECG) anomalies that resolved following glucocorticoid therapy. Methods: We present the case report followed by discussion with literature review. Results: A 25-year-old male with Addison disease (AD) presented with a 1-week history of lightheadedness, shortness of breath, chest pain, abdominal pain, postural hypotension, and tachycardia. The patient was diagnosed with addisonian crisis and started on intravenous, high-dose glucocorticoids. An ECG showed right-heart axis deviation and T-wave inversions. In the context of ongoing chest pain, there was concern for myocardial ischemic attack and the patient underwent an extensive cardiac evaluation. Cardiac workup was negative and an echocardiogram showed an ejection fraction of 50 to 55%. The ECG abnormalities resolved 1 day into his hospital admission and his other symptoms resolved 2 days following treatment with steroids. Conclusion: AD is a rare, potentially lethal, and commonly misdiagnosed disease often first encountered clinically amidst an incident episode of adrenal crisis. Our AD patient was undergoing an adrenal crisis with ECG changes positive for probable cardiac ischemia. Glucocorticoid deficiency has been previously linked with decreased cardiac function and myocardial ischemia, though the underlying mechanisms are not fully clear. This patient recovered within 2 days after receiving corticosteroid supplementation. There have been similar cases previously reported. In each of these, patients underwent extensive and costly workup to evaluate cardiac function, yet all patients fully recovered with corticosteroids. Understanding the physiology and clinical presentation of adrenal crisis will be useful in establishing an earlier diagnosis, thus preventing mortality and avoiding unnecessary, expensive evaluations.

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