scholarly journals Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of nash

2021 ◽  
Author(s):  
Miren Bravo ◽  
Imma Raurell ◽  
Aurora Barberá ◽  
Diana Hide ◽  
Mar Gil ◽  
...  
Keyword(s):  
Combined Treatment ◽  
Underlying Mechanism ◽  
Treated Group ◽  
Normal Serum ◽  
Liver Histology ◽  
Endothelin Receptor ◽  
Lattice Contraction ◽  
Nash Model ◽  
Liver Histopathology ◽  
Enos Phosphorylation

Background & Aims: In non-alcoholic steatohepatitis (NASH) decreased nitric oxide and increased endothelin-1 (ET-1) released by sinusoidal endothelial cells (LSEC), induce hepatic stellate cells (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, while ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Methods: Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or the combination for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblots. Conditioned media experiments were performed in LSEC. HSC were characterized by RT-PCR and a collagen lattice contraction assay was performed. Results: Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamic and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype improving endothelial function, while ambrisentan prevented the contractile response in HSC by blocking ET-1 response. Additionally, ambrisentan also increased eNOS phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the combined treated group reduced to normal serum ALT levels and showed restoration of the HSC quiescent phenotype. Conclusions: Combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for patients with NASH.

POSSIBILITY TO REDUCE THROMBOCYTOPENIA AFTER CHEMORADIOTHERAPY IN ONCOLOGICAL PATIENTS

2017 ◽  
Vol 63 (3) ◽  
pp. 466-469
Author(s):  
Luiza Korytova ◽  
Aleksey Meshechkin ◽  
Oleg Korytov ◽  
V. Krasnikova
Keyword(s):  
Combined Treatment ◽  
Treated Group ◽  
Median Number ◽  
Blood Analysis ◽  
Control Group ◽  
Level Control ◽  
Normal Range ◽  
Oncological Patients ◽  
Level Increase ◽  
And Control

Objective was to establish efficiency of sodium nucleospermat in correcting thrombocytopenia after chemoradiotherapy in oncological patients. Methods and materials. The study included data on 32 patients that had undergone combined treatment from January till May 2016. After detecting thrombocytopenia patients were randomized into two groups (16 patients in each): treated group, where patients received sodium nucleospermat, and control group, where sodium nucleospermat was not used. Thrombocyte level control was done on 5th, 10th and 15th day after treatment was over. Results and discussion. All 16 patients showed positive dynamics in increasing thrombocyte level after Sodium nucleospermat injection course was finished. This was proven by first (5th day) blood analysis. On average thrombocyte level after sodium nucleospermat treatment has risen to normal, at 161х109/1. Only 3 patients from this group had to pause radiotherapy for 5 days. Control group patients, which did not receive sodium nucleospermat, showed evidence of thrombocyte level recovery by 10th day only. On average thrombocyte level increase was insignificant, and median number was 111*109/l. Low thrombocyte level was main reason to pause radiotherapy for 11 (69%) patients in control group. Conclusion. Sodium nucleospermat allowed raising thrombocyte level to the lower normal range, which surpassed by 40%-50% in control group patients. Use of sodium nucleospermat did not show any cases of allergic reactions, toxicity or complications in oncological patients.

scholarly journals A combination of CMC and α-MSH inhibited ROS activated NLRP3 inflammasome in hyperosmolarity stressed HCECs and scopolamine-induced dry eye rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Lv ◽  
Chenchen Chu ◽  
Ke Liu ◽  
Yusha Ru ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Dry Eye ◽  
Nlrp3 Inflammasome ◽  
Ocular Surface ◽  
Combined Treatment ◽  
Underlying Mechanism ◽  
Oxygen Species ◽  
Corneal Epithelial ◽  
Melanocyte Stimulating Hormone ◽  
Human Corneal Epithelial Cells ◽  
Conjunctival Goblet Cells

AbstractAn important mechanism involved in dry eye (DE) is the association between tear hyperosmolarity and inflammation severity. Inflammation in DE might be mediated by the NLRP3 inflammasome, which activated by exposure to reactive oxygen species (ROS). A combination of carboxymethylcellulose (CMC) and α-melanocyte stimulating hormone (α-MSH) may influence DE through this mechanism, thus avoiding defects of signal drug. In this study, we assessed whether treatment comprising CMC combined with α-MSH could ameliorate ocular surface function; we found that it promoted tear secretion, reduced the density of fluorescein sodium staining, enhanced the number of conjunctival goblet cells, and reduced the number of corneal apoptotic cells. Investigation of the underlying mechanism suggested that the synergistic effect of combined treatment alleviated DE inflammation through reduction of ROS level and inhibition of the NLRP3 inflammasome in human corneal epithelial cells. These findings indicate that combined CMC + α-MSH treatment could ameliorate lesions and restore ocular surface function in patients with DE through reduction of ROS level and inhibition of NLRP3 signalling.

scholarly journals Overexpression of CRABP2 inhibits dexamethasone-induced apoptosis in human osteoblast cells

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Haiping Zhang ◽  
Ziliang Yu ◽  
Farui Sun ◽  
Jin Jin
Keyword(s):  
Protein Expression ◽  
Underlying Mechanism ◽  
R Package ◽  
Treated Group ◽  
Gene Expression Omnibus ◽  
Human Osteoblast ◽  
Osteoblast Cells ◽  
Gene And Protein Expression ◽  
Osteoblast Apoptosis ◽  
Induced Apoptosis

Abstract Background The purpose of the current study was to explore the role and underlying mechanism of cellular retinoic acid binding protein 2 (CRABP2) in dexamethasone (DEX)-induced apoptosis in human osteoblast cells. Methods GSE10311 was downloaded from the Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs) by the limma/R package. Primary human osteoblast was isolated and treated with different concentration of DEX (0, 10-8, 10-7, 10-6, 10-5, and 10-4 mol/L), and cell viability and flow cytometry were used to detect cell proliferation and apoptosis. A CRABP2 overexpression plasmid (oe-CRABP2) was used to overexpress CRABP2, and western blotting was conducted to detect protein expression. Results We found that CRABP2 was downregulated in the DEX-treated group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that DEGs were associated with PI3K/Akt signaling pathway. DEX downregulated CRABP2 gene and protein expression, inhibited viability, and induced human osteoblast apoptosis. Overexpression of CRABP2 reversed DEX-induced apoptosis in human osteoblast. Moreover, overexpression of CRABP2 delayed the progression of DEX-induced osteonecrosis of the femoral head (ONFH) animal model. Conclusion In conclusion, CRABP2 is effective at inhibiting DEX-induced human osteoblast apoptosis and delayed ONFH progression.

scholarly journals CXCR2 Blockade Influences Anaplasma phagocytophilum Propagation but Not Histopathology in the Mouse Model of Human Granulocytic Anaplasmosis

2004 ◽  
Vol 11 (5) ◽  
pp. 963-968 ◽  
Author(s):  
Diana G. Scorpio ◽  
Mustafa Akkoyunlu ◽  
Erol Fikrig ◽  
J. Stephen Dumler
Keyword(s):  
Anaplasma Phagocytophilum ◽  
Tissue Injury ◽  
Treated Group ◽  
Obligate Intracellular Bacterium ◽  
Human Granulocytic Anaplasmosis ◽  
Obligate Intracellular ◽  
Liver Histopathology ◽  
Granulocytic Anaplasmosis ◽  
Infected Cells ◽  
And Control

ABSTRACT Anaplasma phagocytophilum is an obligate intracellular bacterium that infects neutrophils and causes human granulocytic anaplasmosis. Infection induces neutrophil secretion of interleukin-8 or murine homologs and perpetuates infection by recruiting susceptible neutrophils. We hypothesized that antibody blockade of CXCR2 would decrease A. phagocytophilum tissue load by interrupting neutrophil recruitment but would not influence murine hepatic pathology. C3H-scid mice were treated with CXCR2 antiserum or control prior to or on day 14 after infection. Quantitative PCR and immunohistochemistry for A. phagocytophilum were performed and severity of liver histopathology was ranked. Control mice had more infected cells in tissues than the anti-CXCR2-treated group. The histopathological rank was not different between treated and control animals. Infected cells of control mice clustered in tissue more than in treated mice. The results support the hypothesis of bacterial propagation through chemokine induction and confirm that tissue injury is unrelated to A. phagocytophilum tissue load.

Pneumothorax and Pneumomediastinum in Infants With ldiopathic Respiratory Distress Syndrome Receiving Continuous Positive Airway Pressure

PEDIATRICS ◽  
1975 ◽  
Vol 55 (4) ◽  
pp. 493-496
Author(s):  
Robert T. Hall ◽  
Philip G. Rhodes
Keyword(s):  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Oxygen Concentration ◽  
Airway Pressure ◽  
Distress Syndrome ◽  
Underlying Mechanism ◽  
Treated Group ◽  
Controlled Study ◽  
Idiopathic Respiratory Distress Syndrome ◽  
Inspired Oxygen

A review of infants with idiopathic respiratory distress syndrome developing pneumomediastinum and pneumothorax reveals (1) an incidence of 20% in patients receiving CPAP with an 11% incidence in comparable infants not receiving this mode of therapy; (2) in the CAPA-treated group the occurrence was at a stage in the illness when the inspired oxygen concentration was being lowered and when ventilation was stable; (3) the inspired oxygen concentration in the CPAP group at the time of the PM and/or PT was 52% (± S.D. 15%) at a mean age of 33 hours (± S.D. 23 hr). These observations suggest that distending airway pressure creates excessive alveolar distention as an underlying mechanism of the air leak. It is recommended that distending airway pressure be lowered prior to achieving an inspired oxygen concentration of 60%. A controlled study is in progress to delineate the optimum distending airway pressures at specific inspired oxygen concentrations in order to reduce the incidence of alveolar rupture to a minimum.

Abstract MP244: Deciphering The Mechanism Of Elevation Of Mir34a And Its Attenuation Via Corm A1 And Subsequent Improvement In Mitochondrial Status In Atherogenic Mdms

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Hitarthi Vyas ◽  
Ranjitsinh Devkar
Keyword(s):  
Epigenetic Modification ◽  
Macrophage Polarization ◽  
Methylation Status ◽  
Human Monocyte ◽  
Underlying Mechanism ◽  
Treated Group ◽  
Docking Studies ◽  
Mrna Levels ◽  
In Silico Docking ◽  
Promotor Region

Elevated levels of miR34a and its association with macrophage polarization is reported in atherosclerosis but the underlying mechanism that upregulates miR34a lacks clarity. Herein, the mechanism of miR34a elevation in atherogenic human monocyte derived macrophages (MdMs) and subsequent changes in mitochondria were monitored. Further, CO supplementation (via Carbon monoxide Releasing Molecule A1; CORM A1) to atherogenic (OxLDL treated) MdMs was used to achieve downregulation of miR34a. Herein, we also hypothesize that lowering of miR34a in atherogenic MdMs improves the cellular health and mitochondrial function. Transcriptional factors (P53, NF-κb), transcriptional inhibitors (Zeb1, snai1, stat3) and epigenetic modification (methylation) in promoter region of miR34a were evaluated. OxLDL treated MdMs recorded significant decrement in mRNA levels of the said transcription inhibitors whereas; the same were reversed in CORM A1 co-treated group. Further, hypomethylation was recorded in the promotor region of miR34a on oxLDL treatment but methylation status was reverted to the control levels following CORM A1 co-supplementation. The mRNA levels of transcription factors showed non-significant changes in all the experimental groups. In silico docking studies had shown that CO effectively binds to the DNA binding domains of p53 that possibly prevents subsequent binding to their respective miR34a promotor regions. Positive docking of miR34a to 3’UTR of SIRT-1 supported our observation on lowered SIRT-1 and PGC-1α levels in oxLDL group that were found to be restored in CORM A1 co-treated group. Poor indices of mitochondrial biogenesis (SIRT-1, PGC1α, Nrf-1, Drp1, Mito Tracker Red staining), function (ATP assay), mitochondrial membrane potential (JC-1) and mitochondrial antioxidants (SOD2 and TrxR2), cellular ROS (DCFDA) following oxLDL treatment was found to be restored by CORM A1 co-treatment. In conclusion, atherogenic elevation of miR34a is as a result of hypomethylation in its promotor region and lowered mRNA transcripts of its inhibitors (Zeb1, snai1, stat3). Further, lowering of miR34a by CORM A1, improves atherogenic status of MdMs as evidenced by an improved cellular and mitochondrial health.

Anticancer Effects of Tacrolimus on Induced Hepatocellular Carcinoma in Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Shireen Sami Mahmoud ◽  
Samia Hussein ◽  
Hayam Rashed ◽  
Eman M. A. Abdelghany ◽  
Alaa I. Ali
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cyclin D1 ◽  
Liver Enzymes ◽  
Combined Treatment ◽  
Treated Group ◽  
Nuclear Antigen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Gamma Glutamyl Transferase ◽  
Anticancer Effects ◽  
Glutamyl Transferase

Background: Tacrolimus is a calcineurin inhibitor widely used for immunological disorders. However, there is a significant controversy regarding its effect on the liver. The present study was conducted to evaluate the anticancer effects of tacrolimus on an induced murine hepatocellular carcinoma (HCC) model and its possible hepatotoxicity at standard therapeutic doses. Methods: Fifty-four male mice were divided into five groups: a control healthy group, control HCC group, tacrolimus-treated group, doxorubicin (DOXO)-treated group, and combined tacrolimus- and DOXO-treated group. The activity of liver enzymes, including alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, alanine transaminase, and aspartate transaminase, was determined. Serum vascular endothelial growth factor (VEGF) was measured using an enzyme-linked immunosorbent assay. A quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to measure the expression of proliferating cell nuclear antigen (PCNA), Bax, and p53 mRNA. Immunohistochemical staining for cyclin D1 and VEGF was performed. Results: Mice that received combined treatment with tacrolimus and DOXO exhibited the best improvement in all parameters when compared with the groups that received DOXO or tacrolimus alone (p < 0.001). Conclusion: The combination of DOXO and tacrolimus was more effective in the management of HCC compared with either agent alone. This improvement was detected by the reduction of liver enzymes and the improvement of the histopathological picture. The involved mechanisms included significant apoptosis induction demonstrated by upregulation of bax along with a reduction in angiogenesis demonstrated by downregulation of VEGF. This was accompanied by inhibition of cell cycle progression mediated by upregulated p53 and downregulated PCNA and cyclin D1.

The Contribution of Sex Difference on Different Liver Histopathology Between Male and Female Mice After Oral Administration of Caffeine

2021 ◽  
Vol 2 (2) ◽  
pp. 37-41
Author(s):  
Muhammad Sholikhuddin Nafi’ ◽  
Tri Hartini Yuliawati ◽  
Prijati Sri Irawati ◽  
Nurina Hasanatuludhhiyah
Keyword(s):  
Oral Administration ◽  
Sex Difference ◽  
Liver Cell ◽  
Histopathological Examination ◽  
Treated Group ◽  
Male And Female ◽  
Female Mice ◽  
Liver Histopathology ◽  
End Of Treatment ◽  
Significant Difference

Background : There are several studies reporting the effect of caffeine on liver histopathology, but it remains controversy. The laboratory animal used in those studies were predominantly male, whereas there is contribution of sex difference on different liver reaction to xenobiotic between male and female subject. Objective : It is necessary to conduct a study to explore the differences between the liver histopathology of male and female mice after oral administration of caffeine. Methods : This study used 36 mice (Mus musculus) that were divided into 4 groups: male & female untreated groups and male & female treated groups which were orally administered with caffeine 0.4 mg / 20 gramBW daily for 30 days. At the end of treatment, mice were euthanized and dissected. Histopathological examination was done to determine the percentage of  liver cell death of each group. Results: The percentage of liver cell deathin female treated group was higher than male treated group (p = 0.0001). But there was no significant difference of liver cells death between male control and treated group and between female control and treated group. Conclusion : There was significant difference in liver histopathology between male and female mice after oral administration of caffeine.

scholarly journals Hsp60 and IL-8 axis promotes apoptosis resistance in cancer

2019 ◽  
Vol 121 (11) ◽  
pp. 934-943 ◽  
Author(s):  
Sandeep Kumar ◽  
Jordan O’Malley ◽  
Ajay Kumar Chaudhary ◽  
Joseph R. Inigo ◽  
Neelu Yadav ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Combined Treatment ◽  
Annexin V ◽  
Underlying Mechanism ◽  
Competitive Inhibitor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Heat Shock Protein 60 ◽  
Apoptosis Resistance ◽  
Upstream Regulator

Abstract Background Interleukin-8 (IL-8) and heat shock protein 60 (Hsp60) play crucial roles in cell survival and maintenance of cellular homoeostasis. However, cross talks between these two proteins are not defined. Methods IL-8 expression in tumour tissue sections was analysed by immunohistochemistry. IL-8 expression and release in cancer cells was quantified using enzyme-linked immunosorbent assay (ELISA). Apoptosis was quantified using caspase activity and Annexin-V/PI staining. Results We observed IL-8 release from cancer cells in response to histone deacetylase inhibitor, apicidin (Api), and non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase, thapsigargin (TG). IL-8 release was increased upon TG-treatment. TG-induced IL-8 expression was reduced in the presence of Api in Bax-dependent manner. Increased apoptosis was associated with decreased IL-8 expression in response to combined treatment of TG and Api. TG and Api combination induced caspase-8 and caspase-9 dependent apoptosis. Hsp60 knockdown abrogated IL-8 expression induced by Api, TG, and their combination. The level of TGF-β, an upstream regulator of IL-8, was decreased upon Hsp60-silencing. Knocking down Hsp60 decreased IL-8 expression and its release in prostate cancer cell xenograft tumours in SCID mice. Conclusion This study describes the underlying mechanism associated with apoptosis resistance mediated via Hsp60-IL-8 axis in cancer.

scholarly journals Contribution of systemic inflammation to permanence of KATP-induced neonatal diabetes in mice

2018 ◽  
Vol 315 (6) ◽  
pp. E1121-E1132
Author(s):  
Christopher H. Emfinger ◽  
Zihan Yan ◽  
Alecia Welscher ◽  
Peter Hung ◽  
William McAllister ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Systemic Inflammation ◽  
Treatment Effectiveness ◽  
Glucose Production ◽  
Neonatal Diabetes ◽  
Underlying Mechanism ◽  
Normal Serum ◽  
Severe Insulin Resistance ◽  
Severe Diabetes ◽  
Glucagon Like Peptide 1

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (KATP) channels cause neonatal diabetes. Despite the well-established genetic root of the disease, pathways modulating disease severity and treatment effectiveness remain poorly understood. Patient phenotypes can vary from severe diabetes to remission, even in individuals with the same mutation and within the same family, suggesting that subtle modifiers can influence disease outcome. We have tested the underlying mechanism of transient vs. permanent neonatal diabetes in KATP-GOF mice treated for 14 days with glibenclamide. Some KATP-GOF mice show remission of diabetes and enhanced insulin sensitivity long after diabetes treatment has ended, while others maintain severe insulin-resistance. However, insulin sensitivity is not different between the two groups before or during diabetes induction, suggesting that improved sensitivity is a consequence, rather than the cause of, remission, implicating other factors modulating glucose early in diabetes progression. Leptin, glucagon, insulin, and glucagon-like peptide-1 are not different between remitters and nonremitters. However, liver glucose production is significantly reduced before transgene induction in remitter, relative to nonremitter and nontreated, mice. Surprisingly, while subsequent remitter animals exhibited normal serum cytokines, nonremitter mice showed increased cytokines, which paralleled the divergence in blood glucose. Together, these results suggest that systemic inflammation may play a role in the remitting versus non-remitting outcome. Supporting this conclusion, treatment with the anti-inflammatory meloxicam significantly increased the fraction of remitting animals. Beyond neonatal diabetes, the potential for inflammation and glucose production to exacerbate other forms of diabetes from a compensated state to a glucotoxic state should be considered.

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