Triterpenoid CDDO-IM protects against lipopolysaccharide-induced inflammatory response and cytotoxicity in macrophages: The involvement of the NF-κB signaling pathway

Lipopolysaccharide (LPS), also known as endotoxin, can trigger septic shock, a severe form of inflammation-mediated sepsis with a very high mortality rate. However, the precise mechanisms underlying this endotoxin remain to be defined and detoxification of LPS is yet to be established. Macrophages, a type of immune cells, initiate a key response responsible for the cascade of events leading to the surge in inflammatory cytokines and immunopathology of septic shock. This study was undertaken to determine whether the LPS-induced inflammation in macrophage cells could be ameliorated via CDDO-IM (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a novel triterpenoid compound. Data from this study show that gene expression levels of inflammatory cytokine genes such as interleukin-1 beta (IL-1β), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) were considerably increased by treatment with LPS in macrophages differentiated from ML-1 monocytes. Interestingly, LPS-induced increase in expression of pro-inflammatory cytokine levels is reduced by CDDO-IM. In addition, endogenous upregulation of a series of antioxidant molecules by CDDO-IM provided protection against LPS-induced cytotoxicity in macrophages. LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) transcriptional activity was also noted to decrease upon treatment with CDDO-IM in macrophages suggesting the involvement of the NF-κB signaling. This study would contribute to improve our understanding of the detoxification of endotoxin LPS by the triterpenoid CDDO-IM.

Intravenous thrombolysis with alteplase in the treatment of acute cerebral infarction

Objectives: To compare the efficacy and safety of intravenous thrombolysis with alteplase and intravenous thrombolysis with urokinase for patients with acute cerebral infarction. Methods: This prospective study included 140 patients with acute cerebral infarction who were admitted to our hospital between June 2018 and June 2019. They were randomly divided into two groups. The control group (70 cases) was treated with urokinase intravenous thrombolysis, and the observation group (70 cases) was given alteplase intravenous thrombolytic therapy. The treatment efficacy and safety of the two groups were compared. Results: The total effective rate of the observation group was 95.7%, and that of the control group was 78.6%, i.e., the total effective rate of the observation group was significantly superior to the that of the control group (P < 0.05). After treatment, the observation group had significantly lower National Institutes of Health Stroke Scale (NIHSS) score and significantly higher mini-mental state examination (MMSE) score than the control group; the difference was statistically significant (P<0.05). After treatment, the levels of inflammatory factors of both groups significantly decreased compared to before treatment, and the decrease in the observation group was larger than that in the control group (P<0.05). The levels of serum homocysteine (Hcy) and monocyte chemoattractant protein-1 (MCP-1) in the observation group were significantly lower than those in the control group after treatment, and the differences were statistically significant (P<0.05). The incidence of hemorrhagic adverse reaction in the observation group was lower than that in the control group (P<0.05). Conclusion: In the treatment of acute cerebral infarction, ccompared with urokinase, alteplase can further relieve cognitive impairment and promote the recovery of nerve function through inhibiting levels of inflammatory factors and levels of serum Hcy and MCP-1. doi: https://doi.org/10.12669/pjms.38.3.4521 How to cite this:Gao L, Zhang S, Wo X, Shen X, Tian Q, Wang G. Intravenous thrombolysis with alteplase in the treatment of acute cerebral infarction. Pak J Med Sci. 2022;38(3):---------. doi: https://doi.org/10.12669/pjms.38.3.4521 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Monocyte chemoattractant protein-1 levels are associated with major depressive disorder

Objectives Major depressive disorder (MDD) is a distressing condition characterized by persistent low mood, loss of interest in daily activities. Researchers consider several biological, psycho-social, and genetic factors are involved in depression. The present study aimed to investigate the serum levels of monocyte chemoattractant protein-1 (MCP-1) in MDD patients to explore its role in depression. Methods This case-control study recruited 114 MDD patients and 106 healthy controls (HCs) matched by age and gender. A specialized psychiatrist diagnosed the cases and evaluated the controls based on the diagnostic and statistical manual for mental disorders, 5th edition. We quantified serum MCP-1 levels using commercially available enzyme-linked immune sorbent assay kits. Also, we applied the Hamilton depression rating scale (Ham-D) to measure the severity of depression. Results We observed the decreased levels of serum MCP-1 in MDD patients compared to HCs. Also, we obtained a significant negative correlation between serum MCP-1 levels and Ham-D scores. Moreover, female MDD patients with higher Ham-D scores exhibited lower serum MCP-1 levels. The receiver operating characteristic analysis demonstrated the good diagnostic value of MCP-1 with the area under the curve at 0.837. Conclusions The depression-related alteration of serum MCP-1 may be more complicated than the current assumption and depends on the characteristics of the individual patients. Our study suggests that the serum MCP-1 levels might involve in the pathophysiology and mechanism of MDD. The present findings, along with the diagnostic evaluation, might be used to evaluate depressive patients.

Markers of kidney tubular and interstitial injury and function among sugarcane workers with cross-harvest serum creatinine elevation

ObjectivesSerum creatinine (SCr) is a routine marker of kidney injury but also increases with dehydration and muscular work. This study was to elucidate whether increase in SCr is associated with more specific markers of kidney tubular and interstitial injury and function, during prolonged heat stress among workers at high risk of chronic kidney disease of non-traditional origin (CKDnt).MethodsUrine monocyte chemoattractant protein-1 (MCP-1), kidney injury molecule-1 (KIM-1), calbindin, glutathione S-transferase-π (GST-π), clusterin, interleukin 18 and albumin, fractional excretion of potassium (FEK), blood haemoglobin, serum potassium, ferritin and erythropoietin were measured before and after harvest in a sample of 30 workers with a ≥0.3 mg/dL SCr increase across harvest (cases), and 53 workers with stable SCr (controls).ResultsUrine MCP-1 (p for differential cross-harvest trend <0.001), KIM-1 (p=0.002), calbindin (p=0.02), GST-π (p=0.04), albumin (p=0.001) and FEK (p<0.001) increased in cases, whereas blood haemoglobin (p<0.001) and serum erythropoietin (p<0.001) decreased.ConclusionSeveral markers of tubular and interstitial injury and function changed as SCr increased across a harvest season, supporting the use of SCr as an indicator of kidney injury in physically active workers regularly exposed to heat stress. Repeated injury similar to that described here, and continued work under strenuous and hot conditions with similarly elevated injury markers is likely to worsen and possibly initiate CKDnt.

Inhibitory Effects of Inonotus obliquus Polysaccharide on Inflammatory Response in Toxoplasma gondii-Infected RAW264.7 Macrophages

Our previous reports have shown that Inonotus obliquus polysaccharide (IOP) has protective effects against Toxoplasma gondii (T. gondii) infection in vivo. The aim of the present research is to explore the in vitro anti-inflammatory effects of IOP and its mechanism in RAW264.7 macrophages infected by T. gondii. In this study, it is indicated that IOP decreased the excessive secretion of inflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-4, and IL-6 in T. gondii-infected RAW264.7 macrophages. IOP effectively suppressed the mRNA expression of these cytokines and chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). Moreover, IOP inhibited the phosphorylation of inhibitor kappa B kinase α/β (IKKα/β), inhibitor κBα (IκBα), p65 in nuclear factor-kappa B (NF-κB) signaling pathway and p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) in mitogen-activated protein kinases (MAPKs) signaling pathway. Meantime, IOP prevented NF-κB p65 and c-Jun translocation from the cytoplasm to the nucleus. Further, IOP downregulated the protein expression of toll-like receptor 2 (TLR2) and TLR4 in T. gondii-infected RAW264.7 macrophages. The above results suggest that IOP can inhibit the inflammatory response infected with T. gondii via regulating TLR2/TLR4-NF-κB/MAPKs pathways and exerting its anti-T. gondii role in vitro.

The Cholesterol Metabolite Cholest-5-en-3-One Alleviates Hyperglycemia and Hyperinsulinemia in Obese (db/db) Mice

Dietary sterols are catabolized into various substances in the intestinal tract. Dietary 3-oxo derivatives of cholesterol and plant sterols (e.g., cholest-4-en-3-one and campest-5-en-3-one) have been shown to have anti-obesity effects. In this study, we tested whether feeding cholest-5-en-3-one (5-cholestenone), a cholesterol metabolite, to db/db mice protects them from obesity-associated metabolic disorders. In db/db mice, dietary 5-cholestenone significantly alleviated hepatomegaly and elevated serum triglyceride levels; however, the effect was not sufficient to improve hepatic steatosis and obesity. On the other hand, hyperglycemia and severe hyperinsulinemia in control db/db mice were markedly attenuated in 5-cholestenone-fed db/db mice. The production of inflammatory cytokines, such as monocyte chemoattractant protein-1, interleukin-6, and tumor necrosis factor-alpha (TNFα), was decreased, suggesting that the suppressive actions of 5-cholestenone were attributable to the alleviation of chronic inflammation in db/db mice. Additionally, 5-cholestenone showed an inhibitory effect on TNFα-induced nuclear factor kappa B (NFκB) activation in the NFκB luciferase gene reporter assay. These results suggest that obesity-induced abnormal glucose metabolism could be alleviated in 5-cholestenone-fed db/db mice by reducing the production of inflammatory cytokines through suppression of the NFκB signaling pathway.

Pharmacological Inhibition of CCR2 Signaling Exacerbates Exercise-Induced Inflammation Independently of Neutrophil Infiltration and Oxidative Stress

Although exercise-induced humoral factors known as exerkines benefit systemic health, the role of most exerkines has not been investigated. Monocyte chemoattractant protein-1 (MCP-1) is a representative chemokine whose circulating concentrations increase after exercise, and it is one of the exerkines. MCP-1 is a ligand for CC chemokine receptor 2 (CCR2), which is expressed on monocytes, macrophages, and muscle cells. However, there is no information on the role of CCR2 signaling in exercise. Therefore, to investigate the research question, we administrated CCR2 antagonist or PBS to mice to inhibit CCR2 signaling before and after exercise. Our results showed that CCR2 signaling inhibition promoted exercise-induced macrophage infiltration and inflammation 24 h after exercise in muscle. CCR2 signaling inhibition also exacerbated exercise-induced inflammation immediately after exercise in muscle. However, neutrophil infiltration and oxidative stress had no contribution to exercise-induced inflammation by CCR2 signaling inhibition. CCR2 signaling inhibition also exacerbated exercise-induced inflammation immediately after exercise in kidney, liver, and adipose tissues. To summarize, pharmacological inhibition of CCR2 signaling exacerbated exercise-induced inflammation independently of neutrophil infiltration and oxidative stress.