Pharmacology lettersLipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: Reduction of MRNA levels for interleukin-1β, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor α (PPARα) in primary endothelial cells
Abstract
We examined the effects of four 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (pravastatin, simvastatin, fluvastatin, and cerivastatin) on the production and expression of inflammatory cytokines and on enzyme expression involving prostaglandin and superoxide production in cultured human umbilical vein endothelial cells (HUVEC). All HMG-CoA reductase inhibitors significantly reduced interleukin-1β and -6 mRNA expression and their protein levels in the culture medium, and also inhibited cyclooxygenase-2 mRNA expression and their protein levels. And these drugs induced peroxisome proliferator-activated receptor α (PPARα) and PPARγ mRNA expression and their protein levels in HUVEC and hepatocyte. Moreover, the mRNA levels of p22phox, a 22-kD subunit and the protein levels of p47phox, a 47-kD subunit of nicotine adenine dinucleotide phosphate (NADPH) oxidase, was decreased by treatment with either simvastatin, fluvastatin or cerivastatin, and this effect was reversed by mevalonate, geranylgeraniol, farnesol, and cholesterol. The changes induced by HMG-CoA reductase inhibitors might be due to regulation of cellular cholesterol content level, cellular cholesterol metabolic pathway, and cellular PPARα activity, which was related with inflammation. This unique anti-inflammatory effect in addition to its hypolipidemic action, may be beneficial in preventing the vascular complications that are induced by hyperlipidemia.
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Simvastatin reduced infiltration of memory subsets of T lymphocytes in the lung tissue during Th2 allergic inflammation
2022, International ImmunopharmacologyLymphocytes infiltration is a key mechanism that drives asthma lung inflammation. Our previous results demonstrated a significant increase in the frequency and persistence of central memory T (TCM) cells in inflamed lung tissue. This could be due to an increase in the infiltration of TCM in the lung tissue, or the possible differentiation of lung effector memory T (TEM) cells into TCM during lung inflammation. Thus, targeting the accumulation of memory T cells provides a potential approach for asthma treatment. Simvastatin and other statins were shown to impact both the structural and immune lung cells, presenting a distinct immunomodulatory effect on T lymphocyte activation, infiltration, and function. Therefore, we sought to evaluate the effect of simvastatin on the frequency and function of CD4 and CD8 TEM and TCM cells in an ovalbumin (OVA)-induced mouse model of asthma. Simvastatin treatment significantly attenuated the infiltration of both TEM and TCM memory subtypes, along with their production of IL-4 and IL-13 cytokines in a T helper 2 (Th2) OVA-sensitized mouse model. Furthermore, we detected a reduction in ICAM-1 and VCAM-1 levels in the lung homogenate of OVA-sensitized and challenged mice, as well as in human umbilical vein endothelial cells (HUVECs) following treatment with simvastatin. The reduction in leucocyte homing receptors following simvastatin treatment might have contributed to the observed decrease in infiltrated memory T cell numbers. In conclusion, this study demonstrated how statin drug may attenuate allergic asthma lung inflammation by targeting memory T cells and reducing their numbers, whilst limiting their cytokine production at the site of inflammation. Longer clinical trials are required to assess the effectiveness and safety of statin treatment in different asthma phenotypes.
Molecular targets of statins and their potential side effects: Not all the glitter is gold
2022, European Journal of PharmacologyStatins are a class of drugs widely used worldwide to manage hypercholesterolemia and the prevention of secondary heart attacks. Currently, available statins vary in terms of their pharmacokinetic and pharmacodynamic profiles. Although the primary target of statins is the inhibition of HMG-CoA reductase (HMGR), the rate-limiting enzyme in cholesterol biosynthesis, statins exhibit many pleiotropic effects downstream of the mevalonate pathway. These pleiotropic effects include the ability to reduce myocardial fibrosis, pathologic cardiac disease states, hypertension, promote bone differentiation, anti-inflammatory, and antitumor effects through multiple mechanisms. Although these pleiotropic effects of statins may be a cause for enthusiasm, there are many adverse effects that, for the most part, are unappreciated and need to be highlighted. These adverse effects include myopathy, new-onset type 2 diabetes, renal and hepatic dysfunction. Although these adverse effects may be relatively uncommon, considering the number of people worldwide who use statins daily, the actual number of people affected becomes quite large. Also, co-administration of statins with several other medications, herbal agents, and foods, which interact through common enzymatic pathways, can have untoward clinical consequences. In this review, we address these concerns.
Novel Immunomodulatory Therapies for Respiratory Pathologies
2022, Comprehensive PharmacologyThe respiratory tract is constantly exposed to environmental aggressions including allergens, infections, and pollution. The immune system is pivotal to fight potential invaders and prevent the establishment of infections in the respiratory tract; however, excessive, misplaced or altered immune responses contribute to increase tissue damage, impair lung function, and exacerbate respiratory diseases. Indeed, asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis are respiratory diseases that have uncontrolled inflammation as a unifying severity factor. In addition, the acute inflammatory responses in pneumonia must be controlled to avoid progression to acute respiratory distress syndrome, which can be lethal. In this regard, immunomodulatory therapies are promising pharmacological strategies to treat important respiratory pathologies. Understanding the pathogenesis of respiratory disorders have paved the way for the development of cytokine-directed therapies, allosteric or non-allosteric inhibitors of inflammatory receptors and enzymes, agonists of resolution of inflammation and other anti-inflammatory compounds. A multitude of studies have evaluated the safety, pharmacokinetics, and pharmacodynamics of several molecules that target inflammation in the respiratory tract, yet only few have been translated to clinical use. This article will summarize important aspects of asthma, COPD, cystic fibrosis, and pneumonia focusing on the role of immune responses in disease development and novel immunomodulatory therapies.
Association of Secreted Frizzled Related Protein 4 with Type 2 Diabetes Mellitus and its complications: A South Indian hospital based case control study
2021, Clinical Epidemiology and Global HealthSecreted frizzled related protein 4 (SFRP4) is a modulator of the Wnt pathway. Its secretion is regulated by interleukin-1β.
Primary objective was to assess the serum levels of SFRP4 in cases of T2DM and normoglycemic (NG) controls. Secondary objectives was to assess the association of serum levels of SFRP4 with chronic micro or macrovascular complications of T2DM.
A case control study conducted after obtaining institutional ethical clearance. Included as cases were those diagnosed with T2DM. Excluded were those who were prediabetics, immunocompromised, endocrinopathies, pregnant and lactating women. Inclusion criteria for NG controls were age >18 years, consenting for participation attending out-patient department for routine care. Exclusion criteria for controls were same as for cases. Serum SFRP4 levels were determined by ELISA using Elabscience kit.
From October 2016 till June 2018, included were 98 T2DM cases and 48 NG controls. The mean age of cases was 52.73 yrs (SD: 10.09), and controls 49.92 yrs (SD: 12.344). The median levels of SFRP4 in cases was 1.36 ng/mL (IQR: 0.85, 2.67) and in controls 0.44 ng/mL (IQR: 0.27, 2.58) (p-value < 0.001). In T2DM with (n = 65, 67.7%) versus without (n = 31, 32.3%) any chronic micro/macro vascular complications median serum SFRP4 level was 1.16 ng/mL (IQR: 0.77, 2.44) and 2.24 ng/mL (IQR: 0.92, 4.84) (p-value: 0.03) respectively.
There was statistically significantly higher levels of serum SFRP4 levels amongst T2DM cases as compared to NG controls. Cases with chronic complications of T2DM had statistically significant lower levels of serum SFRP4.
Prosarcopenic Effects of Statins May Limit Their Effectiveness in Patients with Heart Failure
2018, Trends in Pharmacological SciencesSome studies using small doses of statins revealed significant benefits for patients with chronic heart failure (HF). However, the results of large randomized studies did not confirm these advantages. Along with the primary effect of cholesterol lowering, statins have many ancillary actions that may be relevant for body wasting. In this context, the fear of muscle-related side effects needs to be put into clinical context and assessed appropriately before statins are either withheld or withdrawn in patients with sarcopenia (muscle wasting). Some of the mechanistic bases of statin-mediated muscle dysfunction correspond with mechanisms of sarcopenia observed in HF with reduced ejection fraction patients, connected with insulin-like growth factor 1, inflammation, the ubiquitin–proteasome pathway, apoptosis, and myostatin. Here we present the hypothesis of potential prosarcopenic properties of statins as a possible explanation of the lack of effectiveness of these drugs in HF patients.
Lovastatin inhibits visceral allodynia and increased colonic permeability induced by lipopolysaccharide or repeated water avoidance stress in rats
2018, European Journal of PharmacologyStatins have been reported to block inflammatory somatic pain and have an anti-cytokine property. Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral hypersensitivity and increases gut permeability in rats, which are mediated through proinflammatory cytokine-dependent pathways. Since visceral hypersensitivity with increased gut permeability plays a crucial role in the pathophysiology of irritable bowel syndrome (IBS), these above animal models are considered to simulate IBS. We hypothesized that lovastatin improves symptoms in the patients with IBS by attenuating these visceral changes. The threshold of visceromotor response (VMR) induced by colonic balloon distention was measured for the assessment of visceral sensation in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min using a spectrophotometer. Subcutaneously (s.c.) injected LPS (1 mg/kg) reduced the threshold of VMR after 3 h. Pretreatment with lovastatin (20 mg/kg s.c. daily for 3 days) abolished this response by LPS. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by repeated injection of lovastatin before each stress session. The antinociceptive effect of lovastatin on the LPS-induced allodynia was reversed by mevalonolactone, NG-nitro-L-arginine methyl ester or naloxone. Lovastatin also blocked the LPS- or repeated WAS-induced increased gut permeability. These results indicate the possibility that lovastatin can be useful for treating IBS.