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13 pages, 3053 KiB

Open AccessFeature PaperArticle

Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study

by Fabio Arturo Iannotti, Fabrizia De Maio, Elisabetta Panza, Giovanni Appendino, Orazio Taglialatela-Scafati, Luciano De Petrocellis, Pietro Amodeo and Rosa Maria Vitale

Molecules 2020, 25(5), 1119; https://doi.org/10.3390/molecules25051119 - 03 Mar 2020

Cited by 18 | Viewed by 16301

Abstract

Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ⁹-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and [...] Read more.

Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ⁹-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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9 pages, 1628 KiB

Open AccessArticle

PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice

by Adriano Cleis Arruda, Mauro Sérgio Perilhão, Warley Almeida Santos, Marcos Fernandes Gregnani, Alexandre Budu, José Cesar Rosa Neto, Gabriel Rufino Estrela and Ronaldo Carvalho Araujo

Molecules 2020, 25(2), 392; https://doi.org/10.3390/molecules25020392 - 17 Jan 2020

Cited by 11 | Viewed by 3421

Abstract

Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points [...] Read more.

Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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13 pages, 4478 KiB

Open AccessArticle

Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson’s Disease

by Sonia Burgaz, Concepción García, Maria Gómez-Cañas, Eduardo Muñoz and Javier Fernández-Ruiz

Molecules 2019, 24(15), 2702; https://doi.org/10.3390/molecules24152702 - 25 Jul 2019

Cited by 21 | Viewed by 4016

Abstract

In a recent study, we described the neuroprotective properties of VCE-003.2—an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)—administered intraperitoneally (i.p.) in an inflammatory model of Parkinson’s disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome proliferator-activated [...] Read more.

In a recent study, we described the neuroprotective properties of VCE-003.2—an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)—administered intraperitoneally (i.p.) in an inflammatory model of Parkinson’s disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome proliferator-activated receptor-γ, in particular at a regulatory site within this receptor type. In the present study, we wanted to further confirm this neuroprotective potential using an oral lipid formulation of VCE-003.2, developed to facilitate the clinical development of this phytocannabinoid derivative. To this end, we evaluated VCE-003.2, administered orally at two doses (10 and 20 mg/kg), to mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS), a classic model of inflammation-driven neuronal deterioration that recapitulates characteristics of PD. The administration of VCE-003.2 to these mice showed, as expected, poor activity in the different motor tests (rotarod, computer-aided actimeter) used in experimental parkinsonism, in general due to the lack of evident changes in these behaviors by LPS lesion. However, VCE-003.2, at 20 mg/kg, was highly active in improving the changes detected in LPS-lesioned mice in the cylinder rearing test. In addition, the histopathological analysis of the basal ganglia revealed a trend towards recovery at 20 mg/kg VCE-003.2 in the loss of tyrosine hydroxylase-containing nigrostriatal neurons, as well as a complete reduction in the elevated LAMP-1 immunolabeling (reflecting autophagy impairment) caused by LPS lesion. These effects were not seen at 10 mg/kg. This was associated with a partial reduction in the intense glial reactivity provoked by LPS in the substantia nigra, in particular the astroglial reactivity labeled with glial fibrillary acidic protein. The analysis using qPCR in the striatum of proinflammatory mediators, such as tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2, showed that the marked elevations provoked by the LPS lesion tended to be, in general, attenuated by VCE-003.2 treatment, with the greatest effects normally found with the highest dose of 20 mg/kg. In summary, our data confirm the neuroprotective potential of an oral formulation of VCE-003.2 against neuronal injury in an in vivo model of PD based on neuroinflammation, and this study opens the possibility to further the development of oral VCE-003.2 in the clinic. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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15 pages, 1992 KiB

Open AccessArticle

The PPARγ Agonist Rosiglitazone Suppresses Syngeneic Mouse SCC (Squamous Cell Carcinoma) Tumor Growth through an Immune-Mediated Mechanism

by Raymond L. Konger, Ethel Derr-Yellin, Nurmukambed Ermatov, Lu Ren and Ravi P. Sahu

Molecules 2019, 24(11), 2192; https://doi.org/10.3390/molecules24112192 - 11 Jun 2019

Cited by 14 | Viewed by 3221

Abstract

Recent evidence suggests that PPARγ agonists may promote anti-tumor immunity. We show that immunogenic PDV cutaneous squamous cell carcinoma (CSCC) tumors are rejected when injected intradermally at a low cell number (1 × 10⁶) into immune competent syngeneic hosts, but not [...] Read more.

Recent evidence suggests that PPARγ agonists may promote anti-tumor immunity. We show that immunogenic PDV cutaneous squamous cell carcinoma (CSCC) tumors are rejected when injected intradermally at a low cell number (1 × 10⁶) into immune competent syngeneic hosts, but not immune deficient mice. At higher cell numbers (5 × 10⁶ PDV cells), progressively growing tumors were established in 14 of 15 vehicle treated mice while treatment of mice with the PPARγ agonist rosiglitazone resulted in increased tumor rejection (5 of 14 tumors), a significant decrease in PDV tumor size, and a significant decrease in tumor cell Ki67 labeling. Rosiglitazone treatment had no effect on tumor rejection, tumor volume or PDV tumor cell proliferation in immune deficient NOD.CB17-Prkdc^SCID/J mice. Rosiglitazone treatment also promoted an increase in tumor infiltrating CD3⁺ T-cells at both early and late time points. In contrast, rosiglitazone treatment had no significant effect on myeloid cells expressing either CD11b or Gr-1 but suppressed a late accumulation of myeloid cells expressing both CD11b and Gr-1, suggesting a potential role for CD11b⁺Gr-1⁺ myeloid cells in the late anti-tumor immune response. Overall, our data provides evidence that the PPARγ agonist rosiglitazone promotes immune-mediated anti-neoplastic activity against tumors derived from this immunogenic CSCC cell line. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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14 pages, 2027 KiB

Open AccessArticle

Clofibrate Treatment Decreases Inflammation and Reverses Myocardial Infarction-Induced Remodelation in a Rodent Experimental Model

by Luz Ibarra-Lara, María Sánchez-Aguilar, Elizabeth Soria-Castro, Jesús Vargas-Barrón, Francisco J. Roldán, Natalia Pavón, Juan C. Torres-Narváez, Luz G. Cervantes-Pérez, Gustavo Pastelín-Hernández and Alicia Sánchez-Mendoza

Molecules 2019, 24(2), 270; https://doi.org/10.3390/molecules24020270 - 12 Jan 2019

Cited by 9 | Viewed by 3204

Abstract

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments [...] Read more.

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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12 pages, 5455 KiB

Open AccessArticle

PPARα Agonist Suppresses Inflammation after Corneal Alkali Burn by Suppressing Proinflammatory Cytokines, MCP-1, and Nuclear Translocation of NF-κB

by Yuichiro Nakano, Masaaki Uchiyama, Takeshi Arima, Shinya Nagasaka, Tsutomu Igarashi, Akira Shimizu and Hiroshi Takahashi

Molecules 2019, 24(1), 114; https://doi.org/10.3390/molecules24010114 - 29 Dec 2018

Cited by 23 | Viewed by 4179

Abstract

We investigated the effect of a peroxisome proliferator-activated receptor α (PPARα) agonist after corneal alkali injury. Fenofibrate 0.05% (PPARα agonist group) or vehicle (Vehicle group) was topically instilled onto the rat cornea after injury. Histological, immunohistochemical, and real-time reverse transcription PCR analyses were [...] Read more.

We investigated the effect of a peroxisome proliferator-activated receptor α (PPARα) agonist after corneal alkali injury. Fenofibrate 0.05% (PPARα agonist group) or vehicle (Vehicle group) was topically instilled onto the rat cornea after injury. Histological, immunohistochemical, and real-time reverse transcription PCR analyses were performed. PPARα-positive cells were observed among basal cells of the corneal epithelium in normal and alkali-burned corneas. The number of infiltrating neutrophils and macrophages at the corneal limbus was lower in the PPARα agonist group. Interleukin-1β (IL-1β), IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor-An mRNA expression was suppressed in the PPARα agonist group compared to the Vehicle group. mRNA levels of nuclear factor kappa B (NF-κB) in corneal tissue were not different. However, NF-κB was expressed in the cytoplasm of basal cells in the PPARα agonist group and in the nucleus in the Vehicle group. MCP-1 was more weakly expressed in the PPARα agonist group. The PPARα agonist inhibited inflammation during the early phase after injury. Anti-inflammatory effects of the PPARα agonist included prevention of up-regulation of proinflammatory cytokines and MCP-1, and prevention of inflammatory cell infiltration into the injured cornea. Thus, a PPARα agonist may be a promising treatment for corneal injury. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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Review

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15 pages, 2483 KiB

Open AccessReview

Building and Testing PPARγ Therapeutic ELB00824 with an Improved Therapeutic Window for Neuropathic Pain

by Karin N. Westlund and Morgan Zhang

Molecules 2020, 25(5), 1120; https://doi.org/10.3390/molecules25051120 - 03 Mar 2020

Cited by 5 | Viewed by 3391

Abstract

Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing [...] Read more.

Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood–brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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18 pages, 1336 KiB

Open AccessReview

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

by Michele Tufano and Graziano Pinna

Molecules 2020, 25(5), 1062; https://doi.org/10.3390/molecules25051062 - 27 Feb 2020

Cited by 32 | Viewed by 6396

Abstract

Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and [...] Read more.

Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Hence, the strategy of targeting PPARs for their anti-inflammatory role to improve these disorders is attracting attention. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies. We reviewed running findings in support of a role for PPARs in the treatment of neurological diseases, including Alzheimer’s disease or psychiatric disorders, such as major depression. We discuss the opportunity of targeting PPARs as a future pharmacological approach to decrease neuropsychiatric symptoms at the same time that PPAR ligands resolve neuroinflammatory processes. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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20 pages, 1156 KiB

Open AccessReview

PPARs as Nuclear Receptors for Nutrient and Energy Metabolism

by Fan Hong, Shijia Pan, Yuan Guo, Pengfei Xu and Yonggong Zhai

Molecules 2019, 24(14), 2545; https://doi.org/10.3390/molecules24142545 - 12 Jul 2019

Cited by 135 | Viewed by 13338

Abstract

It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular [...] Read more.

It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications. Full article

(This article belongs to the Special Issue Role of PPAR Receptors in Human Health and Disease)

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