Peroxisome proliferator-activated receptors: Key regulators of tumor progression and growth.

One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and PPARγ, which are important in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. PPARs are receiving interest as possible therapeutic targets for a number of disorders. Numerous clinical studies are being conducted on PPARs as possible therapeutic targets for cancer. Therefore, this review will focus on the existing and future uses of PPARs agonists and antagonists in treating malignancies. PubMed, Science Direct, and Scopus databases were searched regarding the effect of PPARs on various types of cancers until the end of May 2023. The results of the review articles showed the therapeutic influence of PPARs on a wide range of cancer on in vitro, in vivo and clinical studies. However, further experimental and clinical studies are needed to be conducted on the influence of PPARs on various cancers.

Genetic background modulates the effect of glucocorticoids on proliferation, differentiation and myelin formation of oligodendrocyte lineage cells.

Anxiety disorders are prevalent mental disorders. Their predisposition involves a combination of genetic and environmental risk factors, such as psychosocial stress. Myelin plasticity was recently associated with chronic stress in several mouse models. Furthermore, we found that changes in both myelin thickness and node of Ranvier morphology after chronic social defeat stress are influenced by the genetic background of the mouse strain. To understand cellular and molecular effects of stress-associated myelin plasticity, we established an oligodendrocyte (OL) model consisting of OL primary cell cultures isolated from the C57BL/6NCrl (B6; innately non-anxious and mostly stress-resilient strain) and DBA/2NCrl (D2; innately anxious and mostly stress-susceptible strain) mice. Characterization of naïve cells revealed that D2 cultures contained more pre-myelinating and mature OLs compared with B6 cultures. However, B6 cultures contained more proliferating oligodendrocyte progenitor cells (OPCs) than D2 cultures. Acute exposure to corticosterone, the major stress hormone in mice, reduced OPC proliferation and increased OL maturation and myelin production in D2 cultures compared with vehicle treatment, whereas only OL maturation was reduced in B6 cultures. In contrast, prolonged exposure to the synthetic glucocorticoid dexamethasone reduced OPC proliferation in both D2 and B6 cultures, but only D2 cultures displayed a reduction in OPC differentiation and myelin production. Taken together, our results reveal that genetic factors influence OL sensitivity to glucocorticoids, and this effect is dependent on the cellular maturation stage. Our model provides a novel framework for the identification of cellular and molecular mechanisms underlying stress-associated myelin plasticity.

Effect of the cholinergic system of the lateral periaqueductal gray (lPAG) on blood pressure and heart rate in normal and hydralazine hypotensive rats.

Objectives: Due to the presence of the cholinergic system in the lateral periaqueductal gray (lPAG) column, the cardiovascular effects of acetylcholine (ACH) and its receptors in normotensive and hydralazine (HYD) hypotensive rats in this area were evaluated. Materials and Methods: After anesthesia, the femoral artery was cannulated and systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate (HR), and also electrocardiogram for evaluation of low frequency (LF) and high frequency (HF) bands, important components of heart rate variability (HRV), were recorded. ACH, atropine (Atr, a muscarinic antagonist), and hexamethonium (Hex, an antagonist nicotinic) alone and together microinjected into lPAG, changes (Δ) of cardiovascular responses and normalized (n) LF, HF, and LF/HF ratio were analyzed. Results: In normotensive rats, ACH decreased SBP and MAP, and enhanced HR while Atr and Hex did had no effects. In co-injection of Atr and Hex with ACH, only ACH+Atr significantly attenuated parameters. In HYD hypotension, ACH had no affect but Atr and Hex significantly improved the hypotensive effect. Co-injection of Atr and Hex with ACH decreased the hypotensive effect but the effect of Atr+ACH was higher. In normotensive rats, ACH decreased nLF, nHF, and nLF/nHF ratio. These parameters in the Atr +ACH group were significantly higher than in ACH group. In HYD hypotension nLF and nLF/nHF ratio increased which was attenuated by ACH. Also, Atr+ACH decreased nLF and nLF/nHF ratio and increased nHF. Conclusion: The cholinergic system of lPAG mainly via muscarinic receptors has an inhibitory effect on the cardiovascular system. Based on HRV assessment, peripheral cardiovascular effects are mostly mediated by the parasympathetic system.

Cardiovascular Effect of Dorsal Periaqueductal Gray During Lipopolysaccharide-induced Hypotension.

Introduction: The central mechanism related to the cardiovascular response to lipopolysaccharide (LPS)-induced hypotension is not entirely known, but it is suggested that numerous brain areas such as dorsal periaqueductal gray (dPAG) are involved in this process. In the current work, the cardiovascular effect of the dPAG during LPS-induced hypotension is investigated. Methods: The study animals (rats) were divided into four groups: control (saline microinjected into dPAG), lidocaine 2%, LPS (intravenously injected), and lidocaine + LPS. Catheterization of the femoral artery and vein was performed to record blood pressure and LPS injection, respectively. Saline and lidocaine were microinjected into the dPAG nucleus then the LPS injection was performed. The changes (Δ) in systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were measured and compared with those of the control and LPS groups. Results: LPS significantly declined ΔMAP and ΔSBP (P<0.05) but did not change the ΔHR compared to the control. Lidocaine did not significantly affect basic ΔSBP, ΔMAP, and ΔHR compared to the control. Injection of lidocaine before LPS significantly attenuated the reduction of ΔSBP and ΔMAP evoked by LPS (P<0.05). Conclusion: Our data showed that blockade of the dPAG by lidocaine significantly ameliorates the hypotension induced by LPS. this finding confirms the involvement of the dPAG in cardiovascular regulation during LPS-induced hypotension. Highlights: Inactivation of the dPAG by lidocaine significantly ameliorates cardiovascular responses in hypotensive rats.LPS significantly lowers blood pressure and does not affect the heart rate. Plain Language Summary: The mechanism of hypotension induced by endotoxin is not yet clear. However, it is often attributed to the direct effect of lipopolysaccharide (LPS) as a component of the outer wall of Gram-negative bacteria and other vascular mediators, including tumor necrosis factor (TNF) and nitric oxide (NO). One possibility is that the initial drop in LPS-induced arterial hypertension is mediated by a central mechanism. The ventral region of the transcranial gray matter is involved in lowering blood pressure, and the dorsal region is involved in increasing blood pressure. The dorsolateral region of the transcranial gray matter (dlPAG) also causes tachycardia, vasodilation in muscles, and tachypnea. dlPAG contains cells that produce NO and serotonin (5HT) and 5HT1 and 5HT2 receptors, which may play a role in hypotension due to stimulation of this region. LPS (1 mg/kg or higher IV) typically elicits a biphasic hypotensive response in rats. The first stage of this response begins immediately after LPS injection. The second phase begins about 1 hour after LPS injection. Thus, endotoxic hypertension begins through a central mechanism and further suggests that hypotension may play a critical role in developing fatal hypotension, representing the second stage of septic shock. Although dlPAG is an important site for regulating cardiovascular responses, its role in hypotension induced by LPS has not been investigated. We investigated the role of this nucleus in cardiovascular changes after LPS injection.

The possible role of pedunculopontine tegmental nucleus (PPT) opioid receptors in the cardiovascular responses in normotensive and hemorrhagic hypotensive rats.

BACKGROUND: The pedunculopontine tegmental nucleus (PPT) is involved in cardiovascular regulation. The presence of mu (µ) opioid receptors in the PPT nucleus has been determined. In the present study, the role of this nucleus in normotensive conditions and then the role of these receptors on cardiovascular function in hypotension induced by hemorrhage (HEM) were investigated. METHOD: Animals were divided into the following groups: Group 1: control, Group 2: HEM, Group 3: morphine at dose 100 nmol (a general opioid receptor agonist), Group 4: naloxone at dose 100 nmol (a general opioid receptor antagonist), Group 5: morphine + HEM, and Group 6: naloxone + HEM. After anesthesia, two femoral arteries were cannulated to record the cardiovascular parameters and blood withdrawal. Two minutes after induction of HEM, drugs were injected into the nucleus, and cardiovascular parameters were measured. Changes (Δ) in cardiovascular responses due to drug injection and HEM were calculated and compared to control and HEM groups. RESULTS: HEM significantly reduced changes in systolic and mean arterial pressures and increased heart rate changes compared to control. Morphine microinjection in normotensive and HEM rats significantly decreased systolic blood pressure, mean arterial pressure, and heart rate, and naloxone significantly increased all these parameters. CONCLUSION: This study showed that the PPT nucleus plays a role in modulating the cardiovascular responses induced by HEM. The µ opioid receptor of the PPT nucleus in the normotensive and HEM rats have inhibitory effects on blood pressure and heart rate mainly, and these effects are eliminated by naloxone microinjection.

Cardiovascular responses induced by the activation of muscarinic receptors of the pedunculopontine tegmental nucleus in anesthetized rats.

BACKGROUND: The cardiovascular effects of nicotinic receptors of cholinergic system in the pedunculopontine tegmental nucleus (PPT) were shown. OBJECTIVE: In the following, the cardiovascular effects of the muscarinic receptor, another receptor in this system, were examined. METHODS: Rats were divided into eight groups: 1) control; 2 and 3) Ach (acetylcholine, an agonist) 90 and 150 nmol; 4 and 5) Atr (atropine; a muscarinic antagonist) 3 and 9 nmol; 6) Atr 3 + Ach 150; 7) Atr 9 + Ach 150; and 8) Atr 3 + hexamethonium (Hexa; 300 nmol) + Ach 150. After anesthesia, cannulation of the femoral artery was performed, and then the mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were recorded using a power lab apparatus. RESULTS: Following drug microinjection, the maximum change (Δ) in MAP, SBP, and HR was calculated and analyzed. Both doses of Ach (90 and 150) significantly decreased ΔMAP and ΔSBP but could not change ΔHR. Neither of the doses of Atr significantly affected ΔMAP, ΔSBP, and ΔHR. Co-injection of Atr 3 + Ach 150 only increased ΔHR, but Atr 9 + Ach 150 decreased ΔMAP and ΔSBP than Ach 150 alone. The effect of the co-injection of Atr 9 + Hexa 300 + Ach 150 was also the same as the Atr 9 + Ach 150 group. CONCLUSION: The present results revealed that cholinergic muscarinic receptors in the PPT have an inhibitory effect on MAP and SBP with no important effect on HR.

Role of the glutamatergic system of ventrolateral periaqueductal gray (vlPAG) in the cardiovascular responses in normal and hemorrhagic conditions in rats.

OBJECTIVES: Periaqueductal gray (PAG) is a mesencephalic area divided into four columns including ventrolateral periaqueductal gray (vlPAG). vlPAG plays a role in cardiovascular regulation during normal and hemorrhagic (Hem) conditions. Due to presence of glutamate in this area, we evaluated the effect of glutamatergic receptors of this area on cardiovascular activity in normotensive and hypovolemic Hem rats. MATERIALS AND METHODS: Animals were divided into twelve groups: saline (vehicle), Glutamate, GYK52466 (non-NMDA receptor antagonist), and MK801 (NMDA receptor antagonist) with and without Glu microinjected into vlPAG in normal and Hem conditions. Following the femoral artery cannulating and microinjecting, changes (Δ) of heart rate (HR), systolic blood pressure (SBP), and mean arterial pressure (MAP) were recorded via a PowerLab unit. RESULTS: In normotensive conditions, microinjection of Glu increased ΔMAP, ΔSBP, and ΔHR (P<0.001). MK-801 and GYKI-52466 nonsignificant reduced cardiovascular responses than vehicle while their changes were significant compared with glutamate (P<0.001). Co-injection of GYKI- 52466 with Glu did not significantly reduce ΔSBP and ΔMAP induced by Glu (P>0.05) but co-injection of MK-801 with Glu significantly attenuate these effects(P<0.01). In Hem, Glu increased ΔSBP, ΔMAP, and ΔHR (P<0.05). GYKI-52466 alone did not change cardiovascular responses but MK-801 decreased ΔSBP than Hem (P<0.01). Co-injection of GYKI-52466 with Glu had significant(P<0.05) but MK-801 with Glu had no significant effect compared with Hem (P>0.05). CONCLUSION: The glutamatergic system of vlPAG increases cardiovascular values that are mostly mediated through the NMDA receptor. Since vlPAG is well known as an inhibitory region, it seems that glutamate does not have a noteworthy cardiovascular role in vlPAG during Hem and normal conditions.