Peroxisome Proliferator-activated Receptor-γ Agonist Research Articles

Rosiglitazone regulates astrocyte polarization and neuroinflammation in a PPAR-γ dependent manner after experimental traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a leading cause of high mortality and disability worldwide. Overactivation of astrocytes and overexpression of inflammatory responses in the injured brain are characteristic pathological features of TBI. Rosiglitazone (ROS) is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist known for its anti-inflammatory activity. However, the relationship between the inflammatory response involved in ROS treatment and astrocyte A1 polarization remains unclear. ObjectiveThis study aimed to investigate whether ROS treatment improves dysfunction and astrocyte A1 polarization induced after TBI and to elucidate the underlying mechanisms of these functions. MethodsSD rats were randomly divided into sham operation group, TBI group, TBI+ROS group, and TBI+ PPAR-γ antagonist group (GW9662 + TBI). The rat TBI injury model was prepared by the CCI method; brain water content test and wire grip test scores suggested the prognosis; FJB staining showed the changes of ROS on the morphology and number of neurons in the peripheral area of cortical injury; ELISA, immunofluorescence staining, and western blotting analysis revealed the effects of ROS on inflammatory response and astrocyte activation with the degree of A1 polarization after TBI. ResultsBrain water content, inflammatory factor expression, and astrocyte activation in the TBI group were higher than those in the sham-operated group (P < 0.05); compared with the TBI group, the expression of the above indexes in the ROS group was significantly lower (P < 0.05). Compared with the TBI group, PPAR-γ content was significantly higher and C3 content was considerably lower in the ROS group (P < 0.05); compared with the TBI group, PPAR-γ content was significantly lower and C3 content was substantially higher in the inhibitor group (P < 0.05). ConclusionROS can exert neuroprotective effects by inhibiting astrocyte A1 polarization through the PPAR-γ pathway based on the reduction of inflammatory factors and astrocyte activation in the brain after TBI.

Pioglitazone Protects Tubular Epithelial Cells during Kidney Fibrosis by Attenuating miRNA Dysregulation and Autophagy Dysfunction Induced by TGF-β.

Excessive renal TGF-β production and pro-fibrotic miRNAs are important drivers of kidney fibrosis that lack any efficient treatment. Dysfunctional autophagy might play an important role in the pathogenesis. We aimed to study the yet unknown effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (Pio) on renal autophagy and miRNA dysregulation during fibrosis. Mouse primary tubular epithelial cells (PTEC) were isolated, pre-treated with 5 µM pioglitazone, and then stimulated with 10 ng/mL TGF-β1 for 24 h. Male 10-week-old C57Bl6 control (CTL) and TGF-β overexpressing mice were fed with regular chow (TGF) or Pio-containing chow (20 mg/kg/day) for 5 weeks (TGF + Pio). PTEC and kidneys were evaluated for mRNA and protein expression. In PTEC, pioglitazone attenuated (p < 0.05) the TGF-β-induced up-regulation of Col1a1 (1.4-fold), Tgfb1 (2.2-fold), Ctgf (1.5-fold), Egr2 (2.5-fold) mRNAs, miR-130a (1.6-fold), and miR-199a (1.5-fold), inhibited epithelial-to-mesenchymal transition, and rescued autophagy function. In TGF mice, pioglitazone greatly improved kidney fibrosis and related dysfunctional autophagy (increased LC3-II/I ratio and reduced SQSTM1 protein content (p < 0.05)). These were accompanied by 5-fold, 3-fold, 12-fold, and 2-fold suppression (p < 0.05) of renal Ccl2, Il6, C3, and Lgals3 mRNA expression, respectively. Our results implicate that pioglitazone counteracts multiple pro-fibrotic processes in the kidney, including autophagy dysfunction and miRNA dysregulation.

#5503 PIOGLITAZONE REVERSES MIR-130A AND MIR-199 DYSREGULATION INDUCED BY TGF-BETA DURING KIDNEY FIBROSIS

Abstract Background and Aims The peroxisome proliferator-activated receptor-γ (PPARγ) agonists have been shown to dampen TGF-β signaling and suppress miR-130a in VSMCs and also profibrotic miR-21-5p in the kidney. We have recently demonstrated that pioglitazone ameliorates established renal fibrosis by suppressing STAT3 and EGR1 [1], but its effect on renal miR-130a has not been investigated. Thus, we aimed to study how chronic oral pioglitazone treatment would affect TGF-β–driven renal miRNA dysregulation in mice. Method Ten week old male C57Bl6 control (CTL, n = 6) and TGF-β transgenic mice (TGFb, n = 12, having elevated plasma TGF-β1 level) were used. CTL mice and half of TGFb mice received regular chow. The second half of transgenic mice received pioglitazone containing chow (dose: 20mg/kg/day) for 5 weeks (TGFb+Pio, n = 6), when the kidneys were evaluated. Results Untreated TGFb mice had a 4.7-fold and 2.8-fold type I and type III collagen mRNA overexpression as compared to controls, respectively. This was accompanied by 3.8-fold pro-fibrotic Egr2 mRNA, 2.9-fold miR-130a, 3.9-fold miR-199 and 3.3-fold miR-21 overexpression. Chronic treatment with the PPARγ agonist pioglitazone reduced the expression of both collagen mRNAs and miRNAs miR-199 and miR-21 to control levels, but miR-130a reached even lower values than in control kidneys. Interestingly, the expression of miR-200a (regulated by TGF-beta and known to ameliorate fibrosis) was similar in all CTL and TGFb groups, regardless of treatment. Conclusion Our data indicate that PPARγ agonist pioglitazone not only attenuates the TGF-β induced miR-21 overexpression, but also the renal dysregulation of miR-130a and miR-199, supporting its anti-fibrotic effects.

Effect of Rosiglitazone, the Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, on Apoptosis, Inflammatory Cytokines and Oxidative Stress in pentylenetetrazole-Induced Seizures in Kindled Mice.

A growing body of evidence has shown that seizure can trigger inflammatory cascades through increasing the expression of several inflammatory cytokines. It has been proved that peroxisome proliferator-activated receptor-γ agonists have immunomodulatory, anti-inflammatory, and neuroprotective effects beyond the putative hypoglycemic effects. Thus, we investigated the inhibitory effect of rosiglitazone on the development of pentylenetetrazol (PTZ)-induced kindling via affecting the inflammatory pathway. Male C57BL/6 mice were randomly divided into vehicle group (0.1% DMSO), PTZ-group and rosiglitazone-PTZ-group. Kindling was induced by the administration of PTZ (40mg/kg, i.p) every other day and mice were observed for 20min after each PTZ injection. Twenty-four hours after the last dose, animals were euthanized and hippocampus was isolated. The level of Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Catalase (CAT) activity were quantified in hippocampus by biochemical methods. The protein levels of IL-1β, IL-6, IL-10, IFN-γ, TNF-α, caspase-3, iNOS, PPAR-γ, Bcl-2, or Bax factors were measured with western blotting. Also, the quantitative real-time PCR were used to evaluate the mRNA expression of those factors. Pretreatment with rosiglitazone significantly prevented the progression of kindling in comparison with control group. The rosiglitazone significantly decreased the MDA level and increased the CAT, and SOD levels in the rosiglitazone treated mice compared to those in the PTZ group (P < 0.01). Using real-time PCR and Western blotting assay, similar results were obtained. The expression levels of IL-1β, IL-6, IL-10, IFN-γ, TNF-α, Bax or PPAR-γ were significantly changed in the brain. The results of this study suggest that effect of rosiglitazone may be crucial in its ability to protect against the neuronal damage caused by PTZ induced seizure.

Pioglitazone modulates immune activation and ameliorates inflammation induced by injured renal tubular epithelial cells via PPARγ/miRNA‑124/STAT3 signaling.

Acute kidney injury (AKI) is commonly a result of renal ischemia reperfusion injury (IRI), which produces clinical complications characterized by the rapid deterioration of renal function, leading to chronic kidney disease and increases the risk of morbidity and mortality. Currently, only supportive treatment is available. AKI, which is accompanied by immune activation and inflammation, is caused by proximal tubular injury. The present study investigated the role of tubular epithelial cells as drivers of inflammation in renal IRI and their potential function as antigen-presenting cells, as well as the molecular mechanisms by which peroxisome proliferator-activated receptor-γ (PPARγ) agonists [such as pioglitazone (Pio)] exert reno-protective action in renal IRI. A total of 50 Wistar male albino rats were divided into five groups: Sham + DMSO, Sham + Pio, IRI + DMSO, IRI + prophylactic preoperative (pre) Pio and IRI + postoperative Pio. The histopathological changes in renal tissue samples and the renal epithelial cell expression of CD86, miRNA-124, STAT3, pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and Arginase-II were analyzed by immunohistochemistry, reverse transcription-quantitative PCR, western blotting and ELISA respectively. IRI was a potent inducer for CD86 immunoexpression. An ameliorative action of Pio was demonstrated via decreased CD86 immunoexpression, upregulation of miRNA-124, decreased STAT3 expression and beneficial anti-inflammatory effects. The tubular epithelium served a notable role in the inflammatory response in renal IRI. Pio exerted its anti-inflammatory effects via PPARγ/miRNA-124/STAT3 signaling.

A Possible Modulator of Vitiligo Metabolic Impairment: Rethinking a PPARγ Agonist.

Vitiligo is a complex disease wherein derangements in multiple pathways determine the loss of functional melanocytes. Since its pathogenesis is not yet completely understood, vitiligo lacks a definitive safe and efficacious treatment. At present, different therapies are available; however, each modality has its baggage of disadvantages and side effects. Recently we have described several metabolic abnormalities in cells from pigmented skin of vitiligo patients, including alterations of glucose metabolism. Therefore, we conducted a study to evaluate the effect of Pioglitazone (PGZ), a Peroxisome proliferator-activated receptor-γ (PPARγ) agonist, on cells from pigmented vitiligo skin. We treated vitiligo melanocytes and fibroblasts with low doses of PGZ and evaluated the effects on mitochondrial alterations, previously reported by our and other groups. Treatment with PGZ significantly increased mRNA and protein levels of several anaerobic glycolytic enzymes, without increasing glucose consumption. The PGZ administration fully restored the metabolic network, replacing mitochondrial membrane potential and mitochondrial DNA (mtDNA) copy number. These effects, together with a significant increase in ATP content and a decrease in reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in vitiligo cells. Moreover, the expression of HMGB1, Hsp70, defined as a part of DAMPs, and PD-L1 were significantly reduced. In addition, PGZ likely reverts premature senescence phenotype. In summary, the results outline a novel mode of action of Pioglitazone, which may turn out to be relevant to the development of effective new vitiligo therapeutic strategies.

Neuroinflammation in Parkinson"s Disease and its Treatment Opportunities

Parkinson’s disease (PD) is a complex, chronic, and progressive neurodegenerative disease that is characterized by irreversible dopaminergic neuronal loss in the substantia nigra. Alpha-synuclein is normally a synaptic protein that plays a key role in PD due to pathological accumulation as oligomers or fibrils. Clustered alpha-synuclein binds to the Toll-like receptors and activates the microglia, which initiates a process that continues with pro-inflammatory cytokine production and secretion. Pro-inflammatory cytokine overproduction and secretion induce cell death and accelerate PD progression. Microglia are found in a resting state in physiological conditions. Microglia became activated by stimulating Toll-like receptors on it under pathological conditions, such as alpha-synuclein aggregation, environmental toxins, or oxidative stress. The interaction between Toll-like receptors and its downstream pathway triggers an activation series, leads to nuclear factor-kappa B activation, initiates the inflammasome formation, and increases cytokine levels. This consecutive inflammatory process leads to dopaminergic cell damage and cell death. Microglia become overactive in response to chronic inflammation, which is observed in PD and causes excessive cytotoxic factor production, such as reactive oxidase, nitric oxide, and tumor necrosis factor-alpha. This inflammatory process contributes to the exacerbation of pathology by triggering neuronal damage or death. Current treatments, such as dopaminergic agonists, anticholinergics, or monoamine oxidase inhibitors alleviate PD symptoms, but they can not stop the disease progression. Finding a radical treatment option or stopping the progression is essential when considering that PD is the second most reported neurodegenerative disorder. Many cytokines are released during inflammation, and they can start the phagocytic process, which caused the degradation of infected cells along with healthy ones. Therefore, targeting the pathological mechanisms, such as microglial activation, mitochondrial dysfunction, and oxidative stress, that should be involved in the treatment program is important. Neuroinflammation is one of the key factors involved in PD pathogenesis as well as alpha-synuclein accumulation, synaptic dysfunction, or dopaminergic neuronal loss, especially in the substantia nigra. Therefore, evaluating the therapeutic efficiency of the mechanisms is important, such as microglial activation and nuclear factor-kappa B pathway or inflammasome formation inhibition, and cytokine release interruption against neuroinflammation may create new treatment possibilities for PD. This study examined the pathological relation between PD and neuroinflammation, and targeting neuroinflammation as an opportunity for PD treatments, such as Toll-like receptor antagonists, NOD-like receptor family pyrin domain containing-3 inflammasome inhibitors, cytokine inhibitors, peroxisome proliferator-activated receptor-γ agonists, reactive oxygen species inhibitors, and nonsteroidal anti-inflammatory drugs.

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Downregulates the Inflammatory Response in Cutaneous Leishmaniasis Patients Without Interfering in Leishmania braziliensis Killing by Monocytes.

Patients with cutaneous leishmaniasis (CL) due to Leishmania braziliensis infection have an exacerbated inflammatory response associated with tissue damage and ulcer development. An increase in the rate of patients who fail therapy with pentavalent antimony has been documented. An adjuvant therapy with an anti-inflammatory drug with the potential of Leishmania killing would benefit CL patients. The aim of the present study was to investigate the contribution of peroxisome proliferator-activated receptor-γ (PPAR-γ) activation by pioglitazone in the regulation of the inflammatory response and L. braziliensis killing by monocytes. Pioglitazone is an oral drug used in the treatment of diabetes, and its main mechanism of action is through the activation of PPAR-γ, which is expressed in many cell types of the immune response. We found that activation of PPAR-γ by pioglitazone decreases the inflammatory response in CL patients without affecting L. braziliensis killing by monocytes. Our data suggest that pioglitazone may serve as an adjunctive treatment for CL caused by L. braziliensis.

Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone.

Rosiglitazone (RSG) is a synthetic agonist of peroxisome proliferator-activated receptor-γ (PPARγ), which plays a central role in the regulation of metabolism. Meta-analyses have suggested that RSG is associated with increased cardiovascular risk. However, the mechanisms underlying such adverse cardiac effects are still poorly understood. Here, we found that activation of PPARγ by RSG stimulated the endocannabinoid system (ECS), a membrane lipid signaling system, which induced cardiac hypertrophy. In neonatal rat cardiomyocytes, RSG increased the level of anandamide (AEA); upregulated the expression of N-acyl phosphatidylethanolamine phospholipase D (NapePLD), a key enzyme for AEA synthesis; and downregulated the expression of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of AEA. Importantly, PPARγ activation increased the expression of cannabinoid receptor type 1 (CB1) through an identified binding site for PPARγ in the CB1 promoter region. Moreover, both the in vitro and in vivo results showed that inhibition of the ECS by rimonabant, an antagonist of CB1, attenuated RSG-induced cardiac hypertrophy, as indicated by decreased expression of cardiac hypertrophy markers (ANP and BNP), deactivation of the mTOR pathway, and decreased cardiomyocyte size. Thus, these results demonstrated that the ECS functions as a novel target of PPARγ and that the AEA/CB1/mTOR axis mediates RSG-induced cardiac remodeling.

The potential effect of natural compounds from Indonesian spices in alleviating inflammation due to the coronavirus disease (COVID-19): a narrative review

COVID-19 causes increasing of inflammatory cytokines even cytokine storm in the severe condition. Enhance body immune system is one strategy against COVID-19. Spices in traditional Indonesian cuisine are believed as boost immunity. They contain active compounds such as curcumin, allicin, quercetin and capsaicin which can be used to alleviate inflammation. In this literature review, the potency of curcumin, allicin, quercetin, and capsaicin in alleviating inflammation due the COVID-19 was reported. Literatures were gathered from PubMed, Science Direct, and Google Scholar search engines. COVID-19 causes the increase of proinflammatory cytokine levels such as TNFα and IL-6. Curcumin, allicin, quercetin, and capsaicin regulate the expression of proinflammatory cytokines. These nutritional agonists of peroxisome proliferator-activated receptor-γ (PPAR-γ) showed inhibitory effects on pro-inflammatory cytokines and promote immune cell differentiation into anti-inflammatory phenotypes. Curcumin has an anti-inflammatory effect that can prevent pneumocytes, renal cells, and cardiomyocytes damages. Allicin and quercetin can decrease TNFα and IL-6 levels due to they can increase the superoxide dismutase (SOD) levels. In conclusion, curcumin, allicin, quercetin and capsaicin can enhance body immune system due to their anti-inflammatory effect through down-regulation of the inflammatory cytokines expression. These spices could be used as adjuvant therapy to boost body immune system against COVID-19.

18:0 Lyso PC, a natural product with potential PPAR-γ agonistic activity, plays hypoglycemic effect with lower liver toxicity and cardiotoxicity in db/db mice

Rosiglitazone, a specific agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), displays a robust hypoglycemic action in patients with type 2 diabetes mellitus (T2DM) and elicits serious adverse reactions, especially hepatotoxicity and cardiotoxicity. Here, we aims to find a new natural PPAR-γ agonist with less adverse reactions than rosiglitazone in db/db mice. The method of virtual screening was used to identify a PPAR-γ agonist 18:0 Lyso PC from an in-house natural product library. We verified its pharmacological effects and adverse reactions comparing with rosiglitazone in vivo and in vitro. 18:0 Lyso PC exhibited pharmacological effects similar to those of rosiglitazone in db/db mice. Moreover, 18:0 Lyso PC showed a lower extent of liver injury and cardiotoxicity in db/db mice. The mechanism, by which this natural compound alleviates metabolic syndrome, involves a reduction in fatty acid synthesis mediated by activation of the phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase-alpha (AMPKα) and acetyl-CoA carboxylase (ACC) and an increase expression of uncoupled protein 1 (UCP1) and PPAR-γ coactivator-1 alpha (PGC1-α). 18:0 Lyso PC, a natural compound, can show a similar hypoglycemic effect to rosiglitazone by activating PPAR-γ, while eliciting markedly fewer adverse reactions than rosiglitazone.

The Antihypertensive Drug Telmisartan Protects Oligodendrocytes from Cholesterol Accumulation and Promotes Differentiation by a PPAR-γ-Mediated Mechanism.

Our previous studies have demonstrated that specific peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists play a fundamental role in oligodendrocyte progenitor (OP) differentiation, protecting them against oxidative and inflammatory damage. The antihypertensive drug Telmisartan (TLM) was shown to act as a PPAR-γ modulator. This study investigates the TLM effect on OP differentiation and validates its capability to restore damage in a pharmacological model of Niemann-Pick type C (NPC) disease through a PPAR-γ-mediated mechanism. For the first time in purified OPs, we demonstrate that TLM-induced PPAR-γ activation downregulates the type 1 angiotensin II receptor (AT1), the level of which naturally decreases during differentiation. Like other PPAR-γ agonists, we show that TLM promotes peroxisomal proliferation and promotes OP differentiation. Furthermore, TLM can offset the OP maturation arrest induced by a lysosomal cholesterol transport inhibitor (U18666A), which reproduces an NPC1-like phenotype. In the NPC1 model, TLM also reduces cholesterol accumulation within peroxisomal and lysosomal compartments and the contacts between lysosomes and peroxisomes, revealing that TLM can regulate intracellular cholesterol transport, crucial for myelin formation. Altogether, these data indicate a new potential use of TLM in hypomyelination pathologies such as NPC1, underlining the possible repositioning of the drug already used in other pathologies.

Functional effects of berberine in modulating mitochondrial dysfunction and inflammatory response in the respective amyloidogenic cells and activated microglial cells – In vitro models simulating Alzheimer's disease pathology

AimBerberine (BBR) is an alkaloid extracted from Coptidis Rhizoma, also known as Huang-Lian. Huang-Lian has been used extensively in traditional Chinese medicine for the treatment of various diseases, including diabetes and dementia. Because Alzheimer's disease (AD) is a complex disease that involves various pathophysiological changes, the diverse neuroprotective effects of BBR may be useful for improving the brain's energy state at an early stage of the disease. Main methodsWe performed extracellular flux and 1H NMR-based metabolic profiling analyses to investigate the effects of BBR on metabolic processes in these cells. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-γ (PPARγ) agonist has been studied extensively for the treatment of AD. We explored the combination dosing effects of BBR and PIO in vitro, then leveraged computational methods to explain the experimental finding. Key findingsBBR demonstrates potential in modulating the mitochondrial bioenergetics and attenuating dysfunction of the primary energy and glutathione metabolism pathways in an AD cell model. It also suppresses basal respiration and reduces the production of pro-inflammatory cytokines in activated microglial cells. Both experimental and computational observations indicate that BBR and PIO have comparable binding affinities to the PPARγ protein, suggesting both drugs may have some overlapping effects for AD. SignificanceBBR exerts beneficial effects on disrupted metabolic processes in amyloidogenic cells and activated microglial cells, which are important for preventing or delaying early-stage disease progression. The choice of BBR or PIO for AD treatment depends on their respective pharmacokinetic profiles, delivery, efficacy and safety, and warrants further study.

Pioglitazone Attenuates Lupus Nephritis Symptoms in Mice by Modulating miR-21-5p/TIMP3 Axis: the Key Role of the Activation of Peroxisome Proliferator-Activated Receptor-γ.

Lupus nephritis (LN) is a severe symptom of systemic lupus erythematosus and miR-21-5p is upregulated during LN. In the current study, the effects of pioglitazone (Pg), a peroxisome proliferator-activated receptor-γ (PPARγ) agonist, on LN development were assessed and explained by focusing miR-21-5p/TIMP3 axis. The expressions of miR-21-5p and PPARγ in LN mice were detected and then the mice were treated with pioglitazone to evaluate the anti-LN effects of agent. The miR-21-5p level was induced in MRL/lpr mice to confirm the central role of miR-21-5p inhibition in the protective effects of Pg against LN. The level of miR-21-5p was upregulated, while the level of PPARγ was downregulated in MRL/lpr mice. Pg inhibited miR-21-5p in renal tissues, which induced the expression of TIMP3. The changes in miR-21-5p/TIMP3 axis led to the improvements in renal structure and function, and inhibited autoimmune response. The induction of miR-21-5p impaired the effects of Pg, along with the suppression of TIMP3. The expression of miR-21-5p was associated with the progression of LN, contributing to the suppression of TIMP3 and development of LN. The inhibition of the miR-21-5p by Pg would restore the structure and function of kidneys in LN mice via the activation of PPARγ.

A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD.MethodsThis Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function.ResultsEighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24–2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of −3.5% (95% CI −8.4–1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio.ConclusionsIn this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Aging-Related Kidney Diseases.

Clinical Background: Older age has been associated with higher prevalence and progression of chronic kidney disease (CKD). The presence of CKD leads to an increased risk of end-stage renal disease, cardiovascular diseases, and death. Epidemiology: Progressive aging of the population is accompanied by an increase in the prevalence of CKD worldwide. The high prevalence of CKD in the aged population would result in a considerably greater social burden. Challenges: Structural and functional changes are often observed in the aged kidney. The main pathological feature of the aged kidney is nephrosclerosis such as arteriosclerosis, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. As a consequence of renal aging, the nephron number decreases. A lower nephron number approximately parallels with the decline in glomerular filtration rate (GFR), and GFR declines with aging. Recent studies have highlighted several pathological mechanisms involved in renal aging, that can serve as targets for intervention. Decreased renal oxygen levels, mitochondrial dysfunction, and inflammation drive renal fibrosis, one of the hallmarks of renal aging. Prevention and Treatment: Novel therapeutic approaches that target these functional changes are now being developed to prevent an aging-associated inevitable loss of renal function. For example, calorie restriction, Sirtuin 1 activator and peroxisome proliferator-activated receptor-γ agonists have the potential to ameliorate renal deterioration. This chapter provides an overview of the aged kidney and summarizes the current knowledge on therapeutic strategies to attenuate renal aging.

Pathological changes of frozen shoulder in rat model and the therapeutic effect of PPAR-γ agonist.

Frozen shoulder is a common shoulder disorder characterized by a gradual increase of pain and a limited range of motion. However, its pathophysiologic mechanisms remain unclear and there is no consensus as to the most effective treatment. The purpose of the study was to investigate the effect of transforming growth factor-β (TGF-β)on fibrosis and inflammatory response of the shoulder joint of rat models and to explore the therapeutic effect of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist. In the study, the effect of PPAR-γ agonist CDDO-IM treatment on cell proliferation, migration, and extracellular matrix proteins synthesis (vimentin, α-smooth muscle actin, collagen I, and collagen III) were tested by cell proliferation test, scratches test, real-time quantitative polymerase chain reaction, and Western blot analysis. The frozen shoulder was also established on the rat model by injecting adenovirus-TGF-β1 into rats' shoulder capsule. Pathological changes of the frozen shoulder tissue of the experimental group and PPAR-γ agonist treatment group were evaluated. The stiffness of joints of the three groups was tested. Inflammatory mediators' expression including cyclooxygenase-1, interleukin-1β, and tumor necrosis factor-α of the shoulder was tested by enzyme-linked immunosorbent assay, and the expression of extracellular matrix proteins was evaluated by hematoxylin and eosinstaining and immunohistochemistry. The results showed that pathological changes of the frozen shoulder in the rat model include an abnormal proliferation of fibroblasts, infiltration of inflammatory cells, and disorder of fibrous structure, while rosiglitazone reduced the severity of the frozen shoulder in the treatment group. Clinically, PPAR-γ agonists may be a promising target for the treatment of the frozen shoulder.

Characterization of local gut microbiome and intestinal transcriptome responses to rosiglitazone treatment in diabetic db/db mice

The gut microbiota has been implicated in the therapeutic effects of antidiabetics. It is unclear if antidiabetics directly influences gut microbiome-host interaction. Oral peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, such as rosiglitazone, are potent insulin sensitizers used in the treatment of type 2 diabetes (T2D). PPAR-γ is abundantly expressed in the intestine, making it possible that PPAR-γ agonists directly influences gut microbiome-host homeostasis. The presented study therefore aimed to characterize local gut microbiome and intestinal transcriptome responses in diabetic db/db mice following rosiglitazone treatment. Diabetic B6.BKS(D)-Leprdb/J (db/db) mice (8 weeks of age) received oral dosing once daily with vehicle (n = 12) or rosiglitazone (3 mg/kg, n = 12) for 8 weeks. Gut segments (duodenum, jejunum, ileum, caecum, and colon) were sampled for paired analysis of gut microbiota and host transcriptome signatures using full-length bacterial 16S rRNA sequencing and RNA sequencing (n = 5–6 per group). Treatment with rosiglitazone improved glucose homeostasis without influencing local gut microbiome composition in db/db mice. In contrast, rosiglitazone promoted marked changes in ileal and colonic gene expression signatures associated with peroxisomal and mitochondrial lipid metabolism, carbohydrate utilization and immune regulation. In conclusion, rosiglitazone treatment markedly affected transcriptional markers of intestinal lipid metabolism and immune regulation but had no effect on the gut microbiome in diabetic db/db mice.

MiR-30a targets gene networks that promote browning of human and mouse adipocytes.

MicroRNA-30a (miR-30a) impacts adipocyte function, and its expression in white adipose tissue (WAT) correlates with insulin sensitivity in obesity. Bioinformatic analysis demonstrates that miR-30a expression contributes to 2% of all miRNA expression in human tissues. However, molecular mechanisms of miR-30a function in fat cells remain unclear. Here, we expanded our understanding of how miR-30a expression contributes to antidiabetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity and metabolic functions in adipocytes. We found that WAT isolated from diabetic patients shows reduced miR-30a levels and diminished expression of the canonical PPARγ target genes ADIPOQ and FABP4 relative to lean counterparts. In human adipocytes, miR-30a required PPARγ for maximal expression, and the PPARγ agonist rosiglitazone robustly induced miR-30a but not other miR-30 family members. Transcriptional activity studies in human adipocytes also revealed that ectopic expression of miR-30a enhanced the activity of rosiglitazone coupled with higher expression of fatty acid and glucose metabolism markers. Diabetic mice that overexpress ectopic miR-30a in subcutaneous WAT display durable reductions in serum glucose and insulin levels for more than 30 days. In agreement with our in vitro findings, RNA-seq coupled with Gene Set Enrichment Analysis (GSEA) suggested that miR-30a enabled activation of the beige fat program in vivo, as evidenced by enhanced mitochondrial biogenesis and induction of UCP1 expression. Metabolomic and gene expression profiling established that the long-term effects of ectopic miR-30a expression enable accelerated glucose metabolism coupled with subcutaneous WAT hyperplasia. Together, we establish a putative role of miR-30a in mediating PPARγ activity and advancing metabolic programs of white to beige fat conversion.

Persistent Pulmonary Hypertension of the Newborn: Pathophysiological Mechanisms and Novel Therapeutic Approaches.

Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of pulmonary vascular resistance (PVR), preventing an increase in pulmonary blood flow after birth. The affected neonates fail to establish blood oxygenation, precipitating severe respiratory distress, hypoxemia, and eventually death. Inhaled nitric oxide (iNO), the only approved pulmonary vasodilator for PPHN, constitutes, alongside supportive therapy, the basis of its treatment. However, nearly 40% of infants are iNO resistant. The cornerstones of increased PVR in PPHN are pulmonary vasoconstriction and vascular remodeling. A better understanding of PPHN pathophysiology may enlighten targeted and more effective therapies. Sildenafil, prostaglandins, milrinone, and bosentan, acting as vasodilators, besides glucocorticoids, playing a role on reducing inflammation, have all shown potential beneficial effects on newborns with PPHN. Furthermore, experimental evidence in PPHN animal models supports prospective use of emergent therapies, such as soluble guanylyl cyclase (sGC) activators/stimulators, l-citrulline, Rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, recombinant superoxide dismutase (rhSOD), tetrahydrobiopterin (BH4) analogs, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs), 5-HT2A receptor antagonists, and recombinant human vascular endothelial growth factor (rhVEGF). This review focuses on current knowledge on alternative and novel pathways involved in PPHN pathogenesis, as well as recent progress regarding experimental and clinical evidence on potential therapeutic approaches for PPHN.