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Review Article: Targeting Peroxisome Proliferator-Activated Receptors in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterised by cholestasis, progressive fibrosis and symptoms of pruritus and fatigue. Ursodeoxycholic acid (UDCA) is first-line therapy; however, many patients respond inadequately or are intolerant. Peroxisome proliferator-activated receptor (PPAR) agonists have emerged as second-line options. AIMS: This review examines PPAR isoform (PPAR-α, PPAR-δ and PPAR-γ) mediated pathways relevant to PBC, and structural, biochemical and clinical efficacy and safety features of PPAR agonists for PBC. METHODS: P

Molecular insight into the activator and deactivator mutations of peroxisome proliferator-activated receptor gamma.

The nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is essential for inflammation, lipid metabolism, glucose homeostasis, and adipogenesis. The function of PPARγ can be significantly impacted by mutations that either activate or deactivate the receptor. Deactivating variants can act as dominant-negative forms that sequester coactivators, impair ligand recognition, destabilize the activation function-2 (AF-2) surface, or favor corepressor binding. They are frequently found in the ligand-binding or DNA-binding domains. Metabolic disorders like severe insulin re

HPCA1 and CaM3 contribute to peroxisomal H2O2-driven activation of salicylic acid responses.

Intracellular H2O2 generated in peroxisomes via photorespiration serves as a key signal that switches on a plethora of defense responses. Our previous findings revealed that the activation of salicylic acid (SA) responses by such H2O2 requires upregulation of S-nitrosoglutathione reductase (GSNOR). Therefore, the factors mediating GSNOR regulation and oxidative stress responses remain to be determined. Here, we identified a calmodulin CaM3, an interactor of GSNOR, whose mutation was introduced into an intracellular oxidative stress genetic background (leaf catalase-defective, cat2), leading to…

[Peroxisome proliferator activated receptor-α in renal injury: mechanisms and therapeutic implications].

Peroxisome proliferator activated receptor-α (PPAR-α) is significantly expressed in various tissues such as the liver, kidney, myocardium, and skeletal muscle, which plays a central role in the development of various diseases by regulating key physiological processes such as energy homeostasis, redox balance, inflammatory response, and ferroptosis. As an important metabolic and excretory organ of the body, renal dysfunction can lead to water and electrolyte imbalance, toxin accumulation, and multiple system complications. The causes of kidney injury are complex and diverse, including acute inj

PEX11B Palmitoilation пары пероксисомальная дисфункция с клетками Шванна не работают в диабетической нейропатии.

Диабетическая нейропатия (ДН) является распространенным и болезненным осложнением диабета; однако механизмы, лежащие в основе ее патогенеза, остаются неясными, а эффективные клинические методы лечения отсутствуют. Цель этого исследования заключается в изучении роли пероксисома в клетках Шванна в DN. МЕТОДЫ: Изобилие пероксисома в акустических нервах мышей или клеток Шванна анализировалось с помощью лазерной суперразрешительной съемки и западного пятна. Пробоотборник RPF-GPF-SKL (Ser-Lys-Leu) использовался для оценки уровней пексафагии (пероксисомы-автофагика). Для оценки пальмитоилирования PEX

Совпадение в аннотации оригинала
BACKGROUND: Diabetic neuropathy (DN) is a prevalent and painful complication of diabetes; however, the mechanisms underlying its pathogenesis remain unclear, and effective clinical treatments are lacking. This study aims to explore the role of peroxisomes in Schwann cells in DN. METHODS: The abundance of peroxisomes in the sciatic nerves of mice or Schwann …

Pigmentary retinal dystrophy associated with peroxisome biogenesis disorder-Zellweger syndrome spectrum.

Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment epithelium (RPE), which can progress to pigmentary retinopathy (PR). We present a case of PRD in a female pediatric patient who has pathogenic variants in the PRPH2 and PEX1 genes. The patient has associated macular edema and secondary visual impairment. Treatment has included serial dexamethasone intravitreal implant injections and topical dorzolamide. The PEX1 gene mutation is associated with peroxisome biogenesis disorder-Zellwege

Peroxisomal Localization of a Truncated HMG-CoA Reductase under Low Cholesterol Conditions.

3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGCR) is one of the rate-limiting enzymes in the mevalonate pathway required for cholesterol biosynthesis. It is an integral membrane protein of the endoplasmic reticulum (ER) but has occasionally been described in peroxisomes. By co-immunofluorescence microscopy using different HMGCR antibodies, we present evidence for a dual localization of HMGCR in the ER and peroxisomes in differentiated human monocytic THP-1 cells, primary human monocyte-derived macrophages and human primary skin fibroblasts under conditions of low cholesterol …

Diagnostic Immunocytostaining with Peroxisome Proliferator-Activated Receptor-Gamma in Urine Cytology Samples.

INTRODUCTION: Urine cytology is a common method for detection of urothelial carcinoma (UC), however, is not high sensitivity. Improvement of the accuracy of cytodiagnosis using immunocytostaining as an auxiliary method is needed. This study aimed to determine the cytodiagnostic usefulness of peroxisome proliferator-activated receptor-gamma (PPAR-γ) immunocytostaining in urine cytology for the detection of UCs, particularly low-grade urothelial carcinomas (LGUC). METHODS: PPAR-γ immunocytostaining was performed for 37 UC cases and 26 benign cases. Among the UC cases, 22 cases were of the papil

Exploring the Changes of Peroxisomal Polarity in the Liver of Mice with Nonalcoholic Fatty Liver Disease.

Peroxisome proliferator-activated receptor alpha (PPAR-a) is a crucial nuclear transcription regulator of lipid metabolism, which is closely associated with the initiation and development of nonalcoholic fatty liver disease (NAFLD). Because PPAR-a can directly decide the level of peroxisomal metabolic enzymes, its changes might directly cause variations in peroxisomal polarity. Therefore, we developed a new two-photon fluorescence imaging probe, PX-P, in which the triphenylamine and cyanide moieties can real-time sense peroxisomal polarity changes. Using PX-P, we observed a prominent decrease

Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in β Cells.

An adverse intrauterine environment impairs the development of pancreatic islets in the fetus and leads to insufficient β cell mass and β cell dysfunction. We previously reported that Pex14, a peroxin protein involved in the biogenesis and degradation of peroxisomes, is markedly reduced in the pancreas of an intrauterine growth restriction fetus and last into adulthood. Peroxisomes function in a wide range of metabolic processes including fatty acid oxidization, ROS detoxification, and anti-inflammatory responses. To elucidate the impact of downregulation of the Pex14 gene on β cell, Pex14 was…

Peroxisomal Malfunction Caused by Mitochondrial Toxin 3-NP: Protective Role of Oxytocin.

Peroxisomes are single membrane cell organelles with a diversity of metabolic functions. Here we studied the peroxisomal dysfunction and oxidative stress after 3-nitropropionic acid (3-NP) induced neurotoxicity and the possible protective effects of oxytocin. Adult male and female rats were subjected to OXT and/or 3-NP treatment. The antioxidant enzymes, Superoxide dismutase (SOD) and Catalase (CAT) activities as well as expression level of Peroxin 14 (Pex14), a marker for peroxisomal number and Peroxisomal membrane protein of 70 kDa (PMP70), a metabolic transporter in peroxisome in different …

Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.

BACKGROUND: Mutations in PEX16 cause peroxisome biogenesis disorder (PBD). Zellweger syndrome characterized by neurological dysfunction, dysmorphic features, liver disease and early death represents the severe end of this clinical spectrum. Here we discuss the diagnostic challenge of atypical PEX16 related PBD in 3 patients from highly inbred kindred and describe the role of specific metabolites analyses, fibroblasts studies, whole-exome sequencing (WES) and metabolomics profiling to establish the diagnosis. METHODS AND PATIENTS: The proband is a 12-year-old male born to consanguineous parent

TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import.

Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, w … and enhances sensitivity to oxidative stress, underscoring the cellular requirement for functional peroxisomes. Therefore, TRIM37-mediated ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import, suggesting that mulibrey nanism is a new PBD.

Treatment of Mitochondrial Diabetes with a Peroxisome Proliferator-activated Receptor (PPAR)-gamma Agonist.

The 3243 A>G mutation in mitochondrial DNA is the most common cause of monogenic diabetes mellitus in Japan. A 45-year-old woman with mitochondrial diabetes and significant insulin resistance presented with hypoadiponectinemia despite a normal amount of visceral fat. Three months of treatment with pioglitazone (PIO) improved her blood glucose profile and response to the 75-g oral glucose tolerance test. These changes were accompanied by the amelioration of her insulin resistance and the impairment of early-phase insulin secretion. Her serum adiponectin levels increased to the normal range. In

Peroxisome proliferator-activated receptors (PPARs) and PPAR agonists: the 'future' in dermatology therapeutics?

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors and comprise three different isoforms namely PPARα, PPARγ, and PPARβ/δ with PPARβ/δ being the predominant subtype in human keratinocytes. After binding with specific ligands, PPARs regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorogenesis. PPARs also modulate a wide variety of skin functions including keratinocyte proliferation, epidermal barrier formation, wound healing, melanocyte proliferation, and sebum production. Recent studies have shown the importance

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6.

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and ske

Pioglitazone, a peroxisome proliferator-activated receptor γ activator, suppresses coronary spasm.

OBJECTIVE: We examined whether a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, pioglitazone, suppresses coronary spasm. BACKGROUND: Patients with coronary spastic angina (CSA) also have endothelial dysfunction and inflammation. Activation of PPAR-γ improves endothelial dysfunction and inflammation. PARTICIPANTS AND METHODS: The study participants included 73 consecutive CSA patients (47 men and 26 women, mean age 63.6±10.4 years) who were admitted to our institution with a suspicion of CSA because of episodes of chest discomfort occurring mostly at rest in whom coronary spas

Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-

Peroxisome proliferator-activated receptor alpha expression changes in human pregnant myometrium.

Peroxisome proliferator-activated receptor alpha (PPARα) has been demonstrated to exhibit anti-inflammatory activities that are hypothesized to play a key role in labor suppression and maintenance of uterine quiescence. The aim of this study was to identify pregnancy- and labor-associated changes in PPARα in human myometrium. For this investigation, human myometrium was obtained from premenopausal women, and the study participants were categorized into the following 4 groups: nonpregnant (NP; n = 10), preterm not in labor (PNL; n = 10, gestation range 20-35 weeks), term not in labor (TNL; n =

A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder.

Peroxisomal biogenesis disorders (PBD) are groups of inherited neurometabolic disorders caused by defects in PEX genes. We report on a femal … beta oxidation confirmed the diagnosis of PBD. Immunofluoresence microscopy revealed the absence of peroxisomes in fibroblasts. The patient was assigned to the PEX19 complementation group. Subsequent mutation analysis of the PEX19 gene revealed homozygosity for a c.320delA frameshift mutation. The patient had a stormy course with multiple admissions to the pe …