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Microplastics are a widespread environmental hazard and their impact on human health has become a growing concern in last years. Recently, the potential role of microplastics in the development of various diseases, including diabetes, has been highlighted. Therefore, the aim of this study was to investigate the effects of PET microplastics on the pancreas using immature pigs as a model organism. We analyzed the global transcriptomic profile of the pancreas by RNA-Seq in piglets treated with either a low (0.1 g/day) or a high dose (1 g/day) of PET microplastics for 4 weeks. The analysis revealed a dose-dependent effect of PET microplastics on gene expression. A low dose changed the expression of one gene, while a high dose affected the expression of 86 genes. The differentially expressed genes, including immune cell markers, cytokines and chemokines, may activate the immune system in the pancreas in a way that is characteristic of the pathogenesis of diabetes. In addition, PET microplastics induced oxidative stress in the pancreas. These above imply that oral exposure to PET microplastics could be a new risk factor for the development of diabetes.

Anisakis simplex is a cosmopolitan parasitic nematode of marine organisms with a complex life cycle. Consuming fish infected with its larvae poses a health risk, as the parasites can penetrate gastrointestinal mucosa, damage stomach and intestinal walls, and trigger allergic reactions. The resulting disease is known as anisakiasis. The European Food Safety Authority (EFSA) classifies A. simplex as a biohazard. Most of its developmental stages (L3, L4, and adults) occur under anaerobic conditions, and larvae derive energy mainly from saccharides. However, the effect of glucose on L3 and L4 larvae—stages pathogenic to humans—has not been described. This study aimed to identify genes and pathways involved in glucose (10 mg/mL) response through transcriptomic and proteomic analyses of L3 and L4 larvae. Differentially expressed genes (DEGs), long non-coding RNAs (DELs), and differentially regulated proteins (DRPs) were identified. DEGs were involved in cuticle structure, lyase activity, and metabolic processes. Comparing L3 CTR and L4 CTR (control) to glucose-treated samples revealed 1,969 DEGs; 259 overlapped between L4 GLU vs. L3 GLU, (glucose-treated) with 11 showing reversed expression. Additionally, 84 DELs were identified in L3 GLU vs. control, 40 in L4 GLU vs. control, and 163 between glucose-treated L4 and L3. Larval and glucose-specific alternative splicing events were also analyzed. Proteomic analysis revealed 35 DRPs—5 more abundant in L4, 30 in L3. The data reveal that developmental stage exerts a more substantial influence than glucose exposure on gene and protein expression profiles. However, glucose still modulates several pathways related to translation, cytoskeletal remodeling, extracellular matrix (ECM) reorganization, and energy metabolism.

Background The myometrium is involved in many processes during pregnancy and the estrous/menstrual cycle. Peroxisome proliferator-activated receptors (PPARs) can be regulators of the processes occurring in the myometrium. In the present study, we determined the global transcriptome profile of the porcine myometrium during the peri-implantation period and the late luteal phase of the estrous cycle. In addition, we investigated for the first time the influence of PPARγ ligands on the transcriptome profile. Results The myometrium of gilts ( n  = 3) was collected on days 10–11 and 14–15 of pregnancy and on the corresponding days of the estrous cycle. The expression of PPARγ was confirmed in the tissue. Based on the mRNA level, further studies were conducted on myometrial explants obtained from pigs at days 14–15 of pregnancy and the corresponding days of the estrous cycle. The tissue sections were incubated in vitro for 6 h in the presence of a PPARγ agonist, pioglitazone (P; 10 µM), or antagonist, T0070907 (T; 1 µM). To identify the transcription profile of the myometrium, RNA-Seq was performed on the NovaSeq 6000 Illumina platform. This study identified 1082 differentially expressed genes (DEGs; 609 upregulated and 473 downregulated) in the porcine myometrium on days 14–15 of pregnancy compared with the corresponding days of the estrous cycle. During pregnancy, we detected 6 and 80 DEGs related to PPARγ agonist and antagonist, respectively. During the estrous cycle, we identified 4 and 17 DEGs for P and T vs. the control, respectively. Conclusions The results indicate that the DEGs are involved in a number of processes, including the immune response, prostaglandin synthesis, cell differentiation and communication. In addition, the role of PPARγ activity in regulating the expression of genes related to the immune response and hormone synthesis in the porcine myometrium has been demonstrated.

Microplastics and their effects on health are a growing concern. While their full impact is not yet known, they are not harmless. Pancreatic diseases are increasingly common, even in children, which was once rare. This study examined pancreatic changes caused by PET microplastics in young organisms. Gilts received low (0.1 g/day) or high (1 g/day) doses of PET microplastics for four weeks, and their pancreases were analyzed using UPLC-MS/MS. Blood insulin levels and other biochemical parameters were also measured. PET microplastics altered physiological processes in the pancreas, increasing glucose, γ-aminobutyric acid, lysophosphatidylcholine, and lysophosphatidylethanolamine levels in tissues. They also elevated blood insulin concentrations and affected in a dose-dependent manner lipase, cholesterol, and calcium levels. These findings suggest that PET microplastics may contribute to insulin resistance and pancreatitis.

Microplastics are a relatively new discovered environmental hazard that can contribute to the disruption of many physiological processes in the organism. There is evidence that they affect the physiology of the pancreas, but research in this area remains limited. Therefore, the aim of the study was to determine the effects of PET microplastics on the global proteomic profile of the pancreas using LC–MS/MS analysis, with the pig as a model organism. The pigs were treated either with a low (0.1 g/day) or a high dose (1 g/day) of PET microplastics for four weeks. The analysis revealed that PET microplastics affected protein abundance in a dose-dependent manner – the low dose altered the abundance of 7 proteins, while the high dose – 17. The differentially regulated proteins were involved in fatty acid biosynthesis (FASN, KAS), lipid peroxidation (CBR1) and digestive enzyme production (trypsinogen). Complementary colorimetric assays confirmed a significant increase in free fatty acids under the influence of a high dose of PET microplastics. Taken together, these results indicate that PET microplastics may affect oxidative status, induce lipotoxic stress and impair pancreatic exocrine function, suggesting a novel pathway through which microplastics may cause metabolic disturbances.

Glucose transporter (GLUT) research in parasitic nematodes focuses on identifying and characterizing developmentally regulated isoforms, elucidating their regulatory and structural properties, and evaluating their potential as drug targets. While glucose transport mechanisms have been well characterized in the free-living nematode , data on parasitic species remain limited. s. s., a parasitic nematode, relies on host-derived glucose to maintain energy metabolism. It is hypothesized that s. s. utilizes specific glucose transporters to facilitate sugar uptake under varying nutritional conditions. analysis identified five putative facilitated glucose transporter genes ( ) and one Sugars Will Eventually be Exported Transporter ( ) gene. The FGTs were classified as members of the solute carrier family 2 (SLC2), while belonged to the SWEET transporter family. Full-length cDNA sequences were obtained, and encoded proteins structurally characterized using bioinformatic modeling. Expression of transporter genes was assessed in s. s. larvae at stages L3 and L4 cultured under different glucose concentrations and time points. Structural and phylogenetic analyses revealed that and share high similarity with class I GLUTs found in nematodes and vertebrates. Gene expression profiling demonstrated differential regulation between larval stages. Most notably, FGT genes were stably expressed in L4 larvae, whereas in L3 larvae, gene activation was more variable and dependent on glucose concentration, showing a dynamic transcriptional response to nutrient levels. was expressed in both stages, but its regulation differed over time and with glucose availability. Glucose supplementation altered trehalose and glycogen levels, and trehalase activity varied across stages and treatments, indicating stage-specific metabolic adaptation. The observed transcriptional and biochemical differences between L3 and L4 larvae suggest a shift in glucose uptake mechanisms, from transcuticular absorption in L3 to intestinal glucose uptake in L4 following intestine activation. FGT1 and FGT3 are proposed as key facilitators of glucose uptake, with roles varying across developmental stages. These findings indicate that glucose transporters are regulated in response to changing environmental conditions and may represent targets for rational anthelmintic drug design.

Inflammation is a biological response of the immune system, which can be triggered by many factors, including pathogens. These factors may induce acute or chronic inflammation in various organs, including the reproductive system, leading to tissue damage or disease. In this study, the RNA-Seq technique was used to determine the in vitro effects of peroxisome proliferator-activated receptor gamma (PPARγ) ligands on the expression of genes and long non-coding RNA, and alternative splicing events (ASEs) in LPS-induced inflammation of the porcine endometrium during the follicular phase of the estrous cycle. Endometrial slices were incubated in the presence of LPS and PPARγ agonists (PGJ 2 or pioglitazone) and a PPARγ antagonist (T0070907). We identified 169, 200, 599 and 557 differentially expressed genes after LPS, PGJ 2 , pioglitazone or T0070907 treatment, respectively. Moreover, changes in differentially expressed long non-coding RNA and differential alternative splicing events were described after the treatments. The study revealed that PPARγ ligands influence the LPS-triggered expression of genes controlling the DNA damage response ( GADD45β, CDK1, CCNA1, CCNG1, ATM ). Pioglitazone treatment exerted a considerable effect on the expression of genes regulating the DNA damage response.

Peroxisome proliferator-activated receptors (PPARs) belong to a ligand-dependent nuclear receptor family. In the past decade, numerous studies have revealed the presence and significance of PPARs in the reproductive system. PPARs are expressed at different levels of hypothalamic-pituitary-gonadal (HPG) axis. They are also present in the uterus as well as in the placenta and embryonic tissues of different species. PPARs significance has been reported during the estrous/menstrual cycle and pregnancy with the gamma isoform studied most frequently. Several studies indicate that PPARs regulate proliferation of ovarian cells, tissue remodeling and steroidogenesis. In the endometrium, PPARs are engaged in the regulation of prostaglandins, steroids and cytokines synthesis. The role of PPARs in the trophoblast differentiation, maturation and invasion as well as in the embryo development has also been demonstrated. In this review, we summarize current findings concerning the role of PPARs in the regulation of reproductive functions at different levels of the HPG axis during various physiological statuses of females. In addition, the role of PPARs in the modulation of uterine functions as well as the placenta and embryo development has also been discussed.

Pioglitazone Induces Mitochondrial Biogenesis in Human Subcutaneous Adipose Tissue In Vivo Iwona Bogacka , Hui Xie , George A. Bray and Steven R. Smith From the Molecular Endocrinology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana Address correspondence and reprint requests to Iwona Bogacka, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA. E-mail: bogackiu{at}pbrc.edu Abstract Thiazolidenediones such as pioglitazone improve insulin sensitivity in diabetic patients by several mechanisms, including increased uptake and metabolism of free fatty acids in adipose tissue. The purpose of the present study was to determine the effect of pioglitazone on mitochondrial biogenesis and expression of genes involved in fatty acid oxidation in subcutaneous fat. Patients with type 2 diabetes were randomly divided into two groups and treated with placebo or pioglitazone (45 mg/day) for 12 weeks. Mitochodrial DNA copy number and expression of genes involved in mitochondrial biogenesis were quantified by real-time PCR. Pioglitazone treatment significantly increased mitochondrial copy number and expression of factors involved in mitochondrial biogenesis, including peroxisome proliferator–activated receptor (PPAR)-γ coactivator-1α and mitochondrial transcription factor A. Treatment with pioglitazone stimulated the expression of genes in the fatty acid oxidation pathway, including carnitine palmitoyltransferase-1, malonyl-CoA decarboxylase, and medium-chain acyl-CoA dehydrogenase. The expression of PPAR-α, a transcriptional regulator of genes encoding mitochondrial enzymes involved in fatty acid oxidation, was higher after pioglitazone treatment. Finally, the increased mitochondrial copy number and the higher expression of genes involved in fatty acid oxidation in human adipocytes may contribute to the hypolipidemic effects of pioglitazone. ADRB3, adrenergic β-3 receptor CPT-1, carnitine palmitoylotransferase I FPG, fasting plasma glucose MCAD, medium-chain acyl-CoA dehydrogenase MLYCD, malonyl-CoA decarboxylase mtDNA, mitochondrial DNA mtTFA, mitochondrial transcription factor A NRF, nuclear respiratory factor PGC-1α, peroxisome proliferator–activated receptor coactivator-1α PPAR, peroxisome proliferator–activated receptor TZD, thiazolidinedione UCP, uncoupling protein Footnotes I.B. has received grant/research support from Takeda Pharmaceuticals. H.X. has received grant/research support from Takeda Pharmaceuticals. G.A.B. has served on an advisory board of, has received honoraria from, and has received grant/research support from Takeda Pharmaceuticals. S.R.S. has received honoraria/consulting fees and research support from Takeda Pharmaceuticals. Accepted February 17, 2005. Received June 23, 2004. DIABETES

The Effect of Pioglitazone on Peroxisome Proliferator-Activated Receptor-γ Target Genes Related to Lipid Storage In Vivo Iwona Bogacka , PHD , Hui Xie , MS , George A. Bray , MD and Steven R. Smith , MD From the Pennington Biomedical Research Center, Baton Rouge, Louisiana Address correspondence and reprint requests to Iwona Bogacka, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808. E-mail: bogackiu{at}pbrc.edu Abstract OBJECTIVE —Pioglitazone is a member of the thiazolidinediones (TZDs), insulin-sensitizing agents used to treat type 2 diabetes. The aim of this study was to define the effect of pioglitazone on the expression of genes related to carbohydrate and lipid metabolism in subcutaneous fat obtained from type 2 diabetic patients. RESEARCH DESIGN AND METHODS —Forty-eight volunteers with type 2 diabetes were divided into two groups treated for 12 weeks with placebo or pioglitazone (30 mg/day). The expression of several genes was quantified by real-time RT-PCR. RESULTS —Pioglitazone treatment increased the expression of genes involved in glycerol-3-phosphate synthesis. The mRNA expression of PEPCK-C and glycerol-3-phosphate dehydrogenase (GPDH) increased ( P < 0.01) in patients treated with pioglitazone. There was no difference in glycerol kinase (GyK) mRNA levels. The expression of genes that regulate fatty acid availability in adipocytes, including lipoprotein lipase (LPL) and acetyl-CoA synthetase (ACS), was higher ( P < 0.01) in pioglitazone-treated patients. Pioglitazone stimulated ( P < 0.0001) expression of c-Cbl-associated protein (CAP), whereas tumor necrosis factor-α, leptin, resistin, angiopoietin like-4, and 11-β-hydroxysteroid dehydrogenase type 1 (11β HSD 1) were not affected by pioglitazone. The baseline peroxisome proliferator-activated receptor (PPAR)-γ1 mRNA was significantly correlated with mRNA for LPL, CAP, ACS, 11β HSD 1, GyK, fatty acid synthase, leptin, and GPDH, whereas PPAR-γ2 mRNA was correlated with CAP, PEPCK-C, leptin, and GPDH. CONCLUSIONS —Treatment with pioglitazone increased body weight, and this is associated with upregulation of some, but not all, genes previously demonstrated as “TZD responsive” in subcutaneous fat. The results suggest that TZDs might increase body weight through the upregulation of genes facilitating adipocyte lipid storage in vivo. ACS, acetyl-CoA synthetase ANGPTL-4, angiopoietin like-4 CAP, c-Cbl-associated protein FAS, fatty acid synthase GPDH, glycerol-3-phosphate dehydrogenase GyK, glycerol kinase 11β HSD 1, 11-β-hydroxysteroid dehydrogenase type 1 LPL, lipoprotein lipase PPAR, peroxisome proliferator-activated receptor TZD, thiazolidinedione Footnotes I.B. and H.X. are involved in a project sponsored by Takeda Pharmaceuticals. G.A.B. serves on the scientific advisory board for and has received honoraria and laboratory funding from Takeda Pharmaceuticals. S.R.S. has served as an ad hoc consultant for and has received honoraria and laboratory funding from Takeda Pharmaceuticals. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted March 25, 2004. Received January 7, 2004. DIABETES CARE