The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly being supplemented by biological and biosimilar agents. This trend is particularly evident in the development and advancement of anti-diabetic and hypolipemic therapies. This review explores advances in the treatment of hypercholesterolemia and hypertriglyceridemia, elevated lipoprotein(a) [Lp(a)], diabetes, and obesity associated with metabolic syndrome. It focuses mainly on biopharmaceuticals such as proteins and nucleotide-based drugs (antisense oligonucleotides, small interfering RNA), but also on dipeptidyl peptidase-4 (DPP-4) inhibitors classified as incretin drugs along with glucagon-like peptide-1 (GLP-1) analogues. Due to the substantial role of SGLT-2 (sodium/glucose cotransporter 2) inhibitors in novel diabetes therapies, especially for managing cardiovascular risk, this group of compounds was also included in this review. Many clinical data in the field of effectiveness of biopharmaceuticals in metabolic disorders are provided. Therefore, in this review, we mainly include a brief history of drug development and approval, first synthesis and structure modifications, which relevantly influence pharmacokinetics, and safety. We provide only brief comparison of biological drugs with metformin and sulphonylureas derivatives. Databases such as PubMed, Scopus, and Google Scholar are searched for the period between 2000 and 2024.

As tumor research has deepened, the deregulation of cellular metabolism has emerged as yet another recognized hallmark of cancer. Tumor cells adapt different biochemical pathways to support their rapid growth, proliferation, and invasion, resulting in distinct anabolic and catabolic activities compared with healthy tissues. Certain metabolic shifts, such as altered glucose and glutamine utilization and increased de novo fatty acid synthesis, are critical early on, while others may become essential only during metastasis. These metabolic adaptations are closely shaped by, and in turn remodel, the tumor microenvironment, creating favorable conditions for their spread. Anticancer metabolic strategies should integrate pharmacological approaches aimed at inhibiting specific biochemical pathways with well-defined dietary interventions as adjunctive therapies, considering also the role of gut microbiota in modulating diet and treatment responses. Given the established link between the consumption of foods rich in saturated fatty acids and sugars and an increased cancer risk, the effects of diet cannot be ignored. However, current evidence from controlled and multicenter clinical trials remains insufficient to provide definitive clinical recommendations. Further research using modern omics methods, such as metabolomics, proteomics, and lipidomics, is necessary to understand the changes in the metabolic profiles of various cancers at different stages of their development and to determine the potential for modifying these profiles through pharmacological agents and dietary modifications. Therefore, clinical trials should combine standard treatments with novel approaches targeting metabolic reprogramming, such as inhibition of specific enzymes and transporters or binding proteins, alongside the implementation of dietary restrictions that limit nutrient availability for tumor growth. However, to optimize therapeutic efficacy, a precision medicine approach should be adopted that balances the destruction of cancer cells with the protection of healthy ones. This approach, among others, should be based on cell type-specific metabolic profiling, which is crucial for personalizing oncology treatment.

PURPOSE OF REVIEW:Obesity is associated with increased DNA damage, which may in turn contribute to the development of obesity-related complications. DNA damage can also affect adipocyte biology, resulting in increased adiposity. Carefully managed weight loss programs can reverse this process. This article surveys new data that support these contentions.RECENT FINDINGS:Whole exome sequencing analyses have identified rare variants linked to high BMI and adiposity. Two of the identified genes are linked to DNA damage and DNA repair, suggesting that DNA damage itself may play a role in the cause of obesity. It has also been recognized that obesity increases DNA damage in breast tissue of carriers of BRCA mutations and rates of tumour formation in BRCA1+ mice, indicating effect of obesity on cancer development in high-risk populations. In addition, obesity promotes cancer cell chemoresistance by decreasing fatty acid oxidation involved in cellular DNA damage response, leading to apoptotic cellular death. Obesity is also associated with a reduced capacity of oocytes to repair sperm DNA damage, leading to lower in-vitro fertilization rates in women with obesity.SUMMARY:DNA damage and cellular responses to DNA damage can be both the result and the cause of obesity and can strongly influence the development and treatment of obesity-associated diseases.

Obesity and obesity-related complications, including various metabolic diseases and cancers, are significant health problems in developed and developing countries [...]

Introduction Uterine fibroids (UFs) are benign tumors of the female reproductive system originating from the smooth muscle of the uterus. Currently, progesterone is known to play a key role in the differentiation of the myometrial tissue to form UFs and their abnormal growth. The mechanism of action of progesterone in UF tumorigenesis involves its effect on increasing the concentrations and dysregulation of selected growth factors. Material and methods A retrospective cohort study was performed to evaluate and compare tumor necrosis factor α (TNF-α), insulin-like growth factor 1 (IGF-1), plasminogen activator inhibitor-1 (PAI-1) serum concentrations in patients with UFs without prior hormonal treatment, patients with UFs treated with a 3-month standard ulipristal acetate (UPA – a type of selective progesterone receptor modulator) scheme (5 mg/day) and in control patients without UFs. A total of 120 patients were divided into 3 groups (controls, UFs with UPA treatment, UFs without UPA treatment). Results There were no significant differences in TNF-α serum concentrations between patients with UFs who underwent UPA treatment and patients who did not. Serum concentrations of IGF-1 and PAI-1 did not show significant intergroup differences. Conclusions No significant differences were found between TNF-α concentrations in the serum of patients with UFs treated with UPA, and patients without UPA treatment. In addition, our data analysis did not show significant differences in the concentrations of IGF-1 and PAI-1 between patients with UFs and the control group. Further studies on the dependence of specific symptoms on selected growth factors are mandatory.

Extracellular vesicles (EVs) represent a heterogeneous group of particles secreted by cells to transfer information from the cell of origin to recipient cells by carrying various bioactive molecules. Numerous PubMed records on EVs reveal a burgeoning interest in EV-research, with a notable subset focusing on the potential diagnostic and therapeutic applications of EVs for diverse diseases, including cardiovascular disease (CVD), currently a globally leading cause of mortality. However, this great diagnostic and clinical potential has not yet been translated into clinical practice. No EV-based biomarkers and EV-therapeutic products have been approved, and EV-based therapy for CVD has not yet been shown to be effective. Therefore, this paper aims to scrutinize available data and identify what is needed to translate the underlying potential of EVs into specific EV-biomarkers and EV-therapeutic tools applicable in clinical practice.

The most common malignant gynecologic diseases are cervical, uterine, ovarian, vaginal, and vulvar cancer. Among them, ovarian cancer causes more deaths than any other cancer of the female reproductive system. A great number of women suffer from endometriosis, uterine fibroids (UFs), adenomyosis, dysmenorrhea, and polycystic ovary syndrome (PCOS), which are widespread benign health problems causing troublesome and painful symptoms and significantly impairing the quality of life of affected women, and they are some of the main causes of infertility. In addition to the available surgical and pharmacological options, the effects of supporting standard treatment with naturally occurring compounds, mainly polyphenols, are being studied. Catechins are responsible for the majority of potential health benefits attributed to green tea consumption. Epigallocatechin gallate (EGCG) is considered a non-toxic, natural compound with potential anticancer properties. Antioxidant action is its most common function, but attention is also drawn to its participation in cell division inhibition, apoptosis stimulation and epigenetic regulation. In this narrative review, we describe the role of EGCG consumption in preventing the development of benign reproductive disorders such as UF, endometriosis, and PCOS, as well as malignant gynecologic conditions. We discuss possible epigenetic mechanisms that may be related to the action of EGCG.

Research into early predictors of effective weight loss could help determine more effective therapeutic interventions. In this study, 106 subjects with class I obesity, genotyped with the fat mass and obesity-associated (FTO) rs9930506 gene variant, were enrolled into a 12-week weight loss program (WLP). Anthropometric and body composition measurements were controlled with bioelectrical impedance analysis (BIA) at baseline and after 4 and 12 weeks. Biopsies of abdominal subcutaneous adipose tissue (AT) and venous blood samples were collected to monitor changes in interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) mRNA levels in white blood cells (WBCs) and to assess if changes in WBC gene expression reflected changes in adipose tissue. The FTO rs9930506 variant had no effect on weight loss and no reduction in proinflammatory transcripts in WBCs or AT. Changes in anthropometric parameters were associated with changes in carbohydrate metabolism. A linear regression model showed that initial weight loss (after 4 weeks of the WLP) was the most predictive factor of weight loss success after 12 weeks of the WLP. Changes in plasma lipids or proinflammatory transcript levels in WBCs or AT were not associated with weight loss effectiveness. However, the gene expression in WBCs did reflect changes occurring in subcutaneous AT.

Thanks to their valuable assessment possibilities (subjective complaints and changes in nasal patency during the examination), nasal provocation tests may serve as an alternative tool for oral food challenges in the future. However, this test requires successive attempts to regulate its methodology in order to develop a standardized lyophilisate form and determine the threshold dose for a positive result. The study objective was to present the methodological foundation for nasal food allergen provocation tests induced by freeze-dried powdered chicken egg whites. A control group of 25 individuals with no history of allergy to chicken eggs or any other allergy was included in the study. Optical rhinometry and visual analog scales were used to assess the response of nasal mucosa to local allergen challenges. Minor variations in nasal flows, as measured by optical rhinometry, were observed in the provocation tests. The mean optical density measurements (as measured regardless of the allergen dose used) varied from positive to negative values and vice versa, e.g., amounting to 0.018 OD (standard deviation 0.095) at 15 min and −0.011 OD (standard deviation 0.090) at 30 min. No significant differences were observed concerning the perceived nasal discomfort using the visual analog scale. Due to the absence of nasal mucosal reactivity, nasal challenge is an excellent methodological tool for implementing food allergen tests.

Uterine fibroids (UFs) are monoclonal, benign tumors that contain abnormal smooth muscle cells and the accumulation of extracellular matrix (ECM). Although benign, UFs are a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. Many risk factors are involved in the pathogenesis of UFs via genetic and epigenetic mechanisms. The latter involving DNA methylation and demethylation reactions provide specific DNA methylation patterns that regulate gene expression. Active DNA demethylation reactions mediated by ten-eleven translocation proteins (TETs) and elevated levels of 5-hydroxymethylcytosine have been suggested to be involved in UF formation. This review paper summarizes the main findings regarding the function of TET enzymes and their activity dysregulation that may trigger the development of UFs. Understanding the role that epigenetics plays in the pathogenesis of UFs may possibly lead to a new type of pharmacological fertility-sparing treatment method.

[Table: see text] The general guidance for stakeholders on the evaluation of Article 13(1), 13(5) and 14 health claims was first published in March 2011. Since then, the Panel on Dietetic Products Nutrition and Allergies (NDA) has completed the scientific assessment of Article 13(1) claims except for claims put on hold by the European Commission, and has assessedadditional health claim applications submitted pursuant to Articles 13(5), 14 and also 19. In addition, comments received from stakeholders indicate that general issues that are common to all health claims need to be further clarified and addressed. This guidance document aims to explain the general scientific principles applied by the NDA Panel for the scientific assessmentof all health claims and outlines a series of steps for the compilation of applications. The general guidance document represents the views of the NDA Panel based on the experience gained to date with the scientific assessment of health claims, and it may be further updated, as appropriate, when additional issues are addressed.The document also aims to inform applicants of newprovisionsin the pre-submission phase and in the application procedure set out in the General Food Law, as amended by the Transparency Regulation. These new provisions are applicable to all applications submitted as of 27 March 2021. The version of this guidance published in 2016 remains applicable for applications submitted before 27 March 2021.

Abstract Endorsement date 21 January 2021 Implementation date 27 March 2021 Following the adoption of Regulation (EU) 2015/2283 on Novel Foods, the European Commission requested EFSA to develop a scientific and technical guidance for the preparation and submission of notifications for traditional foods from third countries. This guidance presents a common format for the organisation of the information to be presented by applicant for the preparation of a well‐structured dossier. The safety of a traditional food should be substantiated by reliable data on its composition, its experience of continued use and its proposed conditions of use. Its normal consumption should not be nutritionally disadvantageous. This guidance is also intended to support applicants in providing the type and quality of information EU Member States and EFSA need for the assessments of traditional foods from third countries. The applicant should integrate the information on the composition and the experience of continued use and provide a concise overall consideration on how this substantiates the history of safe use of the traditional food and how this relates to the proposed conditions of use for the EU. Where potential health hazards have been identified on the basis of the composition and/or data from the experience of continued use, they should be discussed. On the basis of the information provided, EFSA will assess the safety related to the consumption of the traditional food under the proposed conditions of use. This guidance was originally adopted by the NDA Panel in 2016. It has been revised in 2020 to inform applicants of the new provisions introduced by Regulation (EC) No 178/2002, as amended by Regulation (EU) 2019/1381 on the transparency and sustainability of the EU risk assessment in the food chain.It is applicable to allnotifications and applications submitted as of 27 March 2021. The 2016 version remains applicable to notifications and applications submitted before 27 March 2021.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on Scientific and technical guidance for the preparation and presentation of applications for exemption from mandatory labelling of food allergens and/or products thereof. This guidance applies to food ingredients or substances with known allergenic potential listed in Annex II of Regulation (EU) No 1169/2011 or products thereof, and aims to assist applicants in the preparation and presentation of well-structured applications for exemption from labelling. It presents a common format for the organisation of the information to be provided and outlines the information and scientific data which must be included in the application, the hierarchy of different types of data and study designs, reflecting the relative strength of evidence which may be obtained from different study types, and the key issues which must be addressed in the application in order to assess the likelihood of a food allergen-derived preparation/foodstuff(s) triggering adverse reactions in sensitive individuals under the proposed conditions of use. This guidance document was adopted by the NDA Panel in 2013 and updated in 2017 to reflect the application of Regulation (EU) No 1169/2011. Upon request from the European Commission in 2020, it has been revised to inform applicants of new provisions in the pre-submission phase and submission application procedure set out in Regulation (EC) No 178/2002, as amended by Regulation (EU) 2019/1381 on the transparency and sustainability of the EU risk assessment in the food chain, that are applicable to all applications submitted as of 27 March 2021. (C) European Food Safety Authority, 2021

Abstract Endorsement date 21 January 2021 Implementation date 27 March 2021 Following the adoption of Regulation (EU) 2015/2283 on novel foods, the European Commission requested EFSA develop scientific and technical guidance for the preparation and submission of applications for authorisation of novel foods. This guidance presents a common format for the organisation of the information to be presented by the applicant when preparing a well‐structured application to demonstrate the safety of the novel food. It outlines the data needed for the safety assessments of novel foods. Requirements relate to the description of the novel food, production process, compositional data, specification, proposed uses and use levels, and anticipated intake of the novel food. Further sections on the history of use of the novel food and/or its source, absorption, distribution, metabolism, excretion, nutritional information, toxicological information and allergenicity should be considered by the applicant by default. If not covered in the application, this should be justified. The applicant should integrate the data presented in the different sections to provide their overall considerations on how the information supports the safety of the novel food under the proposed conditions of use. Where potential health hazards have been identified, they should be discussed in relation to the anticipated intakes of the novel food and the proposed target populations. On the basis of the information provided, EFSA will assess the safety of the novel food under the proposed conditions of use. This guidance was originally adopted in 2016.It has beenrevised to informapplicants of the new provisions introduced by Regulation (EC) No 178/2002, as amended by Regulation (EU) 2019/1381 on the transparency and sustainability of the EU risk assessment in the food chain.This revised guidance applies to all dossiers submitted as of 27 March 2021. The 2016 version of this guidance remains applicable to applications submitted before 27 March 2021.

Following a request from the European Commission, EFSA was asked to provide scientific and technical guidance for the preparation and presentation of a dossier for evaluation of an infant and/or follow-on formula manufactured from protein hydrolysates. This guidance document addresses the information and data to be submitted to EFSA on infant and follow-on formulae manufactured from protein hydrolysates with respect to the nutritional safety and suitability of the specific formula and/or the formula's efficacy in reducing the risk of developing allergy to milk proteins. The guidance will be further reviewed and updated with the experience gained from the evaluation of specific dossiers, and in the light of applicable Union guidelines and legislation. The guidance was adopted by the Panel on Dietetic Products, Nutrition and Allergies on 5 April 2017. Upon request from the European Commission in 2020, it has been revised to inform food business operators of the new provisions in the pre-submission phase and in the procedure set out in the General Food Law, as amended by the Transparency Regulation. This revised guidance applies to all dossiers submitted as of 27 March 2021 and shall be consulted for the preparation of dossiers intended to be submitted from that date onwards. For dossiers submitted prior to 27 March 2021, the previous guidance, published in May 2017 remains applicable. (C) 2021 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Following the adoption of Regulation (EU) 2015/2283 on novel foods, the European Commission requested EFSA develop scientific and technical guidance for the preparation and submission of applications for authorisation of novel foods. This guidance presents a common format for the organisation of the information to be presented by the applicant when preparing a well-structured application to demonstrate the safety of the novel food. It outlines the data needed for the safety assessments of novel foods. Requirements relate to the description of the novel food, production process, compositional data, specification, proposed uses and use levels, and anticipated intake of the novel food. Further sections on the history of use of the novel food and/or its source, absorption, distribution, metabolism, excretion, nutritional information, toxicological information and allergenicity should be considered by the applicant by default. If not covered in the application, this should be justified. The applicant should integrate the data presented in the different sections to provide their overall considerations on how the information supports the safety of the novel food under the proposed conditions of use. Where potential health hazards have been identified, they should be discussed in relation to the anticipated intakes of the novel food and the proposed target populations. On the basis of the information provided, EFSA will assess the safety of the novel food under the proposed conditions of use. This guidance was originally adopted in 2016. It has been revised to inform applicants of the new provisions introduced by Regulation (EC) No 178/2002, as amended by Regulation (EU) 2019/1381 on the transparency and sustainability of the EU risk assessment in the food chain. This revised guidance applies to all dossiers submitted as of 27 March 2021. The 2016 version of this guidance remains applicable to applications submitted before 27 March 2021. (C) 2021 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Introduction Caesarean section (CS) is the most common medical procedure performed in women all over the world. There is a hypothesis that caesarean section changes DNA methylation, and it has been linked to immune-mediated diseases such as diabetes in late infant health outcomes. The aim of the study was to evaluate the relationship between caesarean section and DNA methylation patterning in the placenta by measurement of global DNA methylation. Material and methods We included in the study 111 healthy, pregnant women in singular pregnancy at term of delivery (gestational age at least 37 weeks). The study involved global methylation in placental tissue from 46 pregnant women, delivered by vaginal route, and 49 pregnant women, delivered by elective caesarean section (ECS) before the start of labour. In 16 of the elective caesarean section cases, regular uterine contractions were declared. An ELISA-based kit was used for an assessment of the global DNA methylation. Results Global DNA methylation in the placenta in elective caesarean sections (3.02 on average) was significantly lower compared to intrapartum caesarean sections (3.71 on average) and vaginal deliveries (3.64 on average), but did not significantly differ between intrapartum caesarean sections and vaginal deliveries. Global DNA methylation in the placenta in male newborns was significantly higher (4.86 on average) than in female newborns (3.31 on average) in vaginal deliveries but not in either elective or intrapartum caesarean sections. Conclusions Caesarean sections performed without uterine contractions significantly influenced global DNA methylation in the placenta. Moreover, a sexual dimorphism at the level of placental global DNA methylation was demonstrated. Further studies investigating different panels of genes may help to identify genes with aberrant methylation in newborn infants delivered by caesarean section compared to vaginal delivery, as well as demonstrate sexual dimorphism.

Ethanol, as a small-molecule organic compound exhibiting both hydrophilic and lipophilic properties, quickly pass through the biological barriers. Over 95% of absorbed ethanol undergoes biotransformation, the remaining amount is excreted unchanged, mainly with urine and exhaled air.The main route of ethyl alcohol metabolism is its oxidation to acetaldehyde, which is converted into acetic acid with the participation of cytosolic NAD+ - dependent alcohol (ADH) and aldehyde (ALDH) dehydrogenases. Oxidative biotransformation pathways of ethanol also include reactions catalyzed by the microsomal ethanol oxidizing system (MEOS), peroxisomal catalase and aldehyde (AOX) and xanthine (XOR) oxidases. The resulting acetic acid can be activated to acetyl-CoA by the acetyl-CoA synthetase (ACS).It is also possible, to a much smaller extent, non-oxidative routes of ethanol biotransformation including its esterification with fatty acids by ethyl fatty acid synthase (FAEES), re-esterification of phospholipids, especially phosphatidylcholines, with phospholipase D (PLD), coupling with sulfuric acid by alcohol sulfotransferase (SULT) and with glucuronic acid using UDP-glucuronyl transferase (UGT, syn. UDPGT).The intestinal microbiome plays a significant role in the ethanol biotransformation and in the initiation and progression of liver diseases stimulated by ethanol and its metabolite - acetaldehyde, or by lipopolysaccharide and ROS.

Purpose: Comparison of the activity of 11beta-hydroxysteroid dehydrogenase type 2 in the placenta and the umbilical cord blood cortisol level between caesarean sections with or without uterine contraction and vaginal delivery groups. Cortisol is the main stress hormone responsible for the normal adaptation of the neonate to extrauterine life. The disorders resulting from a dysfunction of the 11β-HSD 2–cortisol system can explain the higher risk of developing diseases in children born by caesarean section. Methods: 111 healthy, pregnant women in singular pregnancy at term of delivery were included into the study. The study comprised 11β-HSD 2 in placental tissue from 49 pregnant women delivering by elective caesarean section and 46 pregnant women delivering by vagina. In 16 cases of the elective caesarean section, regular uterine contractions were declared. Cortisol level was estimated in umbilical cord blood directly after delivery. Results: We found no statistically significant differences in the activity of 11β-HSD 2 in placentas delivered via caesarean sections (29.61 on average in elective caesarean sections and 26.65 on average in intrapartum caesarean sections) compared to vaginal deliveries (31.94 on average, p = 0.381), while umbilical cord blood cortisol in the elective caesarean sections group was significantly lower (29.86 on average) compared to the vaginal deliveries (55.50 on average, p < 0.001) and intrapartum caesarean sections (52.27 on average, p < 0.001). Conclusions: The model of placental 11β-HSD 2 activity and umbilical cord blood cortisol concentration seems to be significant in conditions of stress associated with natural uterine contractions in labour.

The tumor microenvironment (TME) is a complex system composed of multiple cells, such as non-cancerous fibroblasts, adipocytes, immune and vascular cells, as well as signal molecules and mediators. Tumor cells recruit and reprogram other cells to produce factors that maintain tumor growth. Communication between cancerous and surrounding cells is a two-way process and engages a diverse range of mechanisms that, in consequence, can lead to rapid proliferation, metastasis, and drug resistance, or can serve as a tumors-suppressor, e.g., through tumor–immune cell interaction. Cross-talk within the cancer microenvironment can be direct by cell-to-cell contact via adhesion molecules, electrical coupling, and passage through gap junctions, or indirect through classical paracrine signaling by cytokines, growth factors, and extracellular vesicles. Therapeutic approaches for modulation of cell-cell communication may be a promising strategy to combat tumors. In particular, integrative approaches targeting tumor communication in combination with conventional chemotherapy seem reasonable. Currently, special attention is paid to suppressing the formation of open-ended channels as well as blocking exosome production or ablating their cargos. However, many aspects of cell-to-cell communication have yet to be clarified, and, in particular, more work is needed in regard to mechanisms of bidirectional signal transfer. Finally, it seems that some interactions in TEM can be not only cancer-specific, but also patient-specific, and their recognition would help to predict patient response to therapy.