Unravelling the Influence of Endocrine-Disrupting Chemicals on Obesity Pathophysiology Pathways.

Obesity represents a global health concern, affecting individuals of all age groups across the world. The prevalence of excess weight and obesity has escalated to pandemic proportions, leading to a substantial increase in the incidence of various comorbidities, such as cardiovascular diseases, type 2 diabetes, and cancer. This chapter seeks to provide a comprehensive exploration of the pathways through which endocrine-disrupting chemicals can influence the pathophysiology of obesity. These mechanisms encompass aspects such as the regulation of food intake and appetite, intestinal fat absorption, lipid metabolism, and the modulation of inflammation. This knowledge may help to elucidate the role of exogenous molecules in both the aetiology and progression of obesity.

In Vitro Screening and Lipid-Lowering Effect of Prickly Pear (Opuntia Ficus-Indica L. Mill.) Fruit Extracts in 3T3-L1 Pre-Adipocytes and Mature Adipocytes.

Opuntia ficus-indica fruits have been widely used due to their nutritional composition and beneficial effects on health, particularly against chronic diseases such as diabetes, obesity, cardiovascular diseases and cancer, among others. In recent years, prickly pear peel and pulp extracts have been characterised, and a high number of bioactive compounds have been identified. This study aimed to analyse the triglyceride-lowering effect of prickly pear peel and pulp extracts obtained from fruits of three varieties (Pelota, Sanguinos, and Colorada) in 3T3-L1 maturing and mature adipocytes. At a concentration of 50 µg/mL, peel extracts from Colorada reduced triglyceride accumulation in pre-adipocytes and mature adipocytes. Additionally, at 25 µg/mL, Pelota peel extract decreased triglyceride content in mature adipocytes. Moreover, maturing pre-adipocytes treated with 50 and 25 µg/mL of Sanguinos pulp extract showed a reduction of triglyceride accumulation. In addition, the lipid-lowering effect of the main individual betalain and phenolic compounds standards were assayed. Piscidic acid and isorhamnetin glycoside (IG2), found in Colorada peel extract, were identified as the bioactive compounds that could contribute more notably to the triglyceride-lowering effect of the extract. Thus, the betalain and phenolic-rich extracts from Opuntia ficus indica fruits may serve as an effective tool in obesity management.

Dataset of chicken-embryo blood cells exposed to quercetin, methyl methanesulfonate, or cadmium chloride.

Toxicological analysis of the effects of natural compounds is frequently mandated to assess their safety. In addition to more simple in vitro cellular systems, more complex biological systems can be used to evaluate toxicity. This dataset is comprised of bright-field microscopy images of chicken-embryo blood cells, a complex biological model that recapitulates several features found in human organisms, including circulation in blood stream and biodistribution to different organs. In the presented collection of blood smear images, cells were exposed to the flavonoid quercetin, and the two mutagens methyl methanesulfonate (MMS) and cadmium chloride (CdCl2). In ovo models offer a unique opportunity to investigate the effects of various substances, pathogens, or cancer treatments on developing embryos, providing valuable insights into potential risks and therapeutic strategies. In toxicology, in ovo models allow for early detection of harmful compounds and their impact on embryonic development, aiding in the assessment of environmental hazards. In immunology, these models offer a controlled system to explore the developing immune responses and the interaction between pathogens and host defenses. Additionally, in ovo models are instrumental in oncology research as they enable the study of tumor development and response to therapies in a dynamic, rapidly developing environment. Thus, these versatile models play a crucial role in advancing our understanding of complex biological processes and guiding the development of safer therapeutics and interventions. The data presented here can aid in understanding the potential toxic effects of these substances on hematopoiesis and the overall health of the developing organism. Moreover, the large dataset of blood smear images can serve as a resource for training machine learning algorithms to automatically detect and classify blood cells, provided that specific optimized conditions such as image magnification and background light are maintained for comparison. This can lead to the development of automated tools for blood cell analysis, which can be useful in research. Moreover, the data is amenable to the use as teaching and learning resource for histology and developmental biology.

Gossypetin Is a Novel Modulator of Inflammatory Cytokine Production and a Suppressor of Osteosarcoma Cell Growth.

Osteosarcoma (OS) is a common childhood sarcoma, and its treatment is hindered by adverse effects, chemoresistance, and recurrence. Interleukin (IL)-6 production by tumors plays a significant role in inflammation, carcinogenesis, and metastasis. This study aimed to investigate the antiproliferative potential of luteolin derivatives in OS and to evaluate interleukin production. MG-63, Saos-2, HOS, and 143B human OS cell lines were incubated with luteolin and eight derivatives containing hydroxy, chlorine, or alkyl substitutions. The cell viability and growth were evaluated in the presence of these compounds. Apoptosis was also examined through the analysis of the Bax expression and caspase-3 activity. Finally, the gossypetin effects were measured regarding the production of proinflammatory cytokines interleukin (IL)-6, IL-1ß, and IL-12p70. Our findings show that gossypetin was the most potent compound, with proliferation-suppressing activities that induced a series of critical events, including the inhibition of the cell viability and growth. Apoptosis was associated with enhanced caspase-3 activity and increased Bax expression, indicating the involvement of the intrinsic pathway of apoptosis. Moreover, pre-/co-treatment with gossypetin significantly reduced the autocrine production of proinflammatory cytokines. Further investigation is required; nevertheless, considering the link between inflammation, carcinogenesis, and metastasis in OS, our findings suggest that gossypetin exhibits anti-proliferative and anti-inflammatory properties that are potentially relevant in the clinical context.

The role of flavonoids in the regulation of epithelial-mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis.

One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.

A comprehensive review on the antidiabetic activity of flavonoids targeting PTP1B and DPP-4: a structure-activity relationship analysis.

Type 2 diabetes (T2D) is an expanding global health problem, resulting from defects in insulin secretion and/or insulin resistance. In the past few years, both protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase-4 (DPP-4), as well as their role in T2D, have attracted the attention of the scientific community. PTP1B plays an important role in insulin resistance and is currently one of the most promising targets for the treatment of T2D, since no available PTP1B inhibitors were still approved. DPP-4 inhibitors are among the most recent agents used in the treatment of T2D (although its use has been associated with possible cardiovascular adverse events). The antidiabetic properties of flavonoids are well-recognized, and include inhibitory effects on the above enzymes, although hitherto not therapeutically explored. In the present study, a comprehensive review of the literature of both synthetic and natural isolated flavonoids as inhibitors of PTP1B and DPP-4 activities is made, including their type of inhibition and experimental conditions, and structure-activity relationship, covering a total of 351 compounds. We intend to provide the most favorable chemical features of flavonoids for the inhibition of PTP1B and DPP-4, gathering information for the future development of compounds with improved potential as T2D therapeutic agents.

3',4'-Dihydroxyflavonol Modulates the Cell Cycle in Cancer Cells: Implication as a Potential Combination Drug in Osteosarcoma.

New agents are demanded to increase the therapeutic options for osteosarcoma (OS). Although OS is the most common bone cancer in children and adolescents, it is considered a rare disorder. Therefore, finding adjuvant drugs has potential to advance therapy for this disease. In this study, 3',4'-dihydroxyflavonol (DiOHF) was investigated to assess the effects in OS cellular models in combination with doxorubicin (Dox). MG-63 and U2OS human OS cells were exposed to DiOHF and Dox and tested for cell viability and growth. To elucidate the inhibitory effects of DiOHF, additional studies were conducted to assess apoptosis and cell cycle distribution, gene expression quantification of cell cycle regulators, and cytokinesis-block cytome assay to determine nuclear division rate. DiOHF decreased OS cell growth and viability in a concentration-dependent manner. Its combination with Dox enabled Dox dose reduction in both cell lines, with synergistic interactions in U2OS cells. Although no significant apoptotic effects were detected at low concentrations, cytostatic effects were demonstrated in both cell lines. Incubation with DiOHF altered cell cycle dynamics and resulted in differential cyclin and cyclin-dependent kinase expression. Overall, this study presents an antiproliferative action of DiOHF in OS combination therapy via modulation of the cell cycle and nuclear division.

The dipeptidyl peptidase-4 inhibitory effect of flavonoids is hindered in protein rich environments.

Dipeptidyl peptidase-4 (DPP-4) inhibitors present a unique approach for the management of type 2 diabetes (T2D). In the present study, the inhibition of DPP-4 was evaluated for a large panel of flavonoids, important components of the human diet, using in vitro and ex vivo models. The activity of the isolated enzyme was assayed in vitro. Subsequently, the most active flavonoids were tested ex vivo in human whole blood and plasma. In this study, contrary to the in vitro fluorometric tests, flavonoids did not show inhibitory activity against DPP-4. Due to the discrepancy in the results between the in vitro and ex vivo approaches, plasma protein binding values were determined, presenting values from 43.9 to 100.0%. This work provides a new insight into the inhibitory activity for DPP-4, based on the flavonoid scaffold. Additionally, the obtained results showed that the inhibitory effect of flavonoids against DPP-4 was hindered in protein rich environments, like that occurring in blood, and indicated the need for experimental refinement in drug discovery for blood targets.

Immunomodulatory Effects of Flavonoids in the Prophylaxis and Treatment of Inflammatory Bowel Diseases: A Comprehensive Review.

Inflammatory Bowel Diseases (IBD) comprised of two disorders of idiopathic chronic intestinal inflammation that affect about three million people worldwide: Crohn's disease and ulcerative colitis. Nowadays, the first-line of treatment for patients with mild to moderate symptoms of IBD is comprised of corticosteroids, immunosuppressants, antibiotics, and biological agents. Unfortunately, none of these drugs are curative, and their long-term use may cause severe side effects and complications. Almost 40% of IBD patients use alternative therapies to complement the conventional one, and flavonoids are gaining attention for this purpose. The biological properties of flavonoids are well documented and their antioxidant and anti-inflammatory activities have been arousing attention in the scientific community. Flavonoids are the most widely distributed polyphenols in plants and fruits, making part of the human diet. Taking into account that all ingested flavonoids are expected to exert biological actions at the gastrointestinal level, research on the modulatory effect of these compounds in IBD is of paramount importance. This review intends to summarize, in an integrated and comprehensive form, the effect of flavonoids, both in vitro and in vivo, in the different phases of the characteristic IBD inflammatory network.

Chlorinated Flavonoids Modulate the Inflammatory Process in Human Blood.

Flavonoids are known to react with neutrophil-generated hypochlorous acid (HOCl) at inflammation loci to form stable mono- and dichlorinated products. Some of these products have been shown to retain or even enhance their inflammatory potential, but further information is required in a broader approach to inflammatory mechanisms. In that sense, we performed an integrated evaluation on the anti-inflammatory potential of a panel of novel chlorinated flavonoids and their parent compounds, in several steps of the complex inflammatory cascade, namely, in the activity of cyclooxygenase (COX)-1 and COX-2, and in the production of cytokines [interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)], and the chemokine, IL-8, as well as in the production of reactive species, using human whole blood as a representative in vitro model, establishing, whenever possible, a structure-activity relationship. Although luteolin was the most active compound, chlorinated flavonoids demonstrated a remarkable pattern of activity for the resolution of the inflammatory processes. Our results demonstrated that 6-chloro-3',4',5,7-tetrahydroxyflavone deserves scientific attention due to its ability to modulate the reactive species and cytokines/chemokine production. In this regard, the therapeutic potential of flavonoids' metabolites, and in this particular case the chlorinated flavonoids, should not be neglected.

Combined dual effect of modulation of human neutrophils' oxidative burst and inhibition of colon cancer cells proliferation by hydroxycinnamic acid derivatives.

Colon cancer is one of the most incident cancers in the Western World. While both genetic and epigenetic factors may contribute to the development of colon cancer, it is known that chronic inflammation associated to excessive production of reactive oxygen and nitrogen species by phagocytes may ultimately initiate the multistep process of colon cancer development. Phenolic compounds, which reveal antioxidant and antiproliferative activities in colon cancer cells, can be a good approach to surpass this problem. In this work, hydroxycinnamic amides and the respective acid precursors were tested in vitro for their capacity to modulate human neutrophils' oxidative burst and simultaneously to inhibit growth of colon cancer cells. A phenolic amide derivative, caffeic acid hexylamide (CAHA) (4) was found to be the most active compound in both assays, inhibiting human neutrophils' oxidative burst, restraining the inflammatory process, inhibiting growth of colon cancer cells and triggering mitochondrial dysfunction that leads cancer cells to apoptosis. Altogether, these achievements can contribute to the understanding of the relationship between antioxidant and anticancer activities and based on the structure-activity relationships (SAR) established can be the starting point to find more effective phenolic compounds as anticancer agents.