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Journal of Xenobiotics May 2024Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome... (Review)
Review
Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome (cyt )'s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1's involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI).
PubMed: 38804287
DOI: 10.3390/jox14020034 -
Scientific Reports May 2024Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years,...
A novel combinatorial approach using sulforaphane- and withaferin A-rich extracts for prevention of estrogen receptor-negative breast cancer through epigenetic and gut microbial mechanisms.
Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years, dietary prevention of BC with epigenetically active phytochemicals has received increased attention due to its feasibility, effectiveness, and ease of implementation. In this regard, combinatorial phytochemical intervention enables more efficacious BC inhibition by simultaneously targeting multiple tumorigenic pathways. We, therefore, focused on investigation of the effect of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich Ashwagandha (Ash) combination on BC prevention in estrogen receptor-negative [ER(-)] mammary cancer using transgenic mice. Our results indicated that combinatorial BSp + Ash treatment significantly reduced tumor incidence and tumor growth (~ 75%) as well as delayed (~ 21%) tumor latency when compared to the control treatment and combinatorial BSp + Ash treatment was statistically more effective in suppressing BC compared to single BSp or Ash intervention. At the molecular level, the BSp and Ash combination upregulated tumor suppressors (p53, p57) along with apoptosis associated proteins (BAX, PUMA) and BAX:BCL-2 ratio. Furthermore, our result indicated an expressional decline of epigenetic machinery HDAC1 and DNMT3A in mammary tumor tissue because of combinatorial treatment. Interestingly, we have reported multiple synergistic interactions between BSp and Ash that have impacted both tumor phenotype and molecular expression due to combinatorial BSp and Ash treatment. Our RNA-seq analysis results also demonstrated a transcriptome-wide expressional reshuffling of genes associated with multiple cell-signaling pathways, transcription factor activity and epigenetic regulations due to combined BSp and Ash administration. In addition, we discovered an alteration of gut microbial composition change because of combinatorial treatment. Overall, combinatorial BSp and Ash supplementation can prevent ER(-) BC through enhanced tumor suppression, apoptosis induction and transcriptome-wide reshuffling of gene expression possibly influencing multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.
Topics: Isothiocyanates; Animals; Withanolides; Sulfoxides; Female; Mice; Epigenesis, Genetic; Breast Neoplasms; Gastrointestinal Microbiome; Mice, Transgenic; Plant Extracts; Receptors, Estrogen; Humans; Brassica; Histone Deacetylase 1; Gene Expression Regulation, Neoplastic; Anticarcinogenic Agents
PubMed: 38802425
DOI: 10.1038/s41598-024-62084-1 -
Frontiers in Pharmacology 2024Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since... (Review)
Review
Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since tumor development and chronic inflammation are linked, sharing common signaling pathways. At least 20% of breast and colorectal cancers are associated with chronic inflammation triggered by infections, irritants, or autoimmune diseases. Obesity, chronic inflammation, and cancer interconnection underscore the importance of population-based interventions in maintaining healthy body weight, to disrupt this axis. Given that the dietary inflammatory index is correlated with an increased risk of cancer, adopting an anti-inflammatory diet supplemented with nutraceuticals may be useful for cancer prevention. Natural products and their derivatives offer promising antitumor activity with favorable adverse effect profiles; however, the development of natural bioactive drugs is challenging due to their variability and complexity, requiring rigorous research processes. It has been shown that combining anti-inflammatory products, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins, with plant-derived products demonstrate clinical utility as accessible adjuvants to traditional therapeutic approaches, with known safety profiles. Pharmacological approaches targeting multiple proteins involved in inflammation and cancer pathogenesis emerge as a particularly promising option. Given the systemic and multifactorial nature of inflammation, comprehensive strategies are essential for long term success in cancer therapy. To gain insights into carcinogenic phenomena and discover diagnostic or clinically relevant biomarkers, is pivotal to understand genetic variability, environmental exposure, dietary habits, and TME composition, to establish therapeutic approaches based on molecular and genetic analysis. Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type compounds as potential therapeutic targets or biomarkers requires further investigation. This review aims to elucidate the role of specific etiological agents and mediators contributing to persistent inflammatory reactions in tumor development. It explores potential therapeutic strategies for cancer treatment, emphasizing the urgent need for cost-effective approaches to address cancer-associated inflammation.
PubMed: 38799159
DOI: 10.3389/fphar.2024.1385479 -
Nature Communications May 2024To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient...
To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2 mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.
Topics: Animals; Male; Mice; Carnitine O-Palmitoyltransferase; Cholesterol; Fasting; Golgi Apparatus; Hepatocytes; Homeostasis; Lipid Metabolism; Liver; Mice, Inbred C57BL; Mice, Knockout; rab GTP-Binding Proteins; Triglycerides
PubMed: 38796472
DOI: 10.1038/s41467-024-48959-x -
Nutrients May 2024Long-term exposure to even slightly elevated plasma cholesterol levels significantly increases the risk of developing cardiovascular disease. The latest evidence... (Review)
Review
Long-term exposure to even slightly elevated plasma cholesterol levels significantly increases the risk of developing cardiovascular disease. The latest evidence recommends an improvement in plasma lipid levels, even in children who are not affected by severe hypercholesterolemia. The risk-benefit profile of pharmacological treatments in pediatric patients with moderate dyslipidemia is uncertain, and several cholesterol-lowering nutraceuticals have been recently tested. In this context, the available randomized clinical trials are small, short-term and mainly tested different types of fibers, plant sterols/stanols, standardized extracts of red yeast rice, polyunsaturated fatty acids, soy derivatives, and some probiotics. In children with dyslipidemia, nutraceuticals can improve lipid profile in the context of an adequate, well-balanced diet combined with regular physical activity. Of course, they should not be considered an alternative to conventional lipid-lowering drugs when necessary.
Topics: Humans; Dietary Supplements; Child; Hypercholesterolemia; Cholesterol; Anticholesteremic Agents; Dyslipidemias; Phytosterols; Randomized Controlled Trials as Topic; Pediatrics; Cardiovascular Diseases
PubMed: 38794764
DOI: 10.3390/nu16101526 -
Nutrients May 2024HDL-cholesterol quality, including cholesterol distribution in HDL subfractions, is emerging as a key discriminant in dictating the effects of these lipoproteins on...
HDL-Cholesterol Subfraction Dimensional Distribution Is Associated with Cardiovascular Disease Risk and Is Predicted by Visceral Adiposity and Dietary Lipid Intake in Women.
HDL-cholesterol quality, including cholesterol distribution in HDL subfractions, is emerging as a key discriminant in dictating the effects of these lipoproteins on cardiovascular health. This study aims at elucidating the relationship between cholesterol distribution in HDL subfractions and CVD risk factors as well as diet quality and energy density in a population of pre- and postmenopausal women. Seventy-two women aged 52 ± 6 years were characterized metabolically and anthropometrically. Serum HDL-C subfractions were quantified using the Lipoprint HDL System. Cholesterol distribution in large HDL subfractions was lower in overweight individuals and study participants with moderate to high estimated CVD risk, hypertension, or insulin resistance. Cholesterol distribution in large, as opposed to small, HDL subfractions correlated negatively with insulin resistance, circulating triglycerides, and visceral adipose tissue (VAT). VAT was an independent positive and negative predictor of cholesterol distribution in large and small HDL subfractions, respectively. Furthermore, an increase in energy intake could predict a decrease in cholesterol levels in large HDL subfractions while lipid intake positively predicted cholesterol levels in small HDL subfractions. Cholesterol distribution in HDL subfractions may represent an additional player in shaping CVD risk and a novel potential mediator of the effect of diet on cardiovascular health.
Topics: Humans; Female; Middle Aged; Cardiovascular Diseases; Cholesterol, HDL; Intra-Abdominal Fat; Dietary Fats; Heart Disease Risk Factors; Obesity, Abdominal; Insulin Resistance; Risk Factors; Adult; Triglycerides; Diet
PubMed: 38794763
DOI: 10.3390/nu16101525 -
Nutrients May 2024Atherosclerosis is closely associated with metabolic disorders such as cholesterol accumulation, bile acid metabolism, and gut dysbiosis. Neoagarotetraose...
Atherosclerosis is closely associated with metabolic disorders such as cholesterol accumulation, bile acid metabolism, and gut dysbiosis. Neoagarotetraose supplementation has been shown to inhibit obesity and alleviate type 2 diabetes, but its effects on modulating the development of atherosclerosis remain unexplored. Therefore, the present study was conducted to investigate the protective effects and potential mechanisms of neoagarotetraose on high-fat, high-cholesterol diet (HFHCD)-induced atherosclerosis in ApoE mice. The results showed that neoagarotetraose supplementation decreased the atherosclerotic lesion area by 50.1% and the aortic arch lesion size by 80.4% compared to the HFHCD group. Furthermore, neoagarotetraose supplementation led to a significant reduction in hepatic lipid content, particularly non-high-density lipoprotein cholesterol. It also resulted in a substantial increase in total bile acid content in both urine and fecal samples by 3.0-fold and 38.7%, respectively. Moreover, neoagarotetraose supplementation effectively downregulated the intestinal farnesoid X receptor by 35.8% and modulated the expressions of its associated genes in both the liver and intestine. In addition, correlation analysis revealed strong associations between gut microbiota composition and fecal bile acid levels. These findings highlight the role of gut microbiota in neoagarotetraose-mitigating atherosclerosis in HFHCD-fed ApoE mice. This study indicates the potential of neoagarotetraose as a functional dietary supplement for the prevention of atherosclerosis.
Topics: Animals; Atherosclerosis; Bile Acids and Salts; Mice; Cholesterol; Gastrointestinal Microbiome; Apolipoproteins E; Diet, High-Fat; Male; Liver; Mice, Inbred C57BL; Mice, Knockout; Disease Models, Animal; Lipid Metabolism; Dietary Supplements; Feces; Mice, Knockout, ApoE; Receptors, Cytoplasmic and Nuclear
PubMed: 38794740
DOI: 10.3390/nu16101502 -
Nutrients May 2024Older adults living in nursing homes (NH) are considered a population group that could be at risk in terms of nutrition, even more so than their community-dwelling...
Older adults living in nursing homes (NH) are considered a population group that could be at risk in terms of nutrition, even more so than their community-dwelling peers. Evidence on the nutritional status of NH residents is scarce, as they are commonly excluded from population-based dietary studies. This is also the case in Slovenia. In the presented pilot study, we assessed the intake of macronutrients as well as the intake and status of vitamin D and vitamin B12 on a sample of NH and NH daycare center users to explore the need for a larger representative study. The pilot study included 37 participants from three Slovenian NH (20 participants) and their daycare centers (17 participants). Daycare centers offer daytime care services for older adults, where users are also provided with major meals during their stay. Intakes of energy and nutrients were estimated by three 24 h dietary records. Fasting blood samples were collected for the assessment of vitamin D and vitamin B12 status. Over 90% of the participants had daily energy and protein intakes below recommendations (reference values: energy intake: males 2100 kcal and females 1700 kcal; protein intake > 1 g/kg body mass). The males' median daily intakes of vitamin D were 1.7 µg (1.5 µg females), and 2.3 µg for vitamin B12 (2.0 µg females). None of the participants had adequate vitamin D intake (>20 µg), and 92.3% males and 87.5% females had inadequate vitamin B12 intake (<4 µg). The prevalence of vitamin D deficiency (serum 25-OH-D conc. < 30 nmol/L) was 100% among NH residents and 53% among NH daycare center users. The prevalence of vitamin B12 deficiency was found in 20% of NH residents. The study results highlighted that certain nutrients might be critical in this population, especially among NH residents; however, a more thorough investigation with the inclusion of other important markers of nutritional status should be performed on a larger, representative sample to support the development and implementation of appropriate public health interventions.
Topics: Humans; Female; Pilot Projects; Male; Nursing Homes; Vitamin B 12; Nutritional Status; Aged; Vitamin D; Aged, 80 and over; Vitamin D Deficiency; Slovenia; Nutrients; Energy Intake; Homes for the Aged; Vitamin B 12 Deficiency; Diet; Nutrition Assessment
PubMed: 38794733
DOI: 10.3390/nu16101495 -
Nutrients May 2024A paucity of vitamin D is a common deficiency globally, with implications for many aspects of health besides the well-known impact on musculoskeletal health. The two...
A paucity of vitamin D is a common deficiency globally, with implications for many aspects of health besides the well-known impact on musculoskeletal health. The two sources of vitamin D are through oral intake, or through endogenous synthesis in the skin when exposed to ultraviolet radiation in sunlight. Assessing nutritional needs, whether by food, food fortification or supplementation, is aided by an understanding of local potential for cutaneous synthesis of the vitamin, dependent on latitude and climate, personal skin type and local culture. To aid these discussions we provide indicative exposure times for the maintenance of vitamin D status as a function of latitude, month and skin type, for the clear-sky case and all-sky conditions, for an ambulatory person wearing modest skirt/shorts and T-shirt. At latitudes greater than ±40 degrees, lack of available sunlight limits vitamin D synthesis in some months for all, while at the equator exposure times range from 3 to 15 min at noontime, for white and black skin, respectively. Rather than a sun exposure prescription, the data are intended to show where nutritional vitamin D intake is necessary, advisable, or can be mitigated by sun exposure, and allows for such advice to be personalized to account for different sub-groups in a multicultural population.
Topics: Humans; Dietary Supplements; Nutritional Status; Seasons; Skin; Sunlight; Time Factors; Ultraviolet Rays; Vitamin D; Vitamin D Deficiency
PubMed: 38794727
DOI: 10.3390/nu16101489 -
Nutrients May 2024Cardiovascular disease risk throughout the life course is increased by abnormal blood lipid levels in youth. The dietary glycemic index (GI) and glycemic load (GL)...
Cardiovascular disease risk throughout the life course is increased by abnormal blood lipid levels in youth. The dietary glycemic index (GI) and glycemic load (GL) during adolescence might be related to abnormal blood lipids. This study aimed to analyze the association between dietary GI, GL and dyslipidemia in adolescents from two marginalized regions of Chiapas, Mexico. A cross-sectional study was conducted with 213 adolescents. Food intake was assessed using 24 h recalls. The association between dyslipidemia and dietary GI or GL was tested by using logistic regression models. Low HDL-c was the most prevalent risk factor (47.4%), followed by hypertriglyceridemia (25.4%). In this population, overall dietary GI was not associated with dyslipidemia. A high dietary GL was associated with 2.39 higher odds of low HDL-c (95% CI: 1.21-4.74) when compared to low GL. Female adolescents with high dietary GL had 3.20 higher odds of hypertriglyceridemia (95% CI: 1.03-9.88), whereas no association was found for males. No associations were observed between overall dietary GL and total cholesterol or LDL-c. In adolescents from urban and rural communities in Chiapas, a high dietary GL was associated with a detrimental effect on HDL-c. In female adolescents, high GL was associated with hypertriglyceridemia.
Topics: Humans; Adolescent; Female; Male; Mexico; Dyslipidemias; Cross-Sectional Studies; Glycemic Load; Glycemic Index; Cholesterol, HDL; Diet; Risk Factors; Hypertriglyceridemia; Prevalence; Logistic Models
PubMed: 38794721
DOI: 10.3390/nu16101483