Metabolic effects of quercetin on inflammatory and autoimmune responses in rheumatoid arthritis are mediated through the inhibition of JAK1/STAT3/HIF-1α signaling.

BACKGROUND: Rheumatoid arthritis, a chronic autoimmune disease, is characterized by synovial hyperplasia and cartilage erosion. Here, we investigated the potential mechanism of action of quercetin, the main component of flavonoids, in treating rheumatoid arthritis. OBJECT: To examine the anti-arthritic effects of quercetin and elucidate the specific mechanisms that differentiate its metabolic effects on autoimmune and inflammatory responses at the synovial cell level. METHODS: We created a collagen-induced arthritis (CIA) model in Wistar rats, which were administered quercetin (50 or 100 mg/kg) continuously for four weeks via stomach perfusion. The arthritis score, histopathological staining, radiological assessment, and serum biochemical parameters were used to study the impact of quercetin on disease improvement. Additionally, immunofluorescence was employed to detect JAK1/STAT3/HIF-1α expression in rat joints. Moreover, the effects of quercetin (20, 40, and 80 µmol/L) on the properties and behavior of synovial fibroblasts were evaluated in an in vitro MH7A cell model using flow cytometry, CCK8, and transwell assays. Further, the mRNA expression levels of inflammatory cytokines IL1ß, IL6, IL17, and TNFα were assessed by quantitative real-time PCR. Glucose, lactate, lactate dehydrogenase, pyruvate, pyruvate dehydrogenase, and adenosine triphosphate assay kits were employed to measure the metabolic effects of quercetin on synovial fibroblasts. Finally, immunoblotting was used to examine the impact of quercetin on the JAK1/STAT3/HIF-1α signaling pathway in synovial fibroblasts. RESULTS: In vivo experiments confirmed the favorable effects of quercetin in CIA rats, including an improved arthritis score and reduced ankle bone destruction, in addition to a decrease in the pro-inflammatory cytokines IL-1ß, IL-6, IL-17, and TNF-α in serum. Immunofluorescence verified that quercetin may ameliorate joint injury in rats with CIA by inhibiting JAK1/STAT3/HIF-1α signaling. Various in vitro experiments demonstrated that quercetin effectively inhibits IL-6-induced proliferation of MH7A cells and reduces their migratory and invasive behavior, while inducing apoptosis and reducing the expression of the pro-inflammatory cytokines IL1ß, IL6, IL17, and TNFα at the mRNA level. Quercetin caused inhibition of glucose, lactate, lactate dehydrogenase, pyruvate, and adenosine triphosphate and increased pyruvate dehydrogenase expression in MH7A cells. It was further confirmed that quercetin may inhibit energy metabolism and inflammatory factor secretion in MH7A cells through JAK1/STAT3/HIF-1α signaling. CONCLUSIONS: Quercetin's action on multiple target molecules and pathways makes it a promising treatment for cartilage injury in rheumatoid arthritis. By reducing joint inflammation, improving joint metabolic homeostasis, and decreasing immune system activation energy, quercetin inhibits the JAK1/STAT3/HIF-1α signaling pathway to improve disease status.

Metabolic Effects of Liposuction on Glucose and Insulin Homeostasis with and Without Abdominal Fat Removal.

BACKGROUND: Liposuction is a common cosmetic procedure aimed at addressing localized fat deposits. While metabolic disruptions associated with adiposity are well documented, the specific impacts of liposuction on metabolic parameters remain unclear. MATERIALS AND METHODS: Seventeen individuals underwent liposuction inclusive of the abdominal area, while eleven underwent liposuction excluding the abdomen. Metabolic parameters including glucose, insulin, HOMA-IR, HbA1c, and C-peptide levels were measured preoperatively and postoperatively at 1, 3, and 6 months. RESULTS: Both groups exhibited significant postoperative reductions in glucose, insulin, HOMA-IR, HbA1c, and C-peptide levels. However, the abdominal liposuction group demonstrated more pronounced reductions of these variables. CONCLUSION: These findings suggest that addressing abdominal adiposity may provide greater metabolic benefits following liposuction. Further research is warranted to explore the long-term sustainability and clinical implications of these metabolic improvements with additional markers. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

The Effects of Growth Hormone Treatment Beyond Growth Promotion in Patients with Genetic Syndromes: A Systematic Review of the Literature.

Recombinant human growth hormone therapy (rhGH) has been widely accepted as the safe treatment for short stature in children with such genetic syndromes as Prader-Willi syndrome and Turner or Noonan syndrome. Some patients with short stature and rare genetic syndromes are treated with rhGH as growth hormone-deficient individuals or as children born small for their gestational age. After years of experience with this therapy in syndromic short stature, it has been proved that there are some aspects of long-term rhGH treatment beyond growth promotion, which can justify rhGH use in these individuals. This paper summarizes the data of a literature review of the effects of rhGH treatment beyond growth promotion in selected genetic syndromes. We chose three of the most common syndromes, Prader-Willi, Turner, and Noonan, in which rhGH treatment is indicated, and three rarer syndromes, Silver-Russel, Kabuki, and Duchenne muscular dystrophy, in which rhGH treatment is not widely indicated. Many studies have shown a significant impact of rhGH therapy on body composition, resting energy expenditure, insulin sensitivity, muscle tonus, motor function, and mental and behavioral development. Growth promotion is undoubtedly the primary benefit of rhGH therapy; nevertheless, especially with genetic syndromes, the additional effects should also be considered as important indications for this treatment.

Short-chain fatty acids as a link between diet and cardiometabolic risk: a narrative review.

AIM: Diet has a profound impact on cardiometabolic health outcomes such as obesity, blood glucose, blood lipids and blood pressure. In recent years, the gut microbiota has emerged as one of several potential key players explaining dietary effects on these outcomes. In this review we aim to summarise current knowledge of interaction between diet and gut microbiota focusing on the gut-derived microbial metabolites short-chain fatty acids and their role in modulating cardiometabolic risk. FINDINGS: Many observational and interventional studies in humans have found that diets rich in fibre or supplemented with prebiotic fibres have a favourable effect on the gut microbiota composition, with increased diversity accompanied by enhancement in short-chain fatty acids and bacteria producing them. High-fat diets, particularly diets high in saturated fatty acids, have shown the opposite effect. Several recent studies indicate that the gut microbiota modulates metabolic responses to diet in, e.g., postprandial blood glucose and blood lipid levels. However, the metabolic responses to dietary interventions, seem to vary depending on individual traits such as age, sex, ethnicity, and existing gut microbiota, as well as genetics. Studies mainly in animal models and cell lines have shown possible pathways through which short-chain fatty acids may mediate these dietary effects on metabolic regulation. Human intervention studies appear to support the favourable effect of short-chain fatty acid in animal studies, but the effects may be modest and vary depending on which cofactors were taken into consideration. CONCLUSION: This is an expanding and active field of research that in the near future is likely to broaden our understanding of the role of the gut microbiota and short-chain fatty acids in modulating metabolic responses to diet. Nevertheless, the findings so far seem to support current dietary guidelines encouraging the intake of fibre rich plant-based foods and discouraging the intake of animal foods rich in saturated fatty acids.

Metabolic effects of kidney donation: A Bayesian analysis of matched cohorts.

The kidney is a notable site of glycolysis, gluconeogenesis, and fatty acid oxidation. Loss of a kidney after kidney donation might, therefore, affect the glucose and lipid metabolism of the donors. This matched cohort study investigated the effect of nephrectomy on glucose and lipid metabolisms using Bayesian hypothesis testing. There were 77 pairs of matched donor-control pairs in the present study. Clinical and laboratory data of the participants, at baseline and 1-year, were extracted from electronic medical records. Comparisons between donor and control groups were performed using the Bayesian independent samples t-test or Bayesian Mann-Whitney test. The Bayes Factor for alternative hypothesis over null hypothesis (BF10 ) was used to compare the two competing hypotheses. The BF10 of 3 or more was considered evidence for the alternative hypothesis. Comparing changes from baseline to 1-year between donors and controls, the BF10 of triglycerides, high-density lipoprotein cholesterol (HDL-C), triglyceride-glucose (TyG) index of insulin resistance, and estimated glomerular filtration rate (eGFR) were 7.95, 3.96, 30.13, and 1.32 x 1041 , respectively signifying that the change of these variables in the donors differed from those in the controls (alternative hypothesis). Triglyceride, HDL-C, and TyG index of the donors increased more than those of the controls while eGFR of the donor decreased more than that of the controls. Our data suggest that triglycerides and insulin resistance increase after donor nephrectomy. Kidney donors should be informed about these metabolic changes and should adhere to lifestyle recommendations that may mitigate insulin resistance.

Invited review: Human, cow, and donkey milk comparison: Focus on metabolic effects.

Milk is an important food of the daily diet. Many countries include it in their dietary recommendations due to its content in several important nutrients that exert beneficial effects on human health. Human milk is a newborn's first food and plays an important role in the growth, development, and future health of every individual. Cow milk is the type of milk most consumed in the world. However, its relatively high content of saturated fats raises concerns about potential adverse effects on human health, although epidemiological studies have disproved this association. Indeed, dairy consumption appear to be linked to a lower risk of mortality and major cardiovascular disease events. In the last few years many researchers have begun to focus their attention on both the production and quality of cow milk as well as the analysis of milk from other animal species to evaluate their effect on human health. The need to investigate the composition and metabolic effects of milk from other animal species arises from the adverse reactions of individuals in several groups to certain components of cow milk. It has emerged that donkey milk compared with that of other animal species, is the nearest to human milk and an excellent substitute for it. Milk from various animal species shows substantial differences in nutritional composition and distinct metabolic effects. In this review, we discussed the main compositional features and metabolic effects of 3 types of milk: human, cow, and donkey milk.

Effects of single and multiple sessions of lower body diastole-synchronized compressions using a pulsating pneumatic suit on endothelium function and metabolic parameters in patients with type 2 diabetes: two controlled cross-over studies.

BACKGROUND: Endothelium function is often impaired in patients with type 2 diabetes. We hypothesized that by improving endothelial function using diastole-synchronized compressions/decompressions (DSCD) to the lower body may improve the metabolic profile. The objective of this research was to evaluate the effects of single and multiple DSCD sessions on microcirculation, endothelium function and metabolic parameters of patients with type 2 diabetes. METHODS: Two monocentric, controlled, randomized cross-over studies (Study 1 and Study 2) were performed. In Study 1, 16 patients received one 20 min DSCD and one simulated (control) session at 2 week intervals; continuous glucose monitoring and cutaneous blood flow were recorded continuously before, during and after DSCD or Control session; other vascular assessments were performed before and after DSCD and control sessions. In Study 2, 38 patients received 60 min DSCD sessions three times/week for three months followed by a 4-6 week washout and 3 month control period (without simulated sessions); vascular, metabolic, body composition, physical activity and quality of life assessments were performed before and after 3 months. RESULTS: Both studies showed significant, multiplex effects of DSCD sessions. In Study 1, cutaneous blood flow and endothelium function increased, and plasma and interstitial glucose levels after a standard breakfast decreased after DSCD sessions. In Study 2, cutaneous endothelium function improved, LDL-cholesterol and non-HDL cholesterol decreased, extra-cell water decreased and SF-36 Vitality score increased after 3 months of DSCD sessions. CONCLUSIONS: Our findings support the beneficial effect of DSCD on the endothelium and show concomitant beneficial metabolic and vitality effects. Future clinical trials need to test whether DSCD use translates into a preventive measure against microvascular diabetic complications and its progression. Trial registration ClinicalTrials.gov identifiers: NCT02293135 and NCT02359461.

The rapid transformation of triclosan in the liver reduces its effectiveness as inhibitor of hepatic energy metabolism.

Triclosan (5-chloro-2'-[2,4-dichlorophenoxi]-phenol) is a polychlorinated biphenolic antimicrobial, utilized as antiseptic and preservative in hygiene products and medical equipment. Triclosan causes mitochondrial dysfunction (uncoupling, inhibition of electron flow), as demonstrated in isolated rat liver mitochondria. These actions in the mitochondria could compromise energy-dependent metabolic fluxes in the liver. For this reason, the present work aimed at investigating how these effects on isolated mitochondria translate to the whole and intact hepatocyte. For accomplishing this, the isolated perfused rat liver was utilized, a system that preserves both microcirculation and the cell-to-cell interactions. In addition, the single-pass triclosan hepatic transformation was also evaluated by HPLC as well as the direct action of triclosan on gluconeogenic enzymes. The results revealed that triclosan decreased anabolic processes (e.g., gluconeogenesis) and increased catabolic processes (e.g., glycolysis, ammonia output) in the liver, generally with a complex pattern of concentration dependences. Unlike the effects on isolated mitochondria, which occur in the micromolar range, the effects on intact liver required the 10-5 to 10-4 M range. The most probable cause for this behavior is the very high single-pass transformation of triclosan, which was superior to 95% at the portal concentration of 100 µM. The concentration gradient along the sinusoidal bed is, thus, very pronounced and the response of the liver reflects mainly that of the periportal cells. The high rates of hepatic biotransformation may be a probable explanation for the low acute toxicity of triclosan upon oral ingestion.

Unhealthy Diets Induce Distinct and Regional Effects on Intestinal Inflammatory Signalling Pathways and Long-Lasting Metabolic Dysfunction in Rats.

The intestinal epithelium is a principal site for environmental agents' detection. Several inflammation- and stress-related signalling pathways have been identified as key players in these processes. However, it is still unclear how the chronic intake of inadequate nutrients triggers inflammatory signalling pathways in different intestinal regions. We aimed to evaluate the impact of unhealthy dietary patterns, starting at a younger age, and the association with metabolic dysfunction, intestinal inflammatory response, and obesity in adulthood. A rat model was used to evaluate the effects of the consumption of sugary beverages (HSD) and a Western diet (WD), composed of ultra-processed foods. Both diets showed a positive correlation with adiposity index, but a positive correlation was found between the HSD diet and the levels of blood glucose and triglycerides, whereas the WD diet correlated positively with triglyceride levels. Moreover, a distinct inflammatory response was associated with either the WD or HSD diets. The WD induced an increase in TLR2, TLR4, and nuclear factor-kappa B (NF-κB) intestinal gene expression, with higher levels in the colon and overexpression of the inducible nitric oxide synthase. In turn, the HSD diet induced activation of the TLR2-mediated NF-κB signalling pathway in the small intestine. Altogether, these findings support the concept that early intake of unhealthy foods and nutrients are a main exogenous signal for disturbances of intestinal immune mechanisms and in a region-specific manner, ultimately leading to obesity-related disorders in later life.

Effect of Older vs Younger Age on Anthropometric and Metabolic Variables During Treatment of Psychotic Depression With Sertraline Plus Olanzapine: The STOP-PD II Study.

OBJECTIVE: To examine the effect of older versus younger age on change in anthropometric and metabolic measures during extended treatment of psychotic depression with sertraline plus olanzapine. METHODS: Two hundred and sixty-nine men and women aged 18-85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. Weight, waist circumference and plasma lipids, glucose, HbA1c, and insulin were measured at regular intervals during the acute, stabilization and randomized phases of the study. Linear mixed models were used to analyze the trajectories of anthropometric and metabolic measures. RESULTS: Participants aged 60 years or older experienced less weight gain and less increase in cholesterol during the combined acute and stabilization phases of the study compared with those aged 18-59 years. At the acute-stabilization termination visit, mean weight in older participants was 6.5 lb. less than premorbid weight, whereas it was 17.9 lb. more than premorbid weight in younger participants. In the RCT, there was a significant interaction of treatment and age group for the trajectory of weight, but the post hoc tests that compared age groups within each treatment arm were not statistically significant. There were no clinically significant differences between younger and older participants in glycemic measures. CONCLUSION: Older patients with psychotic depression experienced less increase in weight and total cholesterol than their younger counterparts during acute and stabilization treatment with sertraline plus olanzapine. In the older group, weight gained during the acute and stabilization phases appeared to be partial restoration of weight lost during the index episode of depression, whereas weight gain in younger participants was not.

Adrenergic and metabolic effects of electrical weapons: review and meta-analysis of human data.

INTRODUCTION: Electronic control with the CEW (conducted electrical weapon) has gained widespread acceptance as the preferred force option due to its significant injury reduction. However, a CEW application does stress the human body. In the case of the CEW, the human body response is similar to the challenge of physical exercise combined with emotional stress over a very short time interval. There has been concern whether the tension of the skeletal-muscle system together with the emotional stress of being exposed to the effects of a CEW, can lead to severe metabolic dysfunction. METHODS: A systematic and careful search of the MedLine database was performed to find publications describing pathophysiological effects of CEWs. Additional publications were collected through a manual search of reference lists in retrieved articles. After preliminary exclusions, we carefully reviewed the remaining publications and found 24 papers reporting prospective human clinical research data on adrenergic, ventilation, or metabolic effects. Where there were multiple studies on the same endpoints, we performed meta-analyses. RESULTS: A CEW exposure provides a clinically insignificant increase in heart rate (7.5 BPM) and a drop in both systolic and diastolic blood pressure. Alpha-amylase goes down but cortisol levels increase-both epinephrine and norepinephrine levels are increased by levels similar to mild exercise. A CEW exposure increases ventilation but does not appear to interfere with gas exchange. Lactate is increased slightly while the pH is decreased slightly with changes equivalent to mild exercise. The lactate and pH changes appear quickly and do not appear to be affected by increasing the exposure duration from 5 to 30 s. CONCLUSIONS: Thorough review and meta-analyses show that electrical weapon exposures have mixed and mild adrenergic effects. Ventilation is increased and there are metabolic changes similar to mild exercise.

Raspberry Polyphenolic Extract Regulates Obesogenic Signals in Hepatocytes.

The aim of this in vitro study was to examine the effect of raspberry polyphenolic extract on the immune-metabolic molecular mechanisms activated by obesity-related signals in hepatocytes (HB-8965®). Alterations in endosomal/lysosomal activity (neutral red uptake assay, NR), the expression of selected genes involved with lipid oxidation, and metabolism and inflammation processes in the liver were studied. Hepatocytes were treated with plasma collected from Wistar rats that were fed a high-fat diet (HF), raspberry polyphenolic extract (PP), serine-type protease inhibitors as an agonist of TLR4 (TD) or a combination of PP with HF or TD treatments. The PP added to the experimental treatments modulated hepatic immune-metabolic mechanisms through the upregulation of STAT1, ANGPTL4, and CD44, as well as considerably reducing the NR uptake and downregulation of COX-2 and the multifunctional protein AhR. The kinetic analysis of AhR expression revealed that HF-related molecular mechanisms activated AhR mRNA expression earlier than PP initiated the regulatory effect. In conclusion, PP might be considered a valuable dietary agent that regulates obesity-related signals in hepatocytes. Moreover, taking AhR kinetic behavior into consideration, it can be assumed that PP might modulate the severity of the HF-induced downstream metabolic signaling of AhR.

Use of herbal extract from Artemisia herba-alba (Shih) in pharmaceutical preparations for dental hygiene.

Antibiotic resistance in bacterial species is opening new avenues to search for alternative modes of antimicrobial treatment, medicinal plant extracts being one among them. The aim of this study was to access the possibility of medicinal plant extract from Shih in the manufacture of pharmaceutical preparations for oral hygiene specifically for the prevention and treatment of dental caries due to Streptococcus mutans. Antimicrobial effects of crude organic extract of Shih on S. mutans isolated from the saliva were examined by taking S. mutans with culture media only (-ve control); S. mutans treated with the antibiotic gentamicin (+ve control) and S. mutans treated with Shih. Minimal Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) were Determination by Iodonitrotetrazolium chloride (INT) colorimetric assay Time-kill dynamic assay was performed using broth microdilution method. The metabolic reason behind the bacteriostatic and bactericidal effect were studied by measuring the glucose utilization by the microbes, pH as a measure of acid production, nucleic acids quantitation to check the DNA status and inhibition of water-insoluble glucan synthesis were undertaken. Shih MIC for S. mutans was at 2.5 mg/ml and MBC was 4 mg/ml. S. mutans bacterial population started reclining within 60 min of incubation with Shih at MBC. Utilization of added glucose was very high at MIC due to bacteria overcoming the stress, whereas at MBC its utilization was less. Accordingly pH also became acidic to 2.9 with MIC and 4.03 with MBC. There was a great degree of inhibition in the formation of nucleic acids indicating this crude extract interferes with DNA replication. Inhibition of glucan synthesis was to the tune of 45% as compared to control. Thus we conclude that Shih has potentially effective antibacterial activity hence it can be proposed as a potentially effective antiplaque and anticariogenic agent in the form of mouth wash or gum paint. However, the cytotoxicity of the extract needs to be evaluated in in-vitro and in-vivo conditions before it is considered as a safe antiplaque and anticariogenic agent.

Pegvisomant in acromegaly: an update.

BACKGROUND: In 2007, we published an opinion document to review the role of pegvisomant (PEG) in the treatment of acromegaly. Since then, new evidence emerged on the biochemical and clinical effects of PEG and on its long-term efficacy and safety. AIM: We here reviewed the emerging aspects of the use of PEG in clinical practice in the light of the most recent literature. RESULTS: The clinical use of PEG is still suboptimal, considering that it remains the most powerful tool to control IGF-I in acromegaly allowing to obtain, with a pharmacological treatment, the most important clinical effects in terms of signs and symptoms, quality of life and comorbidities. The number of patients with acromegaly exposed to PEG worldwide has become quite elevated and the prolonged follow-up allows now to deal quite satisfactorily with many clinical issues including major safety issues, such as the concerns about possible tumour (re)growth under PEG. The positive or neutral impact of PEG on glucose metabolism has been highlighted, and the clinical experience, although limited, with sleep apnoea and pregnancy has been reviewed. Finally, the current concept of somatostatin receptor ligands (SRL) resistance has been addressed, in order to better define the acromegaly patients to whom the PEG option may be offered. CONCLUSIONS: PEG increasingly appears to be an effective and safe medical option for many patients not controlled by SRL but its use still needs to be optimized.

Impact of protein-rich meals on glycaemic response of rice.

Asians typically consume carbohydrate-rich and high-glycaemic-index diets that have been associated with an increased risk of developing type 2 diabetes. Rice is rarely eaten alone such that it is of interest to investigate the effects of co-ingesting different protein-rich meals with rice on insulin and glycaemic response. This study had a randomised, controlled, non-blind, cross-over design in which fifteen healthy Chinese male participants were required to come on non-consecutive days. Five rice-based test meals were served: rice alone (control), rice with fish (RWF), rice with egg white (RWE), rice with soya beancurd (taukwa) (RWT) and rice with chicken (RWC). The control meal consisted of 50 g of available carbohydrate, whereas all other test meals contained additional 25 g of protein. RWT was the only meal that showed significantly lower glucose response when compared with the control (P<0·05). RWF and RWE had significantly higher insulin response, but no significant increase was observed in RWT and RWC when compared with the control (P<0·05). RWT and RWF showed significantly higher glucagon secretion as compared with the control (P<0·05). The four test meals studied showed varying effects, with RWT showing the greatest reduction in glycaemic response. Therefore, the ingestion of soya beancurd with rice may have a direct impact on reducing the risk in Asians transiting from being pre-diabetics to diabetics.

Programming of metabolic effects in C57BL/6JxFVB mice by in utero and lactational exposure to perfluorooctanoic acid.

Perfluorooctanoic acid (PFOA) is known to cause developmental toxicity and is a suggested endocrine disrupting compound (EDC). Early life exposure to EDCs has been implicated in programming of the developing organism for chronic diseases later in life. Here we study perinatal metabolic programming by PFOA using an experimental design relevant for human exposure. C57BL/6JxFVB hybrid mice were exposed during gestation and lactation via maternal feed to seven low doses of PFOA at and below the NOAEL used for current risk assessment (3-3000 µg/kg body weight/day). After weaning, offspring were followed for 23-25 weeks without further exposure. Offspring showed a dose-dependent decrease in body weight from postnatal day 4 to adulthood. Growth under high fat diet in the last 4-6 weeks of follow-up was increased in male and decreased in female offspring. Both sexes showed increased liver weights, hepatic foci of cellular alterations and nuclear dysmorphology. In females, reductions in perigonadal and perirenal fat pad weights, serum triglycerides and cholesterol were also observed. Endocrine parameters, such as glucose tolerance, serum insulin and leptin, were not affected. In conclusion, our study with perinatal exposure to PFOA in mice produced metabolic effects in adult offspring. This is most likely due to disrupted programming of metabolic homeostasis, but the assayed endpoints did not provide a mechanistic explanation. The BMDL of the programming effects in our study is below the current point of departure used for calculation of the tolerable daily intake.

Potential and real 'antineoplastic' and metabolic effect of metformin in diabetic and nondiabetic postmenopausal females.

AIM: The goal of this study was to determine if the single nucleotide polymorphisms marking potential sensitivity to metformin (MF) correlate with hormone-metabolic status as well as with actual response to MF in postmenopausal cancer patients with or without Type 2 diabetes mellitus and in diabetics without cancer. PATIENTS & METHODS: The carriage of ten different SNPs was evaluated in all patients by PCR, and hormone-metabolic status was estimated by anthropometry, ELISA and enzyme colorimetric assays. The response to daily 1-1.7 g of MF was studied based on hormone-metabolic parameters and indirect end points (endometrium thickness, mammographic breast density). RESULTS & CONCLUSION: The changes in evaluated 'antineoplastic' and metabolic response marker values were seen in 33.3 and 61.8% of the cases, respectively. Several genetic markers were found that showed an inclination to less frequent 'antineoplastic' or more frequent metabolic response to MF which may be helpful in further studies of this drug in cancer patients.

Exploring the Role of Circadian Rhythms in Sleep and Recovery: A Review Article.

Sleep is essential for every living organism. Humans spend about one-third of their lives sleeping. Sleep has been studied extensively, and the role of sleep in psychological, mental, and physical well-being is established to be the best. The rhythm of the brain between wakefulness and sleep is called the circadian rhythm, which is mainly controlled by melatonin and the pineal gland. The imbalance of this rhythm can lead to devastating effects on health. Vigorous workouts close to bedtime can interfere with falling asleep. Meal timing and composition can significantly affect sleep quality. It is advised to avoid large meals, caffeine, and alcohol before bedtime. Heavy meals close to bedtime can lead to poor sleep and hormone disruption. By following these guidelines enumerated in the article, individuals can improve sleep quality and overall health. Sleep cycles, especially rapid eye movement sleep, have a profound influence on mental and physical health. Adhering to recommended sleep practices enhances bodily restoration, fortifies the immune system, and upholds metabolic equilibrium. Sleep hygiene aligned with circadian rhythms is crucial for disease prevention and well-being. Healthcare professionals should prioritize sleep optimization strategies for patient care and public health.

Adherence to Recommended Metabolic Monitoring of Children and Adolescents Taking Second-Generation Antipsychotics.

OBJECTIVE: Clinical guidelines recommend periodic monitoring for adverse metabolic effects associated with second-generation antipsychotic medications. The authors sought to evaluate adherence to the guideline-recommended metabolic monitoring schedule for children and adolescents prescribed second-generation antipsychotics. METHODS: The authors used a national electronic medical records database for a retrospective study of children and adolescents ages 1-17 years (N=9,620) who were prescribed second-generation antipsychotics in January 2010-December 2018. Adherence to guideline-recommended monitoring of body mass index (BMI), blood glucose, and cholesterol was categorized as full, partial, and no monitoring. Full monitoring of patients was defined as strict metabolic monitoring, following the guideline-recommended schedule. Patients who received any monitoring, but not meeting the full monitoring criteria, were considered partially monitored. Three multinomial logistic regression models were fitted for each metabolic parameter to identify predictors associated with monitoring status. RESULTS: BMI was the metabolic parameter with the highest adherence to guideline-recommended monitoring (full monitoring, 4.7% of patients; partial monitoring, 44.8%), followed by blood glucose (full monitoring, 6.5%; partial monitoring, 29.4%) and cholesterol (full monitoring, 0.8%; partial monitoring, 22.4%). Being Black (vs. non-Black), having a comorbid mood disorder (vs. none), receiving olanzapine as the index second-generation antipsychotic (vs. aripiprazole), and receiving an antidepressant as a concurrent medication (vs. none) were associated with a higher likelihood of receiving both full and partial monitoring of all three metabolic parameters. CONCLUSIONS: Both full and partial adherence to guideline-recommended monitoring of children and adolescents prescribed second-generation antipsychotics were poor. However, children and adolescents at increased metabolic risk tended to be more closely monitored.

Farnesoid X Receptor Agonists: A Promising Therapeutic Strategy for Gastrointestinal Diseases.

Farnesoid X receptor (FXR) agonists have emerged as a promising therapeutic strategy for the management of various gastrointestinal (GI) diseases, including primary biliary cholangitis, nonalcoholic fatty liver disease, inflammatory bowel disease, alcohol-related liver disease, and primary sclerosing cholangitis. In this review, we discuss the mechanisms of action of FXR agonists, including their metabolic and immunomodulatory effects, and provide an overview of the clinical evidence supporting their use in the treatment of GI diseases. We also highlight the safety, adverse effects, and potential drug interactions associated with FXR agonists. While these agents have demonstrated efficacy in improving liver function, reducing hepatic steatosis, and improving histological endpoints in primary biliary cholangitis and nonalcoholic fatty liver disease, further research is needed to determine their long-term safety and effectiveness in other GI diseases, such as inflammatory bowel disease, alcohol-related liver disease, and primary sclerosing cholangitis. Additionally, the development of next-generation FXR agonists with improved potency and reduced side effects could further enhance their therapeutic potential.