Broadcasters, receivers, functional groups of metabolites, and the link to heart failure by revealing metabolomic network connectivity.

BACKGROUND AND OBJECTIVE: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline. METHODS: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. We incorporated the network structure into the identification of metabolites associated with HF to control the effect of confounding metabolites. RESULTS: We identified metabolites associated with higher and lower risk of HF incidence, such as glycine, ureidopropionic and glycocholic acids, and LPC 18:2. These associations were not confounded by the other metabolites due to uncovering the connectivity among metabolites and adjusting each association for the confounding metabolites. Examples of our findings include the direct influence of asparagine on glycine, both of which were inversely associated with HF. These two metabolites were influenced by polygenic factors and only essential amino acids, which are not synthesized in the human body and are obtained directly from the diet. CONCLUSION: Metabolites may play a critical role in linking genetic background and lifestyle factors to HF incidence. Revealing the underlying connectivity of metabolites associated with HF strengthens the findings and facilitates studying complex conditions like HF.

A review on interplay between small RNAs and oxidative stress in cancer progression.

Oxidative stress has been known to be the underlying cause in many instances of cancer development. The new aspect of cancer genesis that has caught the attention of many researchers worldwide is its connection to non-coding RNAs (ncRNAs). ncRNAs may not be protein coding, but in light of the more recent discovery of their wide range of functions, the term 'dark matter of the genome' has been rendered inapplicable. There is an extensive mention of colon cancer as an example, where some of these ncRNAs and their manipulations have seen significant progress. As of now, the focus is on discovering a non-invasive, cost-effective method for diagnosis that is easier to monitor and can be conducted before visible symptoms indicate cancer in a patient, by which time it may already be too late. The concept of liquid biopsies has revolutionized recent diagnostic measures. It has been possible to detect circulating parts of the cancer genome or other biomarkers in the patients' bodily fluids, resulting in the effective management of the disease. This has led these ncRNAs to be considered effective therapeutic targets and extrinsic modifications in several tumor types, proven to be effective as therapy. However, there is a vast scope for further understanding and pertinent application of our acquired knowledge and expanding it in enhancing the utilization of ncRNAs for a better prognosis, quicker diagnosis, and improved management of cancer. This review explores the prognosis of cancer and related mutations by scrutinizing small ncRNAs in the disease.

Benefits of aged garlic extract in modulating toxicity biomarkers against p-dimethylaminoazobenzene and phenobarbital induced liver damage in Rattus norvegicus.

Garlic (Allium sativum L.), a popular spice, has been used for decades in treating several medical conditions. Although Allicin, an active ingredient of garlic has been extensively studied on carcinogen-induced hepatotoxicity and oxidative stress in rats (Rattus norvegicus), no systematic study on the beneficial effects of generic aged garlic and specific aged garlic extract-Kyolic has been done. The present study involves rats fed chronically with two liver carcinogens, p-dimethylaminoazobenzene and phenobarbital, to produce hepatotoxicity. The aged garlic extract was characterized by UV-spectra, FTIR, HPLC and GC-MS. Biochemical and pathophysiological tests were performed by keeping suitable controls at four fixation intervals, namely, 30, 60, 90, and 120 days, utilizing several widely accepted toxicity biomarkers. Compared to the controls, remarkable elevation in the activities of lactate dehydrogenase, gamma glutamyl transferase and decline in catalase and glucose-6-phosphate dehydrogenase were observed in the carcinogen fed rats. Daily administration of aged garlic extract, could favorably modulate the elevated levels of various toxicity biomarkers including serum triglyceride, creatinine, urea, bilirubin, blood urea nitrogen except total cholesterol. It also altered the levels of blood glucose, HDL-cholesterol, albumin, AST, ALT, and hemoglobin contents in carcinogen intoxicated rats, indicating its protective potential against hepatotoxicity and oxidative stress in the experimental rats. Down-regulation of Bcl-2 and p53 proteins caused cell cycle arrest and apoptosis in garlic fed group. Kyolic exhibited additional benefits by arresting cell viability of cancer cells. This study would thus validate the use of aged garlic extract in the treatment of diseases causing liver toxicity including hepatocarcinoma.

Health hazards of nanoparticles: understanding the toxicity mechanism of nanosized ZnO in cosmetic products.

In recent years, nanoparticles are being used extensively in personal healthcare products such as cosmetics, sunscreens, soaps, and shampoos. Particularly, metal oxide nanoparticles are gaining competence as key industrial constituents, progressing toward a remarkable rise in their applications. Zinc oxide and titanium oxide nanoparticles are the most commonly employed metal oxide nanoparticles in sunscreens, ointments, foot care, and over the counter topical products. Dermal exposure to these metal oxides predominantly occurs through explicit use of cosmetic products and airway exposure to nanoparticle dusts is primarily mediated via occupational exposure. There is a compelling need to understand the toxicity effects of nanoparticles which can easily enter the cells and induce oxidative stress. Consequently, these products have become a direct source of pollution in the environment and thereby greatly impact our ecosystem. A complete understanding of the toxicity mechanism of nano-ZnO is intended to resolve whether and to what extent such nanoparticles may pose a threat to the environment and to human beings. In this review article, we have discussed the characteristics of metal oxide nanoparticles and its applications in the cosmetic industry. We have also highlighted about their toxicity effects and their impact on human health.

Aging and Oxidative Stress Decrease Pineal Elongation Factor 2: In Vivo Protective Effect of Melatonin in Young Rats Treated With Cumene Hydroperoxide.

We studied the alterations of Elongation Factor 2 (eEF2) in the pineal gland of aged rats as well as the possible protective role of exogenous melatonin on these changes in young rats treated with cumene hydroperoxide (CH), a compound that promotes lipid peroxidation and inhibits protein synthesis. The study was performed using male Wistar rats of 3 (control), 12, and 24 months and 3-month-old rats treated with CH, melatonin, and CH plus melatonin. We found that pineal eEF-2 is affected by aging and CH, these changes being prevented by exogenous melatonin in the case of CH-treated rats. The proteomic studies show that many other proteins are affected by aging and oxidative stress in the pineal gland. The results suggest that one of the possible mechanisms underlying pineal gland dysfunction during aging is the effect of lipid peroxidation on eEF-2, which is a key component of protein synthesis machinery. J. Cell. Biochem. 118: 182-190, 2017. © 2016 Wiley Periodicals, Inc.

Beneficial effect of refined red palm oil on lipid peroxidation and monocyte tissue factor in HCV-related liver disease: a randomized controlled study.

BACKGROUND: A large amount of endotoxin can be detected in the peripheral venous blood of patients with liver cirrhosis, contributing to the pathogenesis of hepatotoxicity because of its role in oxidative stress. The present study aimed to test the effect of the supplementation with red palm oil (RPO), which is a natural oil obtained from oil palm fruit (Elaeis guineensis) rich in natural fat-soluble tocopherols, tocotrienols and carotenoids, on lipid peroxidation and endotoxemia with plasma endotoxin-inactivating capacity, proinflammatory cytokines profile, and monocyte tissue factor in patients with chronic liver disease. METHODS: The study group consisted of sixty patients (34 males and 26 females; mean age 62 years, range 54-75) with Child A/B, genotype 1 HCV-related cirrhosis without a history of ethanol consumption, randomly enrolled into an 8-week oral daily treatment with either vitamin E or RPO. All patients had undergone an upper gastrointestinal endoscopy 8 months before, and 13 out of them showed esophageal varices. RESULTS: Both treatments significantly decreased erythrocyte malondialdehyde and urinary isoprostane output, only RPO significantly affected macrophage-colony stimulating factor and monocyte tissue factor. Liver ultrasound imaging did not show any change. CONCLUSIONS: RPO beneficially modulates oxidative stress and, not least, downregulates macrophage/monocyte inflammatory parameters. RPO can be safely advised as a valuable nutritional implementation tool in the management of chronic liver diseases.

Oxidative stress in patients with Alzheimer's disease: effect of extracts of fermented papaya powder.

Brain tissue is particularly susceptible to oxidative stress (OS). Increased production of reactive oxygen species (ROS), reduced antioxidant systems, and decreased efficiency in repairing mechanisms have been linked to Alzheimer's disease (AD). Postmortem studies in AD patients' brains have shown oxidative damage markers (i.e., lipid peroxidation, protein oxidative damage, and glycoxidation). Fermented papaya (FPP, a product of Carica papaya Linn fermentation with yeast) is a nutraceutical supplement with favorable effects on immunological, hematological, inflammatory, and OS parameters in chronic/degenerative diseases. We studied 40 patients (age 78.2 ± 1.1 years), 28 AD patients, and 12 controls. Urinary 8-OHdG was measured to assess OS. Twenty AD patients were supplemented with FPP (Immunage, 4.5 grams/day) for 6 months, while controls did not receive any treatment. At baseline, 8-OHdG was significantly higher in patients with AD versus controls (13.7 ± 1.61 ng/mL versus 1.6 ± 0.12 ng/mL, P < 0.01). In AD patients FPP significantly decreased 8-OHdG (14.1 ± 1.7 ng/mL to 8.45 ± 1.1 ng/mL, P < 0.01), with no significant changes in controls. AD is associated with increased OS, and FPP may be helpful to counteract excessive ROS in AD patients.

Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional carbon dioxide laser treatment.

Vaginal atrophy occurring during menopause is closely related to the dramatic decrease in ovarian estrogens due to the loss of follicular activity. Particularly, significant changes occur in the structure of the vaginal mucosa, with consequent impairment of many physiological functions. In this study, carried out on bioptic vaginal mucosa samples from postmenopausal, nonestrogenized women, we present microscopic and ultrastructural modifications of vaginal mucosa following fractional carbon dioxide (CO2) laser treatment. We observed the restoration of the vaginal thick squamous stratified epithelium with a significant storage of glycogen in the epithelial cells and a high degree of glycogen-rich shedding cells at the epithelial surface. Moreover, in the connective tissue constituting the lamina propria, active fibroblasts synthesized new components of the extracellular matrix including collagen and ground substance (extrafibrillar matrix) molecules. Differently from atrophic mucosa, newly-formed papillae of connective tissue indented in the epithelium and typical blood capillaries penetrating inside the papillae, were also observed. Our morphological findings support the effectiveness of fractional CO2 laser application for the restoration of vaginal mucosa structure and related physiological trophism. These findings clearly coupled with striking clinical relief from symptoms suffered by the patients before treatment.

Nonalcoholic fatty liver disease increases risk for gastroesophageal reflux symptoms.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is now recognized as a leading cause of liver dysfunction. Gastroesophageal reflux disease (GERD) is a common disorder causing symptoms that often impair patients' quality of life. In recent years, the prevalence of both these diseases has increased, partially overlapping the rise of metabolic disorders. AIMS: We investigated whether a relation does exist between NAFLD and GERD symptoms. METHODS: Cross-sectional study among 206 outpatients diagnosed with NAFLD and 183 controls. We collected clinical and laboratory data, assessed severity and frequency of GERD symptoms and the esophageal endoscopic pattern. RESULTS: The prevalence of GERD symptoms was higher in NAFLD patients than controls (61.2 vs. 27.9%, p < 0.001). We found a positive association between NAFLD and the experiencing of heartburn, regurgitation and belching. GERD symptoms were related to body mass index (BMI) and metabolic syndrome (MetS); a strong association persisted after adjustment for all the covariates (adjusted OR 3.49, 95 CI% 2.24-5.44, p < 0.001). CONCLUSIONS: Our data show that the prevalence of GERD typical symptoms is higher in patients with NAFLD. GERD was associated with higher BMI and MetS, but not with age and diabetes type 2. NAFLD remained strongly associated with GERD, independently of a coexisting MetS status. Consistent with these findings, MetS can be considered a shared background, but cannot completely explain this correlation. We suggest NAFLD as an independent risk factor for GERD symptoms.

Inflammatory Bowel Disease Therapies and Acute Liver Injury.

Drug-induced liver disease (DILI) represents one of the main problems in the therapeutic field. There are several non-modifiable risk factors, such as age and sex, and all drugs can cause hepatotoxicity of varying degrees, including those for the treatment of inflammatory bowel diseases (IBD). The aim of this review is to illustrate the adverse effects on the liver of the various drugs used in the treatment of IBD, highlighting which drugs are safest to use based on current knowledge. The mechanism by which drugs cause hepatotoxicity is not fully understood. A possible cause is represented by the formation of toxic metabolites, which in some patients may be increased due to alterations in the enzymatic apparatus involved in drug metabolism. Various studies have shown that the drugs that can most frequently cause hepatotoxicity are immunosuppressants, while mesalazine and biological drugs are, for the most part, less associated with such complications. Therefore, it is possible to assume that in the future, biological therapies could become the first line for the treatment of IBD.

Placebo-resistant gut bacteria: Akkermansia muciniphila spp. and Familial Mediterranean fever disease.

Introduction: Despite numerous investigations into the impact of drugs/probiotics on the gut microbiota composition in Familial Mediterranean Fever (FMF) patients, the question as to whether there exists a significant bacterial diversity(ies) independent of the placebo effect that can be reliably considered in clinical and nutritional trials remains unresolved. Methods: This study represents the in augural analysis of the placebo's influence on the gut microbiota of both healthy individuals and FMF afflicted men, utilizing previously collected data from PhyloChip™ DNA microarray experiments. A total of 15 healthy and 15 FMF male volunteers, aged 18 to 50, participated in this partially randomized placebo trial, which is accessible through the GEO Series accession number GSE111835. Results and Discussion: Key findings from current investigations include i. the anticipated divergence in gut bacteria resistance to placebo between healthy and FMF individuals, ii. the minor impact of placebo on gut bacterial diversities in healthy individuals, with Enterobacteriaceae diversities identified as placebo-resistant among "healthy" gut bacteria, and iii. the comprehensive influence of placebo on all bacterial phyla in the gut microbiome of FMF patients, extending to nearly all bacterial genera, except for the resilience of gut Akkermansia muciniphila spp. to placebo in FMF patients. This study underscores the susceptibility of Faecalibacterium, Blautia, and Clostridium genera to placebo. Consequently, this investigation holds significance for the proper design of placebo-controlled trials and establishes a foundation for further exploration of the gut-brain axis. Furthermore, it contributes valuable insights to discussions regarding proposals for probiotic therapies, particularly focusing on Faecalibacterium spp., Blautia spp., and Clostridium spp.

Diagnostic accuracy of enhanced liver fibrosis test to assess liver fibrosis in patients with chronic hepatitis C.

BACKGROUND: The prognosis and clinical management of patients with chronic liver diseases are closely related to the severity of liver fibrosis. Liver biopsy is considered the gold standard for the staging of liver fibrosis. However, it is an invasive test sometimes related to complications. This study aimed to assess the diagnostic value of enhanced liver fibrosis (ELF) test to predict liver fibrosis in patients with chronic hepatitis C. METHODS: This study included 162 patients with liver disease and 67 healthy controls. Hyaluronic acid, tissue inhibitor of matrix metalloproteinase type 1, and amino-terminal propeptide type III procollagen were measured by enzyme-linked immunosorbent assay with the ELF test ADVIA Centaur® (Siemens Healthcare Diagnostics Inc.). Fibrosis stage was determined using the Metavir scoring system. RESULTS: In our study, for the diagnosis of significant fibrosis (Metavir F≥2) a cut-off value >7.72 provides a sensitivity of 93.0% and a specificity of 83.0%. The areas under the receiver operator characteristic curve, sensitivity, specificity, and positive and negative predictive values were 0.94, 93.3%, 81.0%, 93.3%, and 81.0%, respectively (P<0.001). For the diagnosis of cirrhosis (Metavir F=4) a cut-off value >9.3 provides a sensitivity of 93.0% and a specificity of 86.0%. The areas under the receiver operator characteristic curve, sensitivity, specificity, and positive and negative predictive values were 0.94, 79.1%, 90.8%, 75.6%, and 92.3%, respectively (P<0.001). CONCLUSIONS: The ELF test is a promising non-invasive method for assessing liver fibrosis in patients with chronic hepatitis C. It is effective in the diagnosis of both fibrosis and cirrhosis.

Modulation of expression of Programmed Death-1 by administration of probiotic Dahi in DMH-induced colorectal carcinogenesis in rats.

UNLABELLED: Interaction of probiotic bacteria with the host immune system elicits beneficial immune modulating effects. Although, there are many published studies on interaction of probiotics with immune system focusing on activation of immune system by bacterial cell wall through the engagement of Toll-like receptor family; very few studies have focused on molecules involved in the T-cell activation, and not much work has been executed to study the correlation of probiotics and programmed death-1 in colorectal carcinogenesis in animal models. Hence, the present study was carried out to assess the effect of probiotic Dahi on expression of programmed death (PD-1) in colorectum of 1, 2-dimethylhydrazine treated Wistar rats. METHODS: DMH was injected subcutaneously at the rate of 40 mg/kg body weight per animal twice a week for 2 weeks. A total of 168 male Wistar rats were randomly allocated to seven groups, each group having twenty-four animals. The rats were euthanized at the 8th, 16th and 32nd week of the experiment and examined for the expression of PD-1 in colorectal tissues by immunohistochemical staining. RESULTS: Expression of PD-1 was observed in colorectal tissues of normal and DMH-treated rats. Feeding rats with probiotic Dahi or the treatment with piroxicam decreased the expression of PD-1 in DMH-induced colorectal mucosa, and the combined treatment with probiotic Dahi and piroxicam was significantly more effective in reducing the expression of PD-1. CONCLUSION: PD-1 expressed independent of carcinogen administration in normal colonic mucosa and may play a role in modulation of immune response in DMH-induced colorectal carcinogenesis. The present study suggests that probiotic Dahi can be used as an effective chemopreventive agent in the management of colorectal cancer.

Testing a novel bioactive marine nutraceutical on osteoarthritis patients.

Osteoarthritis (OA) is a slow, chronic joint disease characterized by focal degeneration of articular cartilage and alterations of the chemical and mechanical articular function and also major cause of pain and physical disability. There is clinical evidence that increasing dietary n-3 relative to n-6 may be beneficial in terms of symptom management in humans but not all studies conclude that dietary n-3 PUFA supplementation is of benefit, in the treatment of OA. Our recent studies highlight the effect of a biomarine compound (LD-1227) on MMPs, collagen metabolism and on chondrocyte inflammatory markers. Thus, the aim of the present work was to test such bioactive compound versus a common nutraceutical intervention (glucosamine/chrondroitin sulfate) in knee osteoarthritis patients. The patients population consisted of 60 subjects with a recent diagnosis of knee osteoarthririts of mild-moderate severity. Patients were randomized in a double-blind study comparing LD-1227 (group A) versus a mixture of glucosamine (500 mg), chondroitin sulfate (400 mg) (group B). Patients were allowed their established painkillers on demand. At 4, 9 and 18 weeks patients were evaluated as for: VAS score assessing pain at rest, and during physical exercise, Lequesne index, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale and KOOS scale. Moreover, serum concentrations of IL-6, IL-ß, CRP, TNF-sR1 and TNF-sR2 were assessed. As compared to GC treatment, LD-1227 yielded a quicker and higher degree of improvement of the whole clinical indexes and a lower NSAIDs use at the end of the study. LD-1227 brought about also a more significant downregulation of the tested cytokines cascade. Taken overall, these data suggest that LD-1227 has the potential to be included in the nutraceutical armamentarium in the management of OA.

A sturgeon-derived bioactive compound beneficially modulates nuclear receptors controlling metabolic functions in patients with metabolic syndrome.

The aim of the present study was to test the possible effects of a novel sturgeon-derived compound  (LD-1227) on inflammatory markers related to metabolic nuclear receptors in patients with metabolic syndrome. The study population consisted of 76 patients with metabolic syndrome and 30 healthy subjects who were maintained to their current treatments and randomly supplemented: A) LD-1227 (n=38) or B) placebo (n=38) as compared to C) healthy controls (n=30). LD-1227 or placebo (water-soluble starch) were given daily at breakfast and dinner for three months. Levels of hs-CRP, IL-6, TNF-α, leptin and adiponectin/ resistin index were assayed at the entry, 1 month and 3 months afterwards. At the end of the study period, as compared to B group, LD-1227-treated patients showed a significant improvement of all parameters tested, irrespective of the presence of diabetes. In particular, levels of adiponectin and adiponectin/ resistin index significantly increased following LD-1227 administration. Although the metabolic syndrome remains a multifaceted condition requiring a complex approach, LD-1227 could be a potential safe therapeutic tool to be integrated into a wider treatment and preventive medicine schedule strategy.

Treating Leaky Syndrome in the Over 65s: Progress and Challenges.

As we age, our organ functions gradually decline. Circulating factors in the blood and the integrity of organ barriers can become dysfunctional, resulting in a condition known as leaky syndrome. This condition involves the unregulated exchange or leakage of components between organs. However, the triggers of leaky syndrome, as well as its role in aging-related disorders and illnesses, remain largely unknown. In this editorial, we discuss potential mechanisms that originate from the gut and resident microbes (microbiome) to contribute in leaky syndrome. Furthermore, we explore how the food we consume can impact the development of leaky syndrome, potentially influencing the biology of aging and challenges to diagnose the leaky gut condition accurately and clinically.

Polycystic Ovary Syndrome: Etiology, Current Management, and Future Therapeutics.

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, typically characterized by anovulation, infertility, obesity, insulin resistance, and polycystic ovaries. Lifestyle or diet, environmental pollutants, genetics, gut dysbiosis, neuroendocrine alterations, and obesity are among the risk factors that predispose females to PCOS. These factors might contribute to upsurging metabolic syndrome by causing hyperinsulinemia, oxidative stress, hyperandrogenism, impaired folliculogenesis, and irregular menstrual cycles. Dysbiosis of gut microbiota may play a pathogenic role in the development of PCOS. The restoration of gut microbiota by probiotics, prebiotics, or a fecal microbiota transplant (FMT) might serve as an innovative, efficient, and noninvasive way to prevent and mitigate PCOS. This review deliberates on the variety of risk factors potentially involved in the etiology, prevalence, and modulation of PCOS, in addition to plausible therapeutic interventions, including miRNA therapy and the eubiosis of gut microbiota, that may help treat and manage PCOS.

Natural Compounds as Integrative Therapy for Liver Protection against Inflammatory and Carcinogenic Mechanisms: From Induction to Molecular Biology Advancement.

The liver is exposed to several harmful substances that bear the potential to cause excessive liver damage ranging from hepatitis and non-alcoholic fatty liver disease to extreme cases of liver cirrhosis and hepatocellular carcinoma. Liver ailments have been effectively treated from very old times with Chinese medicinal herbal formulations and later also applied by controlled trials in Japan. However, these traditional practices have been hardly well characterized in the past till in the last decades when more qualified studies have been carried out. Modern advances have given rise to specific molecular targets which are specifically good candidates for affecting the intricate mechanisms that play a role at the molecular level. These therapeutic regimens that mainly affect the progression of the disease by inhibiting the gene expression levels or by blocking essential molecular pathways or releasing cytokines may prove to play a vital role in minimizing the tissue damage. This review, therefore, tries to throw light upon the variation in the therapies for the treatment of benign and malignant liver disease from ancient times to the current date. Nonetheless, clinical research exploring the effectiveness of herbal medicines in the treatment of benign chronic liver diseases as well as prevention and treatment of HCC is still warranted.

The Emerging Role of Senotherapy in Cancer: A Comprehensive Review.

Senotherapy, a promising therapeutic strategy, has drawn a lot attention recently due to its potential for combating cancer. Senotherapy refers to the targeting of senescent cells to restore tissue homeostasis and mitigate the deleterious effects associated with senescence. Senolytic drugs represent a promising avenue in cancer treatment, with the potential to target and modulate senescent cells to improve patient outcomes. The review highlights the intricate interplay between the senescence-associated secretory phenotype (SASP) and the tumor microenvironment, emphasizing the role of senescent cells in promoting chronic inflammation, immune evasion, and tumor-cell proliferation. It then explores the potential of senotherapy as a novel strategy for cancer therapy. This review addresses the emerging evidence on the combination of senotherapy with conventional cancer treatments, such as chemotherapy and immunotherapy.