Underlying Mechanisms behind the Brain-Gut-Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update.

Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain-gut-liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain-gut-liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines.

Green coffee: economic relevance and a systematic review of the effects on human health.

Coffee is probably the most popular beverage after water and is an important component in diet and health since its consumption is high worldwide. Globally, it is the most relevant food commodity being just behind crude oil. Besides its pleasant flavor, it is an antioxidant source due to polyphenols, which are protective compounds against several diseases. This study aimed to evaluate the economic relevance and perform a systematic review of green coffee's effects on human health. Databases such as MEDLINE-PubMed, EMBASE, COCHRANE, and GOOGLE SCHOLAR were searched, and PRISMA guidelines were followed. Green coffee is considered a novel food product because consumers usually consume only roasted coffee. It can be marketed as such or as an extract. Due to the content of bioactive compounds, which are partially lost during the roasting process, the extracts are usually marketed concerning the potential regarding health effects. Green coffee can be used as dietary supplements, cosmetics, and pharmaceuticals, as a source of antioxidants. It can benefit human health, such as improvement in blood pressure, plasma lipids, and body weight (thus contributing to the improvement of risk components of Metabolic Syndrome). Moreover, benefits for cognitive functions may also be included.

The use of vitamin D for patients with inflammatory bowel diseases.

As Vitamin D (VD) plays an essential role in Inflammatory Bowel Diseases, this systematic review aimed to update the participation of this vitamin in the prevention or remission of these diseases. This review has included studies in MEDLINE-PubMed, EMBASE, and Cochrane databases. The authors have followed PRISMA (Preferred Reporting Items for a Systematic Review and Meta-analysis) guidelines. According to the inclusion and exclusion criteria, twenty-two randomized clinical trials were selected. In all, 1,209 patients were included in this systematic review: 1034 received only VD and 175 received VD in combination with calcium. The average doses of VD supplementation were from oral 400 IU daily to 10,000 IU per kilogram of body weight. Single injection of 300,000 IU of VD was also used. Several studies have shown the crucial role that VD plays in the therapeutic approach of IBD due to its effects on the immune system. It effectively decreased inflammatory cytokines such as TNF-α and IFN-γ (p<0.05) and provided a reduction in disease activity assessed through different scores such as Crohn's Disease Activity Index (CDAI) (p<0.05) and Ulcerative Colitis Disease Activity Index (UCDAI) (p<0.05). Unfortunately, the available clinical trials do not have standardization of doses and routes of administration. Existing meta-analyses are biased because they compare studies using different doses or treatments in combination with different drugs or supplements such as calcium. Even though VD has crucial effects on inflammatory processes, there is still a need for standardized studies to establish how the supplementation should be performed and the doses to be administered.

Organokines in Rheumatoid Arthritis: A Critical Review.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, respectively. This study aimed to perform a review to investigate the role of adipokines, osteokines, myokines, and hepatokines on RA progression. PubMed, Embase, Google Scholar, and Cochrane were searched, and 18 studies were selected, comprising more than 17,000 RA patients. Changes in the pattern of organokines secretion were identified, and these could directly or indirectly contribute to aggravating RA, promoting articular alterations, and predicting the disease activity. In addition, organokines have been implicated in higher radiographic damage, immune dysregulation, and angiogenesis. These can also act as RA potent regulators of cells proliferation, differentiation, and apoptosis, controlling osteoclasts, chondrocytes, and fibroblasts as well as immune cells chemotaxis to RA sites. Although much is already known, much more is still unknown, principally about the roles of organokines in the occurrence of RA extra-articular manifestations.

Exploring the logic and conducting a comprehensive evaluation of AdipoRon-based adiponectin replacement therapy against hormone-related cancers-a systematic review.

The potential benefits of adiponectin replacement therapy extend to numerous human diseases, with current research showing particular interest in its effectiveness against specific cancer forms, especially hormone-related. However, limitations in the pharmacological use of the intact protein have led to a focus on alternative options. AdipoRon is an extensively studied non-peptidic drug candidate for adiponectin replacement therapy. While researchers have explored the efficacy and therapeutic applications of AdipoRon in various disease conditions, their effects against cancer models advanced more, with no review regarding AdipoRon's efficacy against hormone-related cancers being published. The present systematic review aims to fill this gap. Preclinical evidence was compiled from PubMed, EMBASE, COCHRANE, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the manuscript's quality assessment was conducted using the Joanna Briggs Institute (JBI) Checklist Critical Appraisal Tool for Systematic Reviews' Quality. The included nine studies incorporated various cell and animal models of the pancreas, gynaecological system, and osteosarcoma cancers. AdipoRon demonstrated effectiveness against pancreatic cancer by activating p44/42 MAPK, mitochondrial dysfunction, and AMPK-mediated inhibition of ACC1. In gynaecological cancers, it exhibited promising anticancer effects through the activation of AMPK, potential inhibition of mTOR, and modulation of the SET1B/BOD1/AdipoR1 signaling cascade. Against osteosarcoma, AdipoRon worked by perturbing ERK1/2 signaling and reducing p70S6K phosphorylation. AdipoRon shows promise in preclinical studies, but human trials are crucial for clinical safety and effectiveness. Caution is needed due to potential off-target effects, especially in cancer therapy with multi-target approaches. Structural biology and computational methods can help predict these effects.

Unraveling the rationale and conducting a comprehensive assessment of KD025 (Belumosudil) as a candidate drug for inhibiting adipogenic differentiation-a systematic review.

Rho-associated kinases (ROCKs) are crucial during the adipocyte differentiation process. KD025 (Belumosudil) is a newly developed inhibitor that selectively targets ROCK2. It has exhibited consistent efficacy in impeding adipogenesis across a spectrum of in vitro models of adipogenic differentiation. Given the novelty of this treatment, a comprehensive systematic review has not been conducted yet. This systematic review aims to fill this knowledge void by providing readers with an extensive examination of the rationale behind KD025 and its impacts on adipogenesis. Preclinical evidence was gathered owing to the absence of clinical trials. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the study's quality was assessed using the Joanna Briggs Institute (JBI) Checklist Critical Appraisal Tool for Systematic Reviews. In various in vitro models, such as 3T3-L1 cells, human orbital fibroblasts, and human adipose-derived stem cells, KD025 demonstrated potent anti-adipogenic actions. At a molecular level, KD025 had significant effects, including decreasing fibronectin (Fn) expression, inhibiting ROCK2 and CK2 activity, suppressing lipid droplet formation, and reducing the expression of proadipogenic genes peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Additionally, KD025 resulted in the suppression of fatty acid-binding protein 4 (FABP4 or AP2) expression, a decrease in sterol regulatory element binding protein 1c (SREBP-1c) and Glut-4 expression. Emphasis must be placed on the fact that while KD025 shows potential in preclinical studies and experimental models, extensive research is crucial to assess its efficacy, safety, and potential therapeutic applications thoroughly and directly in human subjects.

Effects of Medicinal Plants and Phytochemicals in Nrf2 Pathways during Inflammatory Bowel Diseases and Related Colorectal Cancer: A Comprehensive Review.

Inflammatory bowel diseases (IBDs) are related to nuclear factor erythroid 2-related factor 2 (Nrf2) dysregulation. In vitro and in vivo studies using phytocompounds as modulators of the Nrf2 signaling in IBD have already been published. However, no existing review emphasizes the whole scenario for the potential of plants and phytocompounds as regulators of Nrf2 in IBD models and colitis-associated colorectal carcinogenesis. For these reasons, this study aimed to build a review that could fill this void. The PubMed, EMBASE, COCHRANE, and Google Scholar databases were searched. The literature review showed that medicinal plants and phytochemicals regulated the Nrf2 on IBD and IBD-associated colorectal cancer by amplifying the expression of the Nrf2-mediated phase II detoxifying enzymes and diminishing NF-κB-related inflammation. These effects improve the bowel environment, mucosal barrier, colon, and crypt disruption, reduce ulceration and microbial translocation, and consequently, reduce the disease activity index (DAI). Moreover, the modulation of Nrf2 can regulate various genes involved in cellular redox, protein degradation, DNA repair, xenobiotic metabolism, and apoptosis, contributing to the prevention of colorectal cancer.

Curcumin-Based Nanomedicines in the Treatment of Inflammatory and Immunomodulated Diseases: An Evidence-Based Comprehensive Review.

Curcumin (CUR) is a polyphenol extracted from the rhizome of Curcuma longa that possesses potent anti-inflammatory and antioxidant potential. Despite CUR's numerous beneficial effects on human health, it has limitations, such as poor absorption. Nano-based drug delivery systems have recently been applied to improve CUR's solubility and bioavailability and potentialize its health effects. This review investigated the effects of different CUR-based nanomedicines on inflammatory and immunomodulated diseases. PUBMED, EMBASE, COCHRANE, and GOOGLE SCHOLAR databases were searched, and the Scale for Assessment of Narrative Review Articles (SANRA) was used for quality assessment and PRISMA guidelines. Overall, 66 studies were included comprising atherosclerosis, rheumatoid arthritis (RA), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), inflammatory bowel diseases (IBD), psoriasis, liver fibrosis, epilepsy, and COVID-19. The available scientific studies show that there are many known nanoformulations with curcumin. They can be found in nanosuspensions, nanoparticles, nanoemulsions, solid lipid particles, nanocapsules, nanospheres, and liposomes. These formulations can improve CUR bioavailability and can effectively be used as adjuvants in several inflammatory and immune-mediated diseases such as atheroma plaque formation, RA, dementia, AD, PD, MS, IBD, psoriasis, epilepsy, COVID-19, and can be used as potent anti-fibrotic adjuvants in fibrotic liver disease.

Medicinal Plants, Phytochemicals and Regulation of the NLRP3 Inflammasome in Inflammatory Bowel Diseases: A Comprehensive Review.

Ongoing research explores the underlying causes of ulcerative colitis and Crohn's disease. Many experts suggest that dysbiosis in the gut microbiota and genetic, immunological, and environmental factors play significant roles. The term "microbiota" pertains to the collective community of microorganisms, including bacteria, viruses, and fungi, that reside within the gastrointestinal tract, with a particular emphasis on the colon. When there is an imbalance or disruption in the composition of the gut microbiota, it is referred to as dysbiosis. Dysbiosis can trigger inflammation in the intestinal cells and disrupt the innate immune system, leading to oxidative stress, redox signaling, electrophilic stress, and inflammation. The Nod-like Receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome, a key regulator found in immunological and epithelial cells, is crucial in inducing inflammatory diseases, promoting immune responses to the gut microbiota, and regulating the integrity of the intestinal epithelium. Its downstream effectors include caspase-1 and interleukin (IL)-1ß. The present study investigated the therapeutic potential of 13 medicinal plants, such as Litsea cubeba, Artemisia anomala, Piper nigrum, Morus macroura, and Agrimonia pilosa, and 29 phytocompounds such as artemisitene, morroniside, protopine, ferulic acid, quercetin, picroside II, and hydroxytyrosol on in vitro and in vivo models of inflammatory bowel diseases (IBD), with a focus on their effects on the NLRP3 inflammasome. The observed effects of these treatments included reductions in IL-1ß, tumor necrosis factor-alpha, IL-6, interferon-gamma, and caspase levels, and increased expression of antioxidant enzymes, IL-4, and IL-10, as well as regulation of gut microbiota. These effects could potentially provide substantial advantages in treating IBD with few or no adverse effects as caused by synthetic anti-inflammatory and immunomodulated drugs. However, additional research is necessary to validate these findings clinically and to develop effective treatments that can benefit individuals who suffer from these diseases.

Benchside to the bedside of frailty and cardiovascular aging: Main shared cellular and molecular mechanisms.

Due to the impact that frailty and cardiac aging have on society and health systems, the mechanisms surrounding these conditions must be known. If the frailty and cardiovascular complications are due to numerous controllable factors or not, different strategies must be considered to improve the elderly patient's prognosis and improve their quality of life. This review aimed to investigate the main shared mechanisms of cardiac aging and frailty. MEDLINE-PubMed, Cohrane and EMBASE databases were searched to perform this review. The mesh-terms used for this search was frailty, cardiovascular disease, cardiovascular aging, or heart failure (HF). Frailty frequently coexists with heart conditions since they share predisposing pathophysiological alterations, the aging process, and elevated comorbidity burden, contributing to fast functional decline and sarcopenia. Mitochondrial dysfunctions and decreased protein synthesis lead to protein degradation, denervation, atrophy, impairment in the fatty acid oxidation, resulting in cardiomyopathy. The homeostasis of muscle metabolism deteriorates with aging, leading to a reduction in muscle quality and quantity. The installation of a low-grade and chronic inflammatory process adds to an impairment in glucose, protein and lipid metabolism, endothelial dysfunction, cardiovascular conditions, sarcopenia, and HF. The exacerbated rise in inflammatory biomarkers and impaired insulin resistance leads to worsening of the patient's general condition. The good news is that frailty is a dynamic syndrome, fluctuating between different states of seriousness but still has potential for reversibility based on physical activity, cognitive training, nutrition intervention, and a plethora of other approaches that can be performed by a multi-disciplinary team.

Myokines: a descriptive review.

In the last years, scientists have shown that skeletal muscle is not a pure locomotor unit or responsible for propulsion and posture. Skeletal muscle encompasses one of the major organs of the body (constituting about 40% of the body mass in non-obese men). It regulates energy and metabolic processes and is now recognized as an organ capable of producing molecules with vital functions. These molecules are termed myokines, a new field of research in the health sciences, and represent an open field of discoveries and applications in several areas. The aim of this review was to show the role of some well-known myokines in the maintenance of homeostasis. Our search was performed in databases such as Medline/Pubmed, Embase and Scielo. Some relevant myokines are interleukin-6 (IL-6), IL-8, IL-15, irisin, myostatin, fibroblast growth factor 21 (FGF21), leukemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1). They are related to play a positive or negative role in muscle function and metabolism homeostasis. They are associated with the regulation of glucose and lipid metabolism, the deposition of fat in the adipose tissue, and the "browning" of the white adipose tissue. For these reasons, they can interfere with the prevention of obesity, diabetes, metabolic syndrome, and cardiovascular diseases. The discovery of the myokines has opened a new direction in understanding the effects of exercises on humans.

Green tea: A possibility in the therapeutic approach of inflammatory bowel diseases?: Green tea and inflammatory bowel diseases.

OBJECTIVE: this review aimed to investigate the effects of green tea polyphenols (GTP) in Ulcerative colitis and Crohn´s Disease. MATERIALS AND METHODS: The databases used were MEDLINE-and EMBASE (October 2009 to September 2018). Studies that reported the use of green tea and its effects on IBD were included. RESULTS: Ten articles were included in this review. DISCUSSION: GTP play a role in reducing TNF-α, Interleukin 1ß (IL-1ß), IL-6, IL-8, and 17; downregulate cyclooxygenase-mediated I kappa B kinase and transcription of NFκB. They regulate the pathways mediated by the Nuclear erythroid 2-related factor 2, mitogen-activated protein kinases, and signal transducer and the activator of transcription 1/3, and also minimize the lipid peroxidation. Furthermore, GTP can stimulate antioxidant enzymes. These actions reduce inflammatory and oxidant patterns in IBD resulting in improvement of the disease scores. CONCLUSIONS: We suggest that professionals and researchers take into account the use of GTP in further researches and in clinical practice in order to verify the real effects in humans.

Association between vitamin D status and metabolic syndrome risk factors.

BACKGROUND: The concern with the incidence of chronic-degenerative diseases is increasing worldwide, and many studies have shown that insufficiency of vitamin D (VD) can be linked to several metabolic disorders. AIMS: Thus, the objective of this study was to evaluate the association of the metabolic syndrome risk factors, atherogenic indices and VD in a group of patients attended at a Cardiology Center. METHODS: For this study, we invited 200 patients of both sexes attended in a Cardiology Center (Medical School of Marilia - São Paulo - Brazil). Most were female (n = 111) and aged between 41 and 70 years (from march to august, 2017). RESULTS: Our results showed that only 20.0% of the patients presented normal levels of VD. Patients with altered values for this vitamin presented significantly higher values for glycemia, HbA1c, Total cholesterol, LDL-c, triglycerides, Castelli Index I, Castelli Index II, Body Mass Index, waist circumference, non-HDL-c and the estimative of the size of the LDL-c particle. Vitamin D correlated negatively with glycemia, HbA1C, triglycerides, atherogenic indices, Body Mass Index, and blood pressure. Multiple Regression Model showed that for an individual to maintain metabolic parameters, at least at borderline values, the levels of VD should be 37.64 that is not in accordance with the reference values. CONCLUSIONS: These results showed a remarkable prevalence of low concentrations of Vitamin D in patients with cardiovascular risk factors.

Reflections About Inflammatory Bowel Disease and Vitamins A and D.

Ulcerative colitis and Crohn's disease are two major forms of the inflammatory bowel diseases (IBDs). Vitamin A (VA) and vitamin D (VD) may be associated with reduction in inflammation in these disorders. The aim of this review was to show the current evidence that may associate VA and VD with IBDs. Data linking VA, VD, and IBDs were studied. Both VA and VD may be related to the immune system in different manners. The active form of VA, retinoic acid, may be related to the growth factor-ß and release of interleukin-10 (IL-10), thus involved with the resolution of the inflammation. Its deficiency is associated with the increase of disease activity. The active form of VD is 1,25(OH)2D3 that produces biological effects via the nuclear hormone receptor named VD receptor (VDR), which may interfere with the immune cells and macrophages leading to the suppression of the inflammatory process by decreasing the release of TNF-α, IL-1, IL-6, and IL-8, IL-12, and IL-23. VDR may also activate nucleotide-binding oligomerization domain 2 expression and stimulate the production of the defensin and cathelicidin that are important to the homeostasis of the mucosal immune barrier. The use of VA and VD could be helpful in the treatment and prevention of IBDs but more studies are necessary to establish the precise role of these compounds in the prevention or remission of these inflammatory processes.

Phytochemical Characteristics of Seeds and Its Effects on the Intestinal Motility and Toxicity of Joannesia princeps.

Joannesia princeps is a plant commonly used in folk medicine as laxative for menstrual discomfort and as antihelminthic and antimicrobial to reduce edema and improve tissue healing. The seeds are used in many regions of Brazil as laxative; however, studies are needed to confirm its effectiveness and safety. Thus, the aim of this study was to evaluate the effects of using seeds of this plant on intestinal motility of Wistar rats, evaluate the effects and acute toxicity of its management, as well as determine its phytochemical profile. The evaluation of the effect on the intestinal motility was performed according to the model described by Michelin and Salgado (2004) with modifications. For the evaluation of acute toxicity, we used the model described by Craveiro et al. (2008) and Goloni et al. (2005), and for the analysis of the presence of alkaloids, flavonoids, anthraquinones, steroids, and other components, we used the method described by Carvalho et al. (2006). The results showed that J. princeps exhibits laxative effects similar to those of Senna species such as Cassia angustifolia and the phytochemical analysis of ethanol and aqueous extracts showed the presence of alkaloids, triterpenes, and/or steroids compounds. Acute toxicity showed in the first 12 h: piloerection, contortion, decreased respiratory rate, diarrhea, and weight loss. After this period, these changes were no longer observed. It was concluded that the seeds of this plant have potential laxative activity, confirming the popular use and that the dose of 5 g/kg can be considered safe for consumption.

Pereskia aculeata Miller Flour: Metabolic Effects and Composition.

Pereskia aculeata Miller is known in Brazil as ora-pro-nobis (OPN) and has been used commonly in the folklore medicine. The purpose of our study was to evaluate the composition and the effects of OPN flour on the metabolic profile and intestinal motility of Wistar rats. Animals were divided randomly into five groups (n = 10): G1 (control group) and G2 (treated with OPN flour). For the intestinal motility: G3 (control group), G4 (treated with senne), and G5 (treated with OPN flour). After 40 days, G1 and G2 were euthanized and metabolic profiles were analyzed (glycemia, cholesterol, triglycerides, high density lipoprotein [HDL-c], C reactive protein, AST, ALT, Lee Index, weight, and visceral fat). The flour of OPN was effective in reducing percentage of weight gain, visceral fat, levels of total cholesterol, triglycerides, low density lipoprotein, very low density lipoprotein, and increased HDL-c. Significance was also found in the distance covered by the activated charcoal from the pylorus to the beginning of the cecum, which was higher in animals treated with OPN. Our results indicate that OPN flour may bring health benefits, as the improvement of the intestinal motility, and it is associated with reduction of visceral fat and lipid profile, as well as the increase of HDL-c levels. With these results, we may suggest that the incorporation of this flour in different industrial products may be a convenient and effective way for the intake of healthier products.