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Frontiers in Endocrinology 2023Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal (GI) disorder characterized by intestinal inflammation. The etiology of IBD is multifactorial... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal (GI) disorder characterized by intestinal inflammation. The etiology of IBD is multifactorial and results from a complex interplay between mucosal immunity, environmental factors, and host genetics. Future therapeutics for GI disorders, including IBD, that are driven by oxidative stress require a greater understanding of the cellular and molecular mechanisms mediated by reactive oxygen species (ROS). In the GI tract, oxidative stressors include infections and pro-inflammatory responses, which boost ROS generation by promoting the production of pro-inflammatory cytokines. Nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) represent two important signaling pathways in intestinal immune cells that regulate numerous physiological processes, including anti-inflammatory and antioxidant activities. Natural antioxidant compounds exhibit ROS scavenging and increase antioxidant defense capacity to inhibit pro-oxidative enzymes, which may be useful in IBD treatment. In this review, we discuss various polyphenolic substances (such as resveratrol, curcumin, quercetin, green tea flavonoids, caffeic acid phenethyl ester, luteolin, xanthohumol, genistein, alpinetin, proanthocyanidins, anthocyanins, silymarin), phenolic compounds including thymol, alkaloids such as berberine, storage polysaccharides such as tamarind xyloglucan, and other phytochemicals represented by isothiocyanate sulforaphane and food/spices (such as ginger, flaxseed oil), as well as antioxidant hormones like melatonin that target cellular signaling pathways to reduce intestinal inflammation occurring with IBD.
Topics: Humans; Antioxidants; Reactive Oxygen Species; Anthocyanins; Oxidative Stress; Inflammatory Bowel Diseases; Hormones; Inflammation
PubMed: 37701897
DOI: 10.3389/fendo.2023.1217165 -
Journal of Advanced Research Dec 2023Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs)...
INTRODUCTION
Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs) contain inflammation-inducing virulence factors, including gingipains (GPs) and lipopolysaccharide (LPS).
OBJECTIVES
To understand how PG could cause cognitive decline, we investigated the effects of PG and pEVs on the etiology of periodontitis and cognitive impairment in mice.
METHODS
Cognitive behaviors were measured in the Y-maze and novel object recognition tasks. Biomarkers were measured using ELISA, qPCR, immunofluorescence assay, and pyrosequencing.
RESULTS
pEVs contained neurotoxic GPs and inflammation-inducible fimbria protein and LPS. Gingivally exposed, but not orally gavaged, PG or pEVs caused periodontitis and induced memory impairment-like behaviors. Gingival exposure to PG or pEVs increased TNF-α expression in the periodontal and hippocampus tissues. They also increased hippocampal GPIba1, LPSIba1, and NF-κBIba1 cell numbers. Gingivally exposed PG or pEVs decreased BDNF, claudin-5, and N-methyl-D-aspartate receptor expression and BDNFNeuN cell number. Gingivally exposed fluorescein-5-isothiocyanate-labeled pEVs (F-pEVs) were detected in the trigeminal ganglia and hippocampus. However, right trigeminal neurectomy inhibited the translocation of gingivally injected F-EVs into the right trigeminal ganglia. Gingivally exposed PG or pEVs increased blood LPS and TNF-α levels. Furthermore, they caused colitis and gut dysbiosis.
CONCLUSION
Gingivally infected PG, particularly pEVs, may cause cognitive decline with periodontitis. PG products pEVs and LPS may be translocated into the brain through the trigeminal nerve and periodontal blood pathways, respectively, resulting in the cognitive decline, which may cause colitis and gut dysbiosis. Therefore, pEVs may be a remarkable risk factor for dementia.
Topics: Mice; Animals; Porphyromonas gingivalis; Lipopolysaccharides; Dysbiosis; Tumor Necrosis Factor-alpha; Brain-Derived Neurotrophic Factor; Periodontitis; Inflammation; Trigeminal Nerve; Colitis; Cognitive Dysfunction
PubMed: 36796586
DOI: 10.1016/j.jare.2023.02.006 -
Molecules (Basel, Switzerland) Oct 2023Sulforaphane (SFN) is a naturally occurring compound found in cruciferous vegetables such as broccoli and cauliflower. It has been widely studied for its potential as a... (Review)
Review
Sulforaphane (SFN) is a naturally occurring compound found in cruciferous vegetables such as broccoli and cauliflower. It has been widely studied for its potential as a neuroprotective and anticancer agent. This review aims to critically evaluate the current evidence supporting the neuroprotective and anticancer effects of SFN and the potential mechanisms through which it exerts these effects. SFN has been shown to exert neuroprotective effects through the activation of the Nrf2 pathway, the modulation of neuroinflammation, and epigenetic mechanisms. In cancer treatment, SFN has demonstrated the ability to selectively induce cell death in cancer cells, inhibit histone deacetylase, and sensitize cancer cells to chemotherapy. SFN has also shown chemoprotective properties through inhibiting phase I metabolizing enzymes, modulating phase II xenobiotic-metabolizing enzymes, and targeting cancer stem cells. In addition to its potential as a therapeutic agent for neurological disorders and cancer treatment, SFN has shown promise as a potential treatment for cerebral ischemic injury and intracranial hemorrhage. Finally, the ongoing and completed clinical trials on SFN suggest potential therapeutic benefits, but more research is needed to establish its effectiveness. Overall, SFN holds significant promise as a natural compound with diverse therapeutic applications.
Topics: Neuroprotection; Isothiocyanates; Sulfoxides; Histone Deacetylases
PubMed: 37836745
DOI: 10.3390/molecules28196902 -
Frontiers in Oncology 2023Sulforaphane (SFN) is an isothiocyanate with multiple biomedical applications. Sulforaphane can be extracted from the plants of the genus . However, broccoli sprouts are... (Review)
Review
Sulforaphane (SFN) is an isothiocyanate with multiple biomedical applications. Sulforaphane can be extracted from the plants of the genus . However, broccoli sprouts are the chief source of sulforaphane and are 20 to 50 times richer than mature broccoli as they contain 1,153 mg/100 g. SFN is a secondary metabolite that is produced as a result of the hydrolysis of glucoraphanin (a glucosinolate) by the enzyme myrosinase. This review paper aims to summarize and understand the mechanisms behind the anticancer potential of sulforaphane. The data was collected by searching PubMed/MedLine, Scopus, Web of Science, and Google Scholar. This paper concludes that sulforaphane provides cancer protection through the alteration of various epigenetic and non-epigenetic pathways. It is a potent anticancer phytochemical that is safe to consume with minimal side effects. However, there is still a need for further research regarding SFN and the development of a standard dose.
PubMed: 37397365
DOI: 10.3389/fonc.2023.1168321 -
Microbiological Research Nov 2023Chronic intermittent hypoxia (CIH) triggers subclinical intestinal barrier disruption prior to systemic low-grade inflammation. Increasing evidence suggests therapeutic...
BACKGROUND AND PURPOSE
Chronic intermittent hypoxia (CIH) triggers subclinical intestinal barrier disruption prior to systemic low-grade inflammation. Increasing evidence suggests therapeutic effects of melatonin on systemic inflammation and gut microbiota remodelling. However, whether and how melatonin alleviates CIH-induced intestinal barrier dysfunction remains unclear.
EXPERIMENTAL APPROACH
C57BL/6 J mice and Caco-2 cell line were treated. We evaluated gut barrier function spectrophotometrically using fluorescein isothiocyanate (FITC)-labelled dextran. Immunohistochemical and immunofluorescent staining were used to detect morphological changes in the mechanical barrier. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) revealed the expression of tight junctions, signal transducer and activator of transcription 3 (STAT3) levels. 16 S rRNA analysis of the colonic contents microflora. Flow cytometry was used to detect cytokines and Th17 cells with and without melatonin supplementation.
KEY RESULTS
We found that CIH could induce colonic mucosal injury, including reduction in the number of goblet cells and decrease the expression of intestinal tight junction proteins. CIH could decrease the abundance of the beneficial genera Clostridium, Akkermansia, and Bacteroides, while increasing the abundance of the pathogenic genera Desulfovibrio and Bifidobacterium. Finally, CIH facilitated Th17 differentiation via the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in vitro and elevated the circulating pro-inflammatory cytokine in vivo. Melatonin supplementation ameliorated CIH-induced intestinal mucosal injury, gut microbiota dysbiosis, enteric Th17 polarization, and systemic low-grade inflammation reactions mentioned-above.
CONCLUSION AND IMPLICATIONS
Melatonin attenuated CIH-induced intestinal barrier dysfunction by regulating gut flora dysbiosis, mucosal epithelium integrity, and Th17 polarization via STAT3 signalling.
Topics: Animals; Mice; Humans; Mice, Inbred C57BL; Melatonin; STAT3 Transcription Factor; Caco-2 Cells; Dysbiosis; Gastrointestinal Diseases; Cytokines; Hypoxia
PubMed: 37659335
DOI: 10.1016/j.micres.2023.127480 -
Postepy Biochemii Jun 2023It has been known for years that diet impacts human health, including the risk of cancer development. Food components can both increase and reduce the risk of... (Review)
Review
It has been known for years that diet impacts human health, including the risk of cancer development. Food components can both increase and reduce the risk of carcinogenesis. Thereby, a wisely composed diet can extend life span and improve life quality. The favourable effect on health exert glucosinolates (GSLs), a group of secondary plant metabolites found in vegetables of the Brassicaceae family, such as broccoli, cauliflower, cabbage, and kohlrabi. Hydrolysis of GSLs results in the formation of compounds, like sulforaphane (SFN), phenylethyl isothiocyanate (PEITC) and 3,3′-Diindolylmethane (DIM), which are known for versatile anti-cancer activity. This review highlights advances on the role of the chosen GSLs on selected epigenetic mechanisms, i.e. DNA methylation, histone acetylation and microRNAs expression in cancer treatment.
Topics: Humans; Glucosinolates; Neoplasms; Brassica; Epigenesis, Genetic; DNA Methylation
PubMed: 37493557
DOI: 10.18388/pb.2023_478 -
Antioxidants (Basel, Switzerland) Jul 2023The tripeptide glutathione plays important roles in many cell processes, including differentiation, proliferation, and apoptosis; in fact, disorders in glutathione... (Review)
Review
The tripeptide glutathione plays important roles in many cell processes, including differentiation, proliferation, and apoptosis; in fact, disorders in glutathione homeostasis are involved both in the etiology and in the progression of several human diseases, including cancer. Natural compounds have been found to modulate glutathione levels and function beyond their role as mere antioxidants. For example, certain compounds can upregulate the expression of glutathione-related enzymes, increase the availability of cysteine, the limiting amino acid for glutathione synthesis, or directly interact with glutathione and modulate its function. These compounds may have therapeutic potential in a variety of disease states where glutathione dysregulation is a contributing factor. On the other hand, flavonoids' potential to deplete glutathione levels could be significant for cancer treatment. Overall, while natural compounds may have potential therapeutic and/or preventive properties and may be able to increase glutathione levels, more research is needed to fully understand their mechanisms of action and their potential benefits for the prevention and treatment of several diseases. In this review, particular emphasis will be placed on phytochemical compounds belonging to the class of polyphenols, terpenoids, and glucosinolates that have an impact on glutathione-related processes, both in physiological and pathological conditions. These classes of secondary metabolites represent the most food-derived bioactive compounds that have been intensively explored and studied in the last few decades.
PubMed: 37507985
DOI: 10.3390/antiox12071445 -
Frontiers in Endocrinology 2023Hepatocyte nuclear factor 4 alpha (HNF4α) is a multi-faceted nuclear receptor responsible for governing the development and proper functioning of liver and pancreatic... (Review)
Review
Hepatocyte nuclear factor 4 alpha (HNF4α) is a multi-faceted nuclear receptor responsible for governing the development and proper functioning of liver and pancreatic islet cells. Its transcriptional functions encompass the regulation of vital metabolic processes including cholesterol and fatty acid metabolism, and glucose sensing and control. Various genetic mutations and alterations in HNF4α are associated with diabetes, metabolic disorders, and cancers. From a structural perspective, HNF4α is one of the most comprehensively understood nuclear receptors due to its crystallographically observed architecture revealing interconnected DNA binding domains (DBDs) and ligand binding domains (LBDs). This review discusses key properties of HNF4α, including its mode of homodimerization, its binding to fatty acid ligands, the importance of post-translational modifications, and the mechanistic basis for allosteric functions. The surfaces linking HNF4α's DBDs and LBDs create a convergence zone that allows signals originating from any one domain to influence distant domains. The HNF4α-DNA complex serves as a prime illustration of how nuclear receptors utilize individual domains for specific functions, while also integrating these domains to create cohesive higher-order architectures that allow signal responsive functions.
Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Epithelial Cells; Fatty Acids; Lipid Metabolism
PubMed: 37732120
DOI: 10.3389/fendo.2023.1219092 -
Biomolecules Sep 2023Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as... (Review)
Review
Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to these NRs modulation, OA showed prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.
Topics: Mice; Animals; Rabbits; Oleanolic Acid; Receptors, Cytoplasmic and Nuclear; Liver; Transcription Factors; Cholestasis
PubMed: 37892147
DOI: 10.3390/biom13101465 -
Journal of Nuclear Medicine : Official... Jul 2023Primary liver cancer is the third leading cause of cancer-related deaths, and its incidence and mortality are increasing worldwide. Hepatocellular carcinoma (HCC)...
Primary liver cancer is the third leading cause of cancer-related deaths, and its incidence and mortality are increasing worldwide. Hepatocellular carcinoma (HCC) accounts for 80% of primary liver cancer cases. Glypican-3 (GPC3) is a heparan sulfate proteoglycan that histopathologically defines HCC and represents an attractive tumor-selective marker for radiopharmaceutical imaging and therapy for this disease. Single-domain antibodies are a promising scaffold for imaging because of their favorable pharmacokinetic properties, good tumor penetration, and renal clearance. Although conventional lysine-directed bioconjugation can be used to yield conjugates for radiolabeling full-length antibodies, this stochastic approach risks negatively affecting target binding of the smaller single-domain antibodies. To address this challenge, site-specific approaches have been explored. Here, we used conventional and sortase-based site-specific conjugation methods to engineer GPC3-specific human single-domain antibody (HN3) PET probes. Bifunctional deferoxamine (DFO) isothiocyanate was used to synthesize native HN3 (nHN3)-DFO. Site-specifically modified HN3 (ssHN3)-DFO was engineered using sortase-mediated conjugation of triglycine-DFO chelator and HN3 containing an LPETG C-terminal tag. Both conjugates were radiolabeled with Zr, and their binding affinity in vitro and target engagement of GPC3-positive (GPC3) tumors in vivo were determined. Both Zr-ssHN3 and Zr-nHN3 displayed nanomolar affinity for GPC3 in vitro. Biodistribution and PET/CT image analysis in mice bearing isogenic A431 and A431-GPC3 xenografts, as well as in HepG2 liver cancer xenografts, showed that both conjugates specifically identify GPC3 tumors. Zr-ssHN3 exhibited more favorable biodistribution and pharmacokinetic properties, including higher tumor uptake and lower liver accumulation. Comparative PET/CT studies on mice imaged with both F-FDG and Zr-ssHN3 showed more consistent tumor accumulation for the single-domain antibody conjugate, further establishing its potential for PET imaging. Zr-ssHN3 showed clear advantages in tumor uptake and tumor-to-liver signal ratio over the conventionally modified Zr-nHN3 in xenograft models. Our results establish the potential of HN3-based single-domain antibody probes for GPC3-directed PET imaging of liver cancers.
Topics: Humans; Animals; Mice; Liver Neoplasms; Carcinoma, Hepatocellular; Single-Domain Antibodies; Radioisotopes; Glypicans; Positron Emission Tomography Computed Tomography; Antibodies, Monoclonal; Tissue Distribution; Cell Line, Tumor; Positron-Emission Tomography; Zirconium
PubMed: 36997331
DOI: 10.2967/jnumed.122.265171