Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have various biological properties, particularly those for the prevention of cancer and cardiovascular ...diseases. Studies have shown both anti-cancer and cancer chemopreventive effects for Hsd and Hst. Cancer chemopreventive properties of Hsd and Hst are mainly associated with their antioxidant, radical scavenging and anti-inflammatory activities. In addition, Hsd and Hst interfere at different stages of cancer. Unlike conventional anti-cancer drugs, Hsd and Hst inhibit tumor growth by targeting multiple cellular protein targets at the same time, including caspases, Bcl-2 (B-cell lymphoma 2) and Bax (Bcl-2 associated X protein) for the induction of apoptosis, and COX-2 (cyclooxygenase-2), MMP-2 (matrix metalloproteinase-2) and MMP-9 for the inhibition of angiogenesis and metastasis. The results of the recent basic and clinical studies revealed the beneficial effects for Hst, Hsd and their derivatives in the treatment of heart failure and cardiac remodeling, myocardial ischemia and infarction, and hypertension. In addition, the valuable effects of Hst and Hsd in the treatment of diabetes and dyslipidemia with their anti-platelet and anticoagulant effects make them good candidates in the treatment of various cardiovascular diseases. In this review, new findings regarding the molecular targets of Hsd and Hst, animal studies and clinical trials are discussed.
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Many plants produce flavonoids as secondary metabolites. These organic compounds may be involved in the defense against plant-threatening factors, such as microbes and toxins. Certain flavonoids ...protect their origin source against plant pathogens, but they also exhibit potential healthy properties in human organisms. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from the Citrus species that exhibit various biological properties, including antioxidant, antiinflammatory and anticancer effects. Recent studies indicated that Hst and Hsd possess antimicrobial activity. Although the exact mechanisms behind their antimicrobial properties are not fully understood, several mechanisms such as the activation of the host immune system, bacterial membrane disruption, and interference with microbial enzymes, have been proposed.
Hsd and Hst may also have protective effects against toxicity induced by various agents. These natural substances may contribute to the protection of cells and tissues through their antioxidant and radical scavenging activities.
This review discusses the protective activities of Hsd and Hst against microbes and several toxicities induced by oxidants, chemicals, toxins, chemotherapy and radiotherapy agents, which were reported in vitro and in vivo. Furthermore, the probable mechanisms behind these activities are discussed.
A schematic view of the protective effects of hesperidin and hesperetin against microbes and toxins. Display omitted
Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have various biological properties. Over the past decade, a large number of papers have been published ...regarding the biological activities of these compounds and their molecular mechanisms. In this paper, we reviewed the neuropharmacology of Hsd and Hst as a recently emerged topic that has not been addressed in the past. Some of molecular targets and signaling pathways for neuropharmacological effects of Hst and Hsd, including antidepressant, neuroprotective and the effects of Hsd/Hst on memory, have also been included in the review. We also discussed the mechanisms of actions for antidepressant activities of Hsd and Hst. In addition, pharmacokinetics of Hsd and Hst, their interaction with some drugs such as atenolol, diltiazem, felodipine and verapamil, as well as related underlying mechanisms have been discussed.
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Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to the erythropoiesis-iron ...metabolism axis can result in iron imbalances and cause anemia or organ toxicity. Various congenital and acquired diseases associated with abnormal red cell production are characterized by aberrant iron absorption. Several recent studies have shown that improvements in red blood cell production also ameliorate iron metabolism and vice versa. Many therapeutics are now under development with the potential to improve a variety of hematologic diseases, from β-thalassemia and iron-refractory iron deficiency anemia to anemia of inflammation and polycythemia vera. This review summarizes selected mechanisms related to red cell production and iron metabolism and describes potential therapeutics and their current uses. We also consider the potential application of the discussed therapeutics on various diseases, alone or in combination. The vast repertoire of drugs under development offers new opportunities to improve the clinical care of patients suffering from congenital or acquired red blood cell disorders with limited or no treatment options.
Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable ...in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.
Synthetic and biological vesicular carriers have been recognized as attractive and intelligent systems for delivery of a verity of bioactive molecules. The importance of such delivery systems can be ...mostly due to their physicochemical properties, i.e. a lipid bilayer surrounding an aqueous core which allows encapsulation and protection of active hydrophilic molecules such as nucleic acids. Synthetic vesicles such as liposomes have been studied as gene delivery systems for decades. However, due to their fast clearance, toxicity and immunogenicity which impose restrictions on clinical applications, some other natural lipid vesicles such as exosomes have been considered as alternatives. Attractive features of nature's own 'nano-vesicles' such as exosomes, virosomes, bacterial ghosts and erythrocyte ghosts include efficient cellular entry, physicochemical properties and evading immune responses. Nevertheless, there are advantages and disadvantages with both synthetic and biological vesicular systems. Here, we provide an overview into different vesicle-based gene delivery systems and discuss how various modifications in their structure and formulations could improve the transfection efficiency and decrease the toxicity.
Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal ...solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases.
Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with ...antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.
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•Robust pulmonary targeting of mRNA was achieved by endothelial targeted anti-PECAM/LNP-mRNA nanoparticles.•Delivery of targeted Anti-PECAM/LNP-mRNA nanoparticles is independent of apolipoprotein E pathway.•Around 200-fold elevation in pulmonary mRNA expression was reached upon IV administration of targeted nanoparticles.•Rapid, transient, and specific protein expression from reporter mRNA was observed, with limited off-target biodistribution.
Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis ...factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood–brain barrier, thus benefiting numerous brain pathologies.
Current nucleoside-modified RNA lipid nanoparticle (modmRNA-LNP) technology has successfully paved the way for the highest clinical efficacy data from next-generation vaccinations against SARS-CoV-2 ...during the COVID-19 pandemic. However, such modmRNA-LNP technology has not been characterized in common pre-existing inflammatory or immune-challenged conditions, raising the risk of adverse clinical effects when administering modmRNA-LNPs in such cases. Herein, we induce an acute-inflammation model in mice with lipopolysaccharide (LPS) intratracheally (IT), 1 mg kg−1, or intravenously (IV), 2 mg kg−1, and then IV administer modmRNA-LNP, 0.32 mg kg−1, after 4 h, and screen for inflammatory markers, such as pro-inflammatory cytokines. ModmRNA-LNP at this dose caused no significant elevation of cytokine levels in naive mice. In contrast, shortly after LPS immune stimulation, modmRNA-LNP enhanced inflammatory cytokine responses, Interleukin-6 (IL-6) in serum and Macrophage Inflammatory Protein 2 (MIP-2) in liver significantly. Our report identifies this phenomenon as inflammation exacerbation (IE), which was proven to be specific to the LNP, acting independent of mRNA cargo, and was demonstrated to be time- and dose-dependent. Macrophage depletion as well as TLR3 −/− and TLR4−/− knockout mouse studies revealed macrophages were the immune cells involved or responsible for IE. Finally, we show that pretreatment with anti-inflammatory drugs, such as corticosteroids, can partially alleviate IE response in mice. Our findings characterize the importance of LNP-mediated IE phenomena in gram negative bacterial inflammation, however, the generalizability of modmRNA-LNP in other forms of chronic or acute inflammatory and immune contexts needs to be addressed.
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