Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 µM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

Antioxidant and Antitumor Activities of Newly Synthesized Hesperetin Derivatives.

Hesperetin is a class of natural products with a wide range of sources and remarkable biological activities. In this study, we described the synthesis of a series of novel hesperetin derivatives and evaluated the in vitro antioxidant and antitumor activity of these compounds. Eleven novel compounds were synthesized in moderate yields. The compounds synthesized in this work exhibited antioxidant activities against DPPH and ABTS free radicals in a dose-dependent manner. Among them, compound 3f had the best antioxidant activity, with IC50 of 1.2 µM and 24 µM for DPPH and ABTS, respectively. The antitumor activity of the compounds against human cancer cell lines, such as breast MCF-7, liver HepG2, and cervical Hela, was determined by a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Three compounds had moderate IC50 values. Interestingly, compound 3f had better biological activity than hesperetin, which matches the prediction by Maestro from Schrödinger. Therefore, the new hesperidin derivative is a promising drug for the treatment of cancer due to its effective antitumor activity. The results also suggested that the antitumor activities of hesperetin derivatives may be related to their antioxidant activities.

Structural Bases for Hesperetin Derivatives: Inhibition of Protein Tyrosine Phosphatase 1B, Kinetics Mechanism and Molecular Docking Study.

In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC50 value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC50 = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment.

Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives.

To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 µM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) than indomethacin and celecoxib at 10 µM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents.

In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced ß-amyloid (Aß) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer's disease.

Biological evaluation of 7-O-amide hesperetin derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease.

A series of 7-O-amide hesperetin derivatives were subjected to multi-target biological evaluation of anti-Alzheimer's disease. Most of the compounds showed good in vitro inhibitory activity against cholinesterase, of which compound 7c (7-O-(4-(morpholinoethyl)-acetamide) hesperetin) was the most effective anti-eqBuChE derivative (IC50 = 0.28 ± 0.05 µM) and exerted neuroprotective effects. Further biological evaluation found that compounds 4d, 4e and 7c showed strong antioxidant, anti-Aß self-aggregation and anti-neuroinflammatory activities. Compound 7c could inhibit the expression of iNOS and COX-2 proteins and prevent LPS-induced inflammatory response in BV2 cells. In addition, compound 7c could chelate biometal ions such as Cu2+ and Zn2+. In the vivo study, the MWM test confirmed that compound 7c could improve the cognitive impairment caused by scopolamine. In summary, the above studies have shown that the optimized compound 7c has great development potential as MTDL for the treatment of AD.

Pathological analysis of hesperetin-derived small cell lung cancer by artificial intelligence technology under fiberoptic bronchoscopy.

Lung cancer is one of the most common tumors. There are 1.8 million new cases worldwide each year, accounting for about 13% of all new tumors. Lung cancer is the most important cause of cancer-related deaths. 1.4 million people die of lung cancer each year. This article uses artificial intelligence technology to analyze the pathology of hesperetin-derived small cell lung cancer under fiberoptic bronchoscopy. This article takes 48 lung slice samples as the research object. Among them, 36 cases of lung small cell carcinoma have history slices from Lhasa City Institute of Biology, the patient has complete cases, and the other 12 normal lung slices come from Xinjiang Biotechnology Laboratory. In this paper, the above-mentioned 36 lung cancer slices became the study group, and 12 normal slices became the reference group. This article presents a method for hesperetin-fiber bronchoscope to study the pathological mechanism of lung small cell carcinoma (H-FBS), which is used to study slices. The above-mentioned 48 samples were taken for slice observation. First, the 48 slices were technically tested by artificial intelligence fiber bronchoscope combined with hesperetin derivatives, and then the slice observation results were verified by CTC technology. In addition, in each step, the C5orf34 in the tissue is detected separately, which is beneficial to adjust the content of C5orf34 so that the treatment of lung cancer can control the development of lung cancer under fiberoptic bronchoscopy. Experimental results show that the diagnostic accuracy rate of this method is 97.9%, which is higher than that of lung biopsy (89%); compared with multiple CTC detection, the cost is low and the time is shor.

Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer's disease.

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC50 = 3.08 ± 0.29 µM) and exhibited good anti-neuroinflammatory activity (IC50 = 2.91 ± 0.47 µM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 µM concentration. Furthermore, possessing significant self-mediated Aß1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.

Design, synthesis and investigation of potential anti-inflammatory activity of O-alkyl and O-benzyl hesperetin derivatives.

Hesperetin has been known to exert several activities such as anti-oxidant, antitumor and anti-inflammatory. To find hesperetin derivatives showing better activity, sixteen novel hesperetin derivatives were designed and synthesized. The new obtained compounds were investigated for their anti-inflammatory activity by inhibiting interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and production of nitric oxide (NO) in mouse RAW264.7 macrophages, and the structure-activity relationship of them was discussed. Among them, the compound 1l, 2c demonstrated more effective inhibitory activity of IL-1ß and IL-6, meanwhile, the compound 1l showed the best inhibition of NO production. The results of NO inhibition study were basically accord with the molecular docking results of inducible nitric oxide synthase (iNOS). Furthermore, the expression of LPS-induced iNOS and components of NF-κB signaling pathway were reduced by compound 1l. Our results suggest that the inhibitory effect of compound 1l on LPS-stimulated inflammatory mediator production in RAW 264.7 cells is associated with the suppression of NF-κB signaling pathway and inhibition of iNOS protein and iNOS activity. From in vivo study, it was also observed that compound 1l had hepato-protective and anti-inflammatory effects in CCl4-induced acute liver injury mouse models.