Simvastatin attenuates silica-induced pulmonary inflammation and fibrosis in rats via the AMPK-NOX pathway.

BACKGROUND: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms. METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway. RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and transforming growth factor-ß1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions. CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.

Inhibitory Activity Against Rhizoctonia Solani and Chemical Composition of Extract from Moutan Cortex.

Rice sheath blight (RSB), caused by Rhizoctonia solani, is a significant disease of rice. The negative effects of chemical fungicides have created an urgent need for low-toxicity botanical fungicides. Our previous research revealed that the ethanol crude extract of Moutan Cortex (MC) exhibited superior antifungal activity against R. solani at 1000 µg/mL, resulting in a 100 % inhibition rate. The antifungal properties were mainly found in the petroleum ether extract. However, the active ingredients of the extract are still unclear. In this study, gas chromatography-mass spectrometry (GC-MS) was utilised for the analysis of its chemical components. The mycelium growth rate method was utilized to detect the antifungal activity. The findings indicated that paeonol constituted the primary active component, with a content of more than 96 %. Meanwhile, paeonol was the most significant antifungal active ingredient, the antifungal activity of paeonol (EC50=44.83 µg/mL) was much higher than that of ß-sitosterol and ethyl propionate against R. solani. Observation under an optical microscope revealed that paeonol resulted in abnormal mycelial morphology. This study provided theoretical support for identifying monomer antifungal compounds and developing biological fungicides for R. solani.

Paeonol interferes with lupus nephritis by regulating M1/M2 polarization of macrophages.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology. It is marked by the production of pathogenic autoantibodies and the deposition of immune complexes. Lupus nephritis (LN) is a prevalent and challenging clinical complications of SLE. Cortex Moutan contains paeonol as its main effective component. In this study, using the animal model of SLE induced by R848, it was found that paeonol could alleviate the lupus-like symptoms of lupus mouse model induced by R848 activating TLR7, reduce the mortality and ameliorate the renal damage of mice. In order to explore the mechanism of paeonol on lupus nephritis, we studied the effect of paeonol on the polarization of Raw264.7 macrophages in vitro. The experimental results show that paeonol can inhibit the polarization of macrophages to M1 and promote their polarization to M2, which may be related to the inhibition of MAPK and NF-κB signaling pathways. Our research provides a new insight into paeonol in the treatment of lupus nephritis, which is of great importance for the treatment of systemic lupus erythematosus and its complications.

Analysis and validation of hub genes in neutrophil extracellular traps for the long-term prognosis of myocardial infarction.

INTRODUCTION: The study focuses on the long-term prognosis of myocardial infarction (MI) influenced by neutrophil extracellular traps (NETs). It also aims to analyze and validate relative hub genes in this process, in order to further explore new therapeutic targets that can improve the prognosis of MI. MATERIALS AND METHODS: We established a MI model in mice by ligating the left anterior descending branch (LAD) and conducted an 8-week continuous observation to study the dynamic changes in the structure and function of the heart in these mice. Meanwhile, we administered Apocynin, an inhibitor of NADPH Oxidase, which has also been shown to inhibit the formation of NETs, to mice undergoing MI surgery in order to compare. This study employed hematoxylin-eosin (HE) staining, echocardiography, immunofluorescence, and real-time quantitative PCR (RT-qPCR) to examine the impact of NETs on the long-term prognosis of MI. Next, datasets related to MI and NETs were downloaded from the GEO database, respectively. The Limma package of R software was used to identify differentially expressed genes (DEGs). After analyzing the "Robust Rank Aggregation (RRA)" package, we conducted a screening for robust differentially expressed genes (DEGs) and performed pathway enrichment analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to determine the functional roles of these robust DEGs. The protein-protein interaction (PPI) network was visualized and hub genes were filtered using Cytoscape. RESULTS: Immunofluorescence and qPCR results showed an increase in the expression of Myeloperoxidase (MPO) at week 1 and week 8 in the hearts of mice after MI. HE staining reveals a series of pathological manifestations in the heart of the MI group during 8 weeks, including enlarged size, disordered arrangement of cardiomyocytes, infiltration of inflammatory cells, and excessive deposition of collagen fibers, among others. The utilization of Apocynin could significantly improve these poor performances. The echocardiography displayed the cardiac function of the heart in mice. The MI group has a reduced range of heart movement and decreased ejection ability. Moreover, the ventricular systolic movement was found to be abnormal, and its wall thickening rate decreased over time, indicating a progressive worsening of myocardial ischemia. The Apocynin group, on the contrary, showed fewer abnormal changes in the aforementioned aspects. A total of 81 DEGs and 4 hub genes (FOS, EGR1, PTGS2, and HIST1H4H) were obtained. The results of RT-qPCR demonstrated abnormal expression of these four genes in the MI group, which could be reversed by treatment of Apocynin. CONCLUSION: The NETs formation could be highly related to MI and the long-term prognosis of MI can be significantly influenced by the NETs formation. Four hub genes, namely FOS, EGR1, PTGS2, and HIST1H4H, have the potential to be key genes related to this process. They could also serve as biomarkers for predicting MI prognosis and as targets for gene therapy.

Paeonol Derivative, 6'-Methyl Paeonol, Attenuates Aß-Induced Pathophysiology in Cortical Neurons and in an Alzheimer's Disease Mice Model.

Herbs themselves and various herbal medicines are great resources for discovering therapeutic drugs for various diseases, including Alzheimer's disease (AD), one of the common neurodegenerative diseases. Utilizing mouse primary cortical neurons and DiBAC4(3), a voltage-sensitive indicator, we have set up a drug screening system and identified an herbal extraction compound, paeonol, obtained from Paeonia lactiflora; this compound is able to ameliorate the abnormal depolarization induced by Aß42 oligomers. Our aim was to further find effective paeonol derivatives since paeonol has been previously studied. 6'-Methyl paeonol, one of the six paeonol derivatives surveyed, is able to inhibit the abnormal depolarization induced by Aß oligomers. Furthermore, 6'-methyl paeonol is able to alleviate the NMDA- and AMPA-induced depolarization. When a molecular mechanism was investigated, 6'-methyl paeonol was found to reverse the Aß-induced increase in ERK phosphorylation. At the animal level, mice injected with 6'-methyl paeonol showed little change in their basic physical parameters compared to the control mice. 6'-Methyl paeonol was able to ameliorate the impairment of memory and learning behavior in J20 mice, an AD mouse model, as measured by the Morris water maze. Thus, paeonol derivatives could provide a structural foundation for developing and designing an effective compound with promising clinical benefits.

Protective mechanism of Paeonol on central nervous system.

Cerebrovascular diseases involve neuronal damage, resulting in degenerative neuropathy and posing a serious threat to human health. The discovery of effective drug components from natural plants and the study of their mechanism are a research idea different from chemical synthetic medicines. Paeonol is the main active component of traditional Chinese medicine Paeonia lactiflora Pall. It widely exists in many medicinal plants and has pharmacological effects such as anti-atherosclerosis, antiplatelet aggregation, anti-oxidation, and anti-inflammatory, which keeps generally used in the treatment of cardiovascular and cerebrovascular diseases. Based on the therapeutic effects of Paeonol for cardiovascular and cerebrovascular diseases, this article reviewed the pharmacological effects of Paeonol in Alzheimer's disease, Parkinson's disease, stroke, epilepsy, diabetes encephalopathy, and other neurological diseases, providing a reference for the research of the mechanism of Paeonol in central nervous system diseases.

Apocynin exerts cytoprotective effects on dexamethasone-induced osteoblasts by inhibiting oxidative stress through the Nrf2 signalling pathway.

Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.

Investigation on the inhibition mechanism and binding behavior of paeonol to tyrosinase and its anti-browning property by multi-spectroscopic and molecular docking methods.

Paeonol, as one effective tyrosinase inhibitor, had been used as food preservative and clinical medication for skin disorders. In this study, the inhibition mechanism and binding behavior of paeonol to tyrosinase and its anti-browning property were investigated using multi-spectroscopic and molecular docking methods. Activity assay and kinetic results confirmed paeonol as a reversible mixed-type tyrosinase inhibitor. Results of the mechanistic studies were clarified using fluorescence quenching, synchronous fluorescence, CD spectra and 3D fluorescence, and showed that the binding of paeonol to tyrosinase might change the chromophore microenvironment and conformation of tyrosinase to inhibit enzyme catalytic activity. Molecular docking results revealed the detailed binding between paeonol and tyrosinase. Moreover, paeonol could prevent the browning of fresh-cut apples, as well as inhibiting PPO and POD activities and increasing APX activity. All above findings established a reliable basis for the inhibitory mechanism of paeonol against tyrosinase and therefore contributed to its application in anti-browning.

Review of the Protective Mechanism of Paeonol on Cardiovascular Disease.

Cardiovascular disease (CVD) is one of the leading causes of death in the world. Paeonol(Pae) is a phenolic component extracted from peony bark, peony root and Xu Changqing. Studies have shown that Pae can protect cardiomyocytes by inhibiting oxidative stress, promoting mitochondrial fusion, regulating mitochondrial autophagy and inhibiting inflammation. In addition, Pae improves ventricular remodeling by inhibiting myocardial apoptosis, hypertrophy and fibrosis. Pae also has a good protective effect on blood vessels by inhibiting vascular inflammation, reducing the expression of adhesion molecules, inhibiting vascular proliferation, and inhibiting oxidative stress and endoplasmic reticulum stress(ERS). Pae also has the effect of anti-endothelial cell senescence, promoting thrombus recanalization and vasodilating. In conclusion, the molecular targets of Pae are very complex, and the relationship between different targets and signaling pathways cannot be clearly explained, which requires us to use systems biology methods to further study specific molecular targets of Pae. It has to be mentioned that the bioavailability of Pae is poor, and some nanotechnology-assisted drug delivery systems improve the therapeutic effect of Pae. We reviewed the protective mechanism of paeonol on the cardiovascular system, hoping to provide help for drug development in the treatment of CVD.

Paeonol repurposing for cancer therapy: From mechanism to clinical translation.

Paeonol (PAE) is a natural phenolic monomer isolated from the root bark of Paeonia suffruticosa that has been widely used in the clinical treatment of some inflammatory-related diseases and cardiovascular diseases. Much preclinical evidence has demonstrated that PAE not only exhibits a broad spectrum of anticancer effects by inhibiting cell proliferation, invasion and migration and inducing cell apoptosis and cycle arrest through multiple molecular pathways, but also shows excellent performance in improving cancer drug sensitivity, reversing chemoresistance and reducing the toxic side effects of anticancer drugs. However, studies indicate that PAE has the characteristics of poor stability, low bioavailability and short half-life, which makes the effective dose of PAE in many cancers usually high and greatly limits its clinical translation. Fortunately, nanomaterials and derivatives are being developed to ameliorate PAE's shortcomings. This review aims to systematically cover the anticancer advances of PAE in pharmacology, pharmacokinetics, nano delivery systems and derivatives, to provide researchers with the latest and comprehensive information, and to point out the limitations of current studies and areas that need to be strengthened in future studies. We believe this work will be beneficial for further exploration and repurposing of this natural compound as a new clinical anticancer drug.

In vitro-in vivo assessments of apocynin-hybrid nanoparticle-based gel as an effective nanophytomedicine for treatment of rheumatoid arthritis.

Apocynin (APO), a well-known bioactive plant-based phenolic phytochemical with renowned anti-inflammatory and antioxidant pharmacological activities, has recently emerged as a specific nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase inhibitor. As far as we know, no information has been issued yet regarding its topical application as a nanostructured-based delivery system. Herein, APO-loaded Compritol® 888 ATO (lipid)/chitosan (polymer) hybrid nanoparticles (APO-loaded CPT/CS hybrid NPs) were successfully developed, characterized, and optimized, adopting a fully randomized design (32) with two independent active parameters (IAPs), namely, CPT amount (XA) and Pluronic® F-68 (PF-68) concentration (XB), at three levels. Further in vitro-ex vivo investigation of the optimized formulation was performed before its incorporation into a gel base matrix to prolong its residence time with consequent therapeutic efficacy enhancement. Subsequently, scrupulous ex vivo-in vivo evaluations of APO-hybrid NPs-based gel (containing the optimized formulation) to scout out its momentous activity as a topical nanostructured system for beneficial remedy of rheumatoid arthritis (RA) were performed. Imperatively, the results support an anticipated effectual therapeutic activity of the APO-hybrid NPs-based gel formulation against Complete Freund's Adjuvant-induced rheumatoid arthritis (CFA-induced RA) in rats. In conclusion, APO-hybrid NPs-based gel could be considered a promising topical nanostructured system to break new ground for phytopharmaceutical medical involvement in inflammatory-dependent ailments.

Inhibition of melanogenesis by 3-(1'-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone via suppressing the activity of cAMP response element-binding protein (CREB) and nuclear exclusion of CREB-regulated transcription coactivator 1 (CRTC1).

Exposure to Ultraviolet radiation or α-melanocyte-stimulating hormone (α-MSH) stimulates the Cyclic Adenosine Monophosphate/Protein Kinase A signalling pathway, which leads to the synthesis and deposition of melanin granules in the epidermis. Skin pigmentation is the major physiological defence against inimical effects of sunlight. However, excessive melanin production and accumulation can cause various skin hyperpigmentation disorders. The present study involved the identification of 3-(1'-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone (IIIM-8) as an inhibitor of melanogenesis, IIIM-8 significantly inhibited pigment production both in vitro and in vivo without incurring any cytotoxicity in Human Adult Epidermal Melanocytes (HAEM). IIIM-8 repressed melanin synthesis and secretion both at basal levels and in α-MSH stimulated cultured HAEM cells by decreasing the levels of Cyclic Adenosine Monophosphate (cAMP) and inhibiting the phosphorylation of cAMP response element-binding (CREB) protein, coupled with restoring the phosphorylation of CREB-regulated transcription coactivator 1 (CRTC1) and its nuclear exclusion in HAEM cells. This impeding effect correlates with diminished expression of master melanogenic proteins including microphthalmia-associated transcription factor (MITF), Tyrosinase (TYR), Tyrosinase related protein 1 (TRP1), and Tyrosinase related protein 2 (TRP2). Additionally, topical application of IIIM-8 induced tail depigmentation in C57BL/6J mice. Furthermore, IIIM-8 efficiently mitigated the effect of ultraviolet-B radiation on melanin synthesis in the auricles of C57BL/6J mice. This study demonstrates that IIIM-8 is an active anti-melanogenic agent against ultraviolet radiation-induced melanogenesis and other hyperpigmentation disorders.

Modulatory Activity of the Copper Chelate, Copper N-(2-Hydroxy Acetophenone) Glycinate, in ABC-transporter-expressing Cell Lines.

BACKGROUND/AIM: Metal-containing compounds (e.g., platinum complexes) belong to the standard armamentarium of cancer chemotherapy. Copper N-(2-hydroxy acetophenone) glycinate (CuNG) exerts anticancer activity in vitro and in vivo and modulates drug resistance related to glutathione or P-glycoprotein. The potential of CuNG to interact with ATP-binding cassette (ABC) transporters has not been fully explored yet. This study focused on the modulatory effects of CuNG on four ABC transporters (MRP1, MRP1, BCRP, and P-glycoprotein). MATERIALS AND METHODS: Cell viability, drug uptake and ABC transporter expression were measured by resazurin assays, flow cytometry, and ELISA in HL60AR, MDCKII-hBCRP, and Caco-2 cells. RESULTS: CuNG increased doxorubicin sensitivity of MRP1-over-expressing HL60AR with a similar efficacy as the control MRP1 inhibitor MK571. CuNG also increased MRP1's efflux activity. Comparable results were obtained with MDCKII cells over-expressing hBCRP. ELISA assays revealed that the expression of MRP1 in HL60AR cells and BCRP in MDCKII- cells was predominant but other ABC-transporters were also expressed at lower levels. Caco-2 cells expressed high levels of MRP2, but MRP1, BCRP, and P-glycoprotein were also expressed. In contrast to the two former cell lines, CuNG increased doxorubicin resistance and decreased efflux activity in Caco-2 cells. CONCLUSION: CuNG exerted different modulatory activities towards ABC-transporter-expressing cells. While CuNG-mediated ABC-transporter inhibition may improve tumor chemotherapy (like in HL60AR and MDCKII-hBCRP cells), CuNG-mediated enhanced ABC-transport (like in Caco-2 cells) may be a new strategy to ameliorate inflammatory diseases associated with decreased ABC-transporter expression such as ulcerative colitis.

Combination Therapy of Niacin and Apocynin Attenuates Lung Injury During Sepsis in Rats.

INTRODUCTION: Oxidative stress contributes to tissue injury through reactive oxygen species-dependent signaling pathways during sepsis. We studied therapeutic benefits of the combination therapy of niacin, which increased reduced glutathione levels, and apocynin, which suppressed reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity, in septic rats. MATERIALS AND METHODS: Polymicrobial sepsis was induced through cecal ligation and puncture (CLP) with antibiotics in male Sprague-Dawley rats (n = 189). The rats were randomly divided into sham, CLP, CLP + niacin, CLP + apocynin, and CLP + niacin + apocynin groups. Six hours after CLP, vehicle, niacin (360 mg/kg through the orogastric tube), and/or apocynin (20 mg/kg through intraperitoneal injection) were administered. The occurrence of mortality for 72 h after CLP was observed. Next, a separate set of animals was euthanized at 24 h post-CLP for lung tissue analyses. RESULTS: Combination therapy with niacin and apocynin significantly improved survival in rats with sepsis (75.0% versus 28.8%, P = 0.006) but monotherapy with niacin or apocynin did not. Monotherapy with niacin and apocynin appeared to increase NADPH levels and decrease Nox levels and activity, respectively, but failed to show statistical significances. However, combination therapy significantly decreased Nox levels and activity, increased NADPH and glutathione levels, decreased intranuclear nuclear factor-κB (NF-κB) p65 levels, reduced inflammatory cytokine expression and malondialdehyde levels, and attenuated histological lung injuries. CONCLUSIONS: Combination therapy with niacin and apocynin synergistically attenuated lung injuries and improved survival in rats with sepsis through niacin-induced glutathione redox cycle activation and apocynin-induced Nox suppression.

A new polyphenolic isoprenylated acetophenone dimer from the stem bark of Acronychia pedunculata (L.) Miq.

A new acetophenone dimer, 5'-prenylacrovestone (1), together with nineteen known compounds (2-20), were isolated from the stem bark of Acronychia pedunculata (L.) Miq. Their structures were identified by thorough analysis of spectroscopic (IR, 1D and 2D NMR) and mass spectrometric data. The isolated compounds were tested against the bacterial pathogens MRSA, B. cereus, S. aureus and E. coli. Compound 3 demonstrated exceptionally potent antibacterial activity against each of the four strains (MIC values of 1 µg/mL).

A hydroalcoholic extract of Senecio nutans SCh. Bip (Asteraceae); its effects on cardiac function and chemical characterization.

ETHNOPHARMACOLOGY RELEVANCE: The plant Senecio nutans SCh. Bip. is used by Andean communities to treat altitude sickness. Recent evidence suggests it may produce vasodilation and negative cardiac inotropy, though the cellular mechanisms have not been elucidated. PURPOSE: To determinate the mechanisms action of S. nutans on cardiovascular function in normotensive animals. METHODS: The effect of the extract on rat blood pressure was measured with a transducer in the carotid artery and intraventricular pressure by a Langendorff system. The effects on sheep ventricular intracellular calcium handling and contractility were evaluated using photometry. Ultra-high-performance liquid-chromatography with diode array detection coupled with heated electrospray-ionization quadrupole-orbitrap mass spectrometric detection (UHPLC-DAD-ESI-Q-OT-MSn) was used for extract chemical characterization. RESULTS: In normotensive rats, S. nutans (10 mg/kg) reduced mean arterial pressure (MAP) by 40% (p < 0.05), causing a dose-dependent coronary artery dilation and decreased left ventricular pressure. In isolated cells, S. nutans extract (1 µg/ml) rapidly reduced the [Ca2+]i transient amplitude and sarcomere shorting by 40 and 49% (p < 0.001), respectively. The amplitude of the caffeine evoked [Ca2+]i transient was reduced by 24% (p < 0.001), indicating reduced sarcoplasmic reticulum (SR) Ca2+ content. Sodium-calcium exchanger (NCX) activity increased by 17% (p < 0.05), while sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) activity was decreased by 21% (p < 0.05). LC-MS results showed the presence of vitamin C, malic acid, and several antioxidant phenolic acids reported for the first time. Dihydroeuparin and 4-hydroxy-3-(3-methylbut-2-enyl) acetophenone were abundant in the extract. CONCLUSION: In normotensive animals, S. nutans partially reduces MAP by decreasing heart rate and cardiac contractility. This negative inotropy is accounted for by decreased SERCA activity and increased NCX activity which reduces SR Ca2+ content. These results highlight the plant's potential as a source of novel cardio-active phytopharmaceuticals or nutraceuticals.

Acetophenone-Based 3,4-Dihydropyrimidine-2(1H)-Thione as Potential Inhibitor of Tyrosinase and Ribonucleotide Reductase: Facile Synthesis, Crystal Structure, In-Vitro and In-Silico Investigations.

The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1H-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N-H ⋯ S and C-H ⋯ O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R22 (8) and R22 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⋯ H (59.5%), H ⋯ S/S ⋯ H (16.1%), and H ⋯ C/C ⋯ H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density functional theory (DFT) studies using B3LYP functional and 6-31G* as a basis set. The compound 4 displayed the high chemical reactivity with chemical softness of 2.48. In comparison to the already reported known tyrosinase inhibitor, the newly synthesized derivatives exhibited almost seven-fold better inhibition of tyrosinase (IC50 = 1.97 µM), which was further supported by molecular docking studies. The compound 4 inside the active pocket of ribonucleotide reductase (RNR) exhibited a binding energy of -19.68 kJ/mol, and with mammalian deoxy ribonucleic acid (DNA) it acts as an effective DNA groove binder with a binding energy of -21.32 kJ/mol. The results suggested further exploration of this compound at molecular level to synthesize more potential leads for the treatment of cancer.

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones.

ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating tubulin assembly through polymerization. A series of natural and synthetic chalcones have been reported to have very good anticancer activity, with a half-maximal inhibitory concentration lower than 1 µM. By modulation, it is observed in case of the first mechanism that methoxy substituents on the aromatic cycle of acetophenone residue and substitution of phenyl nucleus by a heterocycle and by methoxy or hydroxyl groups have a positive impact. To inhibit tubulin, compounds bind to colchicine binding site. Presence of methoxy groups, amino groups or heterocyclic substituents increase activity.

Diterpene glycosides, acetophenone glycosides and tannins from polar extracts of the root of Euphorbia fischeriana with cytotoxicity and antibacterial activities.

The phytochemical study on Euphorbia fischeriana, a folk medicinal plant in China, led to the isolation of eight undescribed glycosides, including two diterpene glycosides, three acetophenone glycosides and three tannins together with eight known ones. Their planar structures were elucidated by extensive analyses of 1D, 2D NMR experiments and HRESIMS. The absolute configurations were determined by NOESY experiments, ECD calculations. All undescribed compounds were evaluated for their cytotoxicity and antibacterial activities in vitro. Two diterpene glycosides (1-2) showed cytotoxic activity with IC50 values ranging from 5.4 to 16.2 µM toward Hep-G2, Hep-3B, A549, NCI-H460 and AGS cells. Tannins (6-8) showed the significant antibacterial activity with MIC values in the range of 1.56-6.25 µg/mL.

Paeonol exerts neuroprotective and anticonvulsant effects in intrahippocampal kainate model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is presented the most common form of focal epilepsy with involvement of oxidative stress and neuroinflammation as important factors in its development. About one third of epileptic patients are intractable to currently available medications. Paeonol isolated from some herbs with traditional and medicinal uses has shown anti-oxidative and anti-inflammatory effects in different models of neurological disorders. In this research, we tried to evaluate the possible protective effect of paeonol in intrahippocampal kainate murine model of TLE. To induce TLE, kainate was microinjected into CA3 area of the hippocampus and paeonol was administered at two doses of 30 or 50 mg/kg. The results of this study showed that paeonol at the higher dose significantly reduces incidence of status epilepticus, hippocampal aberrant mossy fiber sprouting and also preserves neuronal density. Beneficial protective effect of paeonol was in parallel with partial reversal of some hippocampal oxidative stress markers (reactive oxygen species and malondialdehyde), caspase 1, glial fibrillary acidic protein, heme oxygenase 1, DNA fragmentation, and inflammation-associated factors (nuclear factor-kappa B, toll-like receptor 4, and tumor necrosis factor α). Our obtained data indicated anticonvulsant and neuroprotective effects of paeonol which is somewhat attributed to its anti-oxidative and anti-inflammation properties besides its attenuation of apoptosis, pyroptosis, and astrocyte activity.