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Background. T helper 17 (Th17) and regulatory T (Treg) cell imbalance in the immune microenvironment is involved in the pathogenesis of myelodysplastic syndrome (MDS) and inflammatory bowel disease (IBD). DNA demethylation agents are the main treatment for MDS/ chronic myelomonocytic leukemia (CMML). However, the clinical efficacy of the demethylation agent decitabine (DAC) in the treatment of MDS /CMML-associated IBD has not been reported. Methods. In this study, Decitabine was used to treat two patients with MDS/CMML-associated inflammatory bowel disease. Clinical efficacy was assessed after 5 courses of DAC treatment. Meanwhile, we performed dynamic monitoring of immune-related indicators in the intestinal, bone marrow, and peripheral blood microenvironment of one patient with CMML-associated ulcerative colitis. Results. IBD was improved in 2 patients with haematological remission in MDS or CMML. Immunohistochemical analysis of bone marrow specimens showed that PD-1, PD-L1, and Foxp3 were upregulated, and IL-17 was downregulated. In the bone marrow and intestine, quantitative RT-PCR showed that the mRNA level of IL-17 decreased after DAC treatment, whereas those Foxp3, PD-1, and PD-L1 mRNA increased. Flow cytometry showed that the percentage of Th17 cells in peripheral blood mononuclear cells decreased, whereas that of Treg cells increased. Conclusions. Our results suggest that DAC may effectively treat CMML/MDS associated IBD by affecting the balance of Th17/Treg via PD-1/PD-L1 pathway in the immune microenvironment.

As nitrogen-containing five-membered heterocyclic structural units, the substituted pyrazole derivatives have a broad spectrum of pharmacological activities, especially 4,5-dihydro-1H-pyrazoles that also commonly known as 2-pyrazolines. Since 2010, considerable studies have been found that the 2-pyrazoline derivatives possess potent anticancer activities. In the present review, it covers the pyrazoline derivatives reported by literature from 2010 till date (2010-2019). This review aims to establish the relationship between the anticancer activities variation and different substituents introduced into a 2-pyrazoline core, which could provide important pharmacophore clues for the discovery of new anticancer agents containing 2-pyrazoline scaffold.

Fourteen avermectin B2a aglycon derivatives were designed and synthesized after removing the oleandrose disaccharide of avermectin B2a. Their structures were characterized by 1H NMR, 13C NMR, HMRS. Preliminary bioassays indicated that these compounds exhibited good insecticidal activity against diamondback moth at 200 mg/L, with mortality no less than 90%. Compounds 10b, 12a, 12c, 17 demonstrated good acaricidal activity against the adult mites, larvae, and good inhibition rate of hatching to mite eggs of Tetranychus cinnabarinus. Compounds 5, 10b, 10c exhibited excellent fungicidal activity against fourteen fungal pathogens in vitro. 3D-QSAR analysis showed that the fungicidal activity of avermectin B2a aglycon derivatives would be increased when a negatively charged and bulky group was introduced at 13-position, which will be instructive for the further modification of avermectin B2a aglycon.

Mitochondrion-related cardiotoxicity due to cardiotoxin stimuli is closely linked to abnormal activities of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), followed by co-inactivation of nuclear respiratory factor-1(NRF1). Pharmacological interventions targeting mitochondria may be effective for developing agents against cardiotoxicity. Herein, in triptolide-treated H9C2 cardiomyocytes, we observed defective mitochondrial biogenesis and respiration, characterized by depletion of mitochondrial mass and mitochondrial DNA copy number, downregulation of mitochondrial respiratory chain complexes subunits, and disorders of mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Dysregulation of mitochondria led to cardiac pathological features, such as myocardial fiber fracture, intercellular space enlargement, and elevation of serum aspartate aminotransferase, creatine kinase isoenzyme, lactate dehydrogenase, and cardiac troponin I. However, following calycosin treatment, an active compound from Astragali Radix, the mitochondrion-related disorders at both cell and tissue levels were significantly ameliorated, which was facilitated by the activation of PGC-1α via deacetylation, followed by NRF1 co-activation. Calycosin-enhanced PGC-1α deacetylation is impelled by increasing sirtuin-1 expression and NAD

Abstract: The oxadiazole core is considered a privileged moiety in many medicinal chemistry applications. The oxadiazole class includes 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, and 1,2,5-oxadiazole. Compounds bearing an oxadiazole ring show a wide range of biological activities, such as anticancer, antibacterial, anti-inflammatory, anti-malarial, and insecticidal properties. Among oxadiazoles, the 1,3,4-oxadiazole has been the most widely explored moiety in medicinal chemistry research. This review is primarily focused on the anticancer, antibacterial, and anti-inflammatory activities of compounds containing 1,2,4-oxadiazole, 1,3,4-oxadiazole and 1,2,5-oxadiazole reported in the last five years.

Studies have shown that the abnormal activation of the NLRP3 inflammasome is involved in a variety of inflammatory-based diseases. In this study, a high content screening model targeting the activation of inflammasome was first established and pterostilbene was discovered as the active scaffold. Based on this finding, total of 50 pterostilbene derivatives were then designed and synthesized. Among them, compound 47 was found to be the best one for inhibiting cell pyroptosis [inhibitory rate (IR) = 73.09% at 10 μM], showing low toxicity and high efficiency [against interleukin-1β (IL-1β): half-maximal inhibitory concentration (IC50) = 0.56 μM]. Further studies showed that compound 47 affected the assembly of the NLRP3 inflammasomes by targeting NLRP3. The in vivo biological activity showed that this compound significantly alleviated dextran sodium sulfate (DSS)-induced colitis in mice. In general, our study provided a novel lead compound directly targeting the NLRP3 protein, which is worthy of further research and structural optimization.

Directly targeting caveolar caveolin-1 is a potential mechanism to regulate endothelial permeability, especially during oxidative stress, but little evidence on the topic limits therapeutics discoveries. In this study, we investigated the pharmacological effect of an antioxidant LM49 (5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanoe) and its five diphenylmethanone derivatives on endothelial permeability and establish two distinct mechanisms of action. Multiplex molecular assays with theoretical modeling indicate that diphenylmethanone molecules, including LM49, directly bind the caveolin-1 steric pocket of ASN53/ARG54, ILE49/ASP50, ILE18, LEU59, ASN60, GLU48 and ARG19 residues. They also indicated dynamic binding-affinity for diphenylmethanone derivatives. First, this molecular interaction at caveolin-1 pocket inhibits its phosphorylation at TYR14 residue in H

Systemic inflammatory response syndrome is a major feature of sepsis which is one of the major causes of death worldwide. It has been reported that 3,5-diaryl-4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazole moiety into dihydropyrazole skeleton to design and synthesize a novel series of 2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole derivatives, and evaluated their anti-inflammatory activities for sepsis treatment. Preliminary structure−activity relationship (SAR) analysis was conducted by their inhibitory activities against nitric oxide (NO) release in LPS-induced RAW264.7 cells, and the optimal compound E26 exhibited more potent anti-inflammatory activity than the positive control treatment indomethacin and dexamethasone. In further mechanism study, our results showed that compound E26 significantly suppressed the production of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), NO and inhibited the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) through blocking MAPKs signaling pathway. In addition, in vivo administration of compound E26 resulted in a significant improvement of LPS-induced sepsis in C57BL/6J mice, with reducing toxicity in multiple organs. Taken together, this study demonstrated the compound E26 could be a promising agent for the treatment of sepsis.

Novel 1H-purin-6(9H)-one (D) and 3H-imidazo[4,5-d][1,2,3]trazin-4(7H)-one (E) derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry spectra. Their herbicidal activity bioassay showed that compound 7d exhibited relatively good activity with 70.4% inhibition rate against Amaranthus retroflexus in postemergence treatments at 1500 g/ha. Antitumor activity indicated that most of the title compounds displayed potent antitumor activity at 20 μM, among all of the promising compounds possessing lower IC50 values than that of temozolomide, compound 7i demonstrated highest activity inhibiting both HepG-2 and U-118 MG cell lines with IC50 values of 2.0 and 3.8 μM, respectively. The structure–activity relationship analysis revealed that introduction of halogen atoms, a bulky bridging bond between benzene ring and nitrogen atom, longer R2 substituents could contribute to the improvement of antitumor activity. Analysis suggested that compound 7i might have potential as new highly active antitumor agent. Overall, D series had better anticancer activities than E series derivatives.

5,2'-Dibromo-2,4',5'-trihydroxydiphenylmethanone (LM49) exerted therapeutic effects against rat acute pyelonephritis by regulating immune responses, especially affecting T lymphocytes. However, its underlying action mechanism remains unclear. T lymphocytes play an irreplaceable role in immune responses. Therefore, we sought to understand whether LM49 is an immunomodulator of T lymphocytes. The results showed that LM49 promoted T lymphocyte proliferation, increased the number of CD4+ T cells, and increased the CD4+/CD8+ T cell ratio. LM49 regulated the CD4+ T cell subset balance by increasing the production of CD4+IL-2+, CD4+IL-4+, and CD4+IL-10+, and reducing the production of CD4+IL-17+, without changing the production of interferon-γ. LM49 had a significant effect on the mRNA expression of the transcription factors T-bet, GATA3, Foxp3, and RORγt. Furthermore, LM49 raised the phospho (p)-extracellular signal-regulated protein kinase 1/2, p-p38, and p-c-Jun N-terminal kinase expression levels. T cell proliferation, and the production of CD4+IL-2+, CD4+IL-4+, and CD4+IL-10+ induced by LM49, were decreased by inhibitors of mitogen-activated protein kinases (MAPKs). These results revealed that LM49 possesses immunomodulatory activity on T lymphocytes, in which the MAPK pathway plays an essential role.

In the present study, we introduced the nitrogenated heterocycles and fluorine atoms into the 2,5′-dibromo-4,5,2′-trihydroxyl diphenylmethanone (LM49), a bromophenol analog previously reported for its strong antioxidant ability involving in the Keap1–Nrf2 pathway. Twenty-seven fluorophenols 6a–6g, 8a–8k, 10a–10g, and 12a–12b were prepared, evaluated for their antioxidant activity in EA.hy926 cells, and investigated their interacted approach and probable mode of action with key protein Keap1 by molecular docking. Fluorophenols 6f, 8d, 8f, 8h, and 8i with EC50 values ranging from 0.82 to 6.71 µM were found to be more active compared with the standard control quercetin (EC50 = 18 µM). Among them, compound 8h with an EC50 value of 0.82 µM showed the identical activity to lead compound LM49 (EC50 = 0.7 µM). Moreover, the preferable water solubility and forming salt possibility of 8h contribute to its druggability. Further molecular docking of the optimal compound 8h with key protein Keap1 indicated that 8h stably bonded to the receptor protein by the formation of hydrogen bonds, the conjugated six-membered ring was close to the key residue Arg-415 attached to the Nrf2 on Keap1-Kelch, affecting its properties, and the change leaded to the dissociation of Nrf2 from the junction with Keap1-Kelch into the nucleus exerting its antioxidant protective effect. This study introduced a class of fluorophenols containing nitrogenated heterocycles for the development of novel Keap1-Nrf2 protein–protein interaction (PPI) inhibitors. Keap1-Kelch is suggested the most potential target protein for such class of halophenols.

To study the pesticide effect, action mode, structure-activity relationships (SARs) of anthranilic diamide insecticide and screen highly active pesticides, novel anthranilic diamide derivatives were synthesized. Bioassays indicated that all of the title compounds displayed 100% mortality against diamondback moth and oriental armyworm at 100 mg/L, among which 12v and 12w showed 100% insecticidal acitvity at 5 mg/L. Surprisingly compound 12w exhibited better insecticidal acitvity than commercialized chlorantraniliprole against Pyrausta nubilalis (0.1 mg/L) and Cnaphalocrocis Medinalis (2 mg/L). 3D-QSAR and SARs statistical analysis revealed that title compounds with R2 fixed as methoxy had the highest probability possessing high activity. The calcium fluorescence measurements on neurons revealed that E series compounds containing pyrazinyl may have a molecular target different from caffeine on ryanodine receptors rather than the voltage-gated calcium channel present on cytomembran.

Doxorubicin (DOX) is widely used in the chemotherapy of a wide range of cancers. However, intravenous administration of DOX causes toxicity to most major organs which limits its clinical application. DOX-loaded drug delivery system could provide a continuous sustained-release of drugs and enables high drug concentrations at the target site, while reducing systemic toxicity. Additionally, local chemotherapy with DOX may be a promising approach for lowering post-surgical recurrence of cancer. In this study, the sustained-release DOX-loaded implants were prepared by melt-molding method. The implants were characterized with regards to drug content uniformity, micromorphology and drug release profiles. Furthermore, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) analyses were carried out to investigate the drug-excipient compatibility. To determine the local penetration of DOX in liver, the minipigs received intrahepatic implantation of DOX-loaded implants by abdominal surgery. UPLC-MS/MS method was used to detect the concentration of DOX in liver tissues. Our results suggested that DOX-loaded implants delivered high doses of drug at the implantation site for a prolonged period and provided valuable information for the future clinical applications of the DOX-loaded implants.

An important concept, the natural product derivatization method, was introduced and defined to comprehensively evaluate the significance of natural product derivatization in the design and development of pharmaceutical molecules. Therefore, based on the analysis of 464 new molecular entities registered for drugs worldwide from 2010 to 2018, the source, action mode, proportion of new active ingredients contained in “NP (natural product)” and “ND (natural product derivatives),” and structure–activity relationships were reviewed. Finally, the prospect of this method in the field of drug design is discussed.

Chronic inflammation represents a long-term reaction of the body's immune system to noxious stimuli. Such a sustained inflammatory response sometimes results in lasting damage to healthy tissues and organs. In fact, chronic inflammation is implicated in the development and progression of various diseases, including cardiovascular diseases, respiratory diseases, metabolic diseases, neurodegenerative diseases, and even cancers. Targeting nonresolving inflammation thus provides new opportunities for treating relevant diseases. In this review, we will go over several chronic inflammation-associated diseases first with emphasis on the role of inflammation in their pathogenesis. Then, we will summarize a number of natural products that exhibit therapeutic effects against those diseases by acting on different markers in the inflammatory response. We envision that natural products will remain a rich resource for the discovery of new drugs treating diseases associated with chronic inflammation.

Gastric cancer is one of the leading causes of cancer-related death worldwide with a poor prognosis. Gastric cancer is usually treated with surgery and chemotherapy, accompanied by a high rate of metastasis and recurrence. In this paper, R

A feasible analytical method based on high performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry (HPLC-Q/orbitrap MS) has been established for the identification and characterization of anticancer constituents in ethyl acetate components from Hedyotis diffusa in our work. The mass spectrometer provided significant fragment information both in the full MS scan and data-dependent MS2 modes. Sixty-two possible compounds were analyzed and identified from the above results. Of the above 62 compounds, 12 have good separation in the positive ion mode, and 27 compounds have good separation in the anion mode. Currently, 39 have been reported in the literature related to the chemical composition of the plant, while the other 23 of the 62 compounds have not been reported. Fifteen tentatively identified compounds were given detailed descriptions. Four representative compounds from the ethyl acetate extract among the fifteen were actually isolated in good yield with silica gel column chromatography. Meanwhile, their structures were unambiguously identified as scopoletin, vanillic acid, p-coumaric acid and E-6-O-p-coumaroyl scandoside methyl ester using 1H NMR, 13C NMR, IR and UV spectroscopy. The purity of the ethyl acetate extracts, the total flavonoids, from Hedyotis diffusa could reach 65.6%. The inhibitory effect on HepG-2 cells of the total flavonoids was up to 66.2 ± 2.7%. Amentoflavone, quercetin, naringenin, and rutin were selected from the total flavonoids. The amentoflavone and quercetin had better hepatoprotective activity. The inhibition rates of 500 μmol L-1 amentoflavone and quercetin on HepG-2 cells could reach 56.2 ± 8.1% and 78.0 ± 9.3%, respectively. The EtOAc extracts could induce apoptosis in HepG2 cells by blocking the cell cycle in the G0/G1 phase. To the best of our knowledge, this is the first time that Q-orbitrap HRMS was applied to detect potential anticancer compounds in Hedyotis diffusa. This analytical method proved to be a feasible approach for the rapid detection of the potential anticancer compounds from Hedyotis diffusa.

High grade-gliomas are highly invasive and prone to metastasis, leading to poor survival and prognosis. Currently, we urgently need a new treatment strategy to effectively inhibit glioma. In this study, artemether and paclitaxel were used as two agents for tumour suppression. Two functional materials were synthesised and modified on the surface of the micelle as targeting molecules. The addition of two functional materials confers the ability of the micelles to effectively cross the blood-brain barrier (BBB) and then target the glioma cells. Thus, this dual-targeted delivery system allows the drug to play a better role in inhibiting tumour invasion and vasculogenic mimicry (VM) channels. In this paper, the anticancer effects of dual-targeted artemether plus paclitaxel micelles on glioma U87 cells were studied in three aspects: (I)

Thiazole is an important 5-membered heterocyclic compound containing nitrogen and sulfur atoms with various pharmaceutical applications including anti-inflammatory, anti-cancer, anti-viral, hypoglycemic, anti-bacterial and anti-fungal activities. Until now, the FDA-approved drugs containing thiazole moiety have achieved great success such as dasatinib and dabrafenib. In recent years, considerable research has been focused on thiazole derivatives, especially 2,4,5-trisubstituted thiazole derivatives, due to their multiple medicinal applications. This review covers related literature in the past 20 years, which reported the 2,4,5-trisubstituted thiazole as a privileged scaffold in drug design and activity improvement. Moreover, this review aimed to provide greater insights into the rational design of more potent pharmaceutical molecules based on 2,4,5-trisubstituted thiazole in the future.

In this study, total flavonoids and total triterpenoid acid were extracted with ethyl acetate from Hedyotis diffusa Willd, and hepatoprotective activities of them and five compounds from total flavonoids against H

Interfascial plane block is a quick,safe and simple technique that offers effective analgesia for video-assisted thoracotomy.However,the currently described methods still have certain limitations.We explored the application of a novel interfascial plane block method-iliocostal plane block in video-assisted thoracotomy,along with the use of stained cadaveric anatomy,with an attempt to shed new light on the analgesia for video-assisted thoracotomy.