Natural linear coumarin-heterocyclic conjugates: A review of their roles in phytotherapy.

Heterocycle conjugates provide a fresh investigative scope to find novel molecules with enhanced phytotherapeutic characteristics. Coumarin-based products are widely used in the synthesis of several compounds with biological and medicinal properties since they are naturally occurring heterocycles with a broad dispersion. The investigation of coumarin-based phytochemicals with annulated heterocyclic rings is a promising approach to discovering novel conjugates with significant phytotherapeutic attributes. Due to the applicable coumarin extraction processes, a range of linear coumarin-heterocyclic conjugates were isolated from different natural resources and exhibited remarkable therapeutic efficacy. This review highlights the phytotherapeutic potential and origins of various natural linear coumarin-heterocyclic conjugates. We searched several databases, including Science Direct, Web of Science, Springer, Google Scholar, and PubMed. After sieving, we ultimately identified and included 118 pertinent studies published between 2000 and the middle of 2023. This will inspire medicinal chemists with extremely insightful ideas for designing and synthesizing therapeutically active lead compounds in the future that are built on the pharmacophores of coumarin-heterocyclic conjugates and have significant therapeutic attributes.

Synthesis and evaluation of larvicidal efficacy against C. pipiens of some new heterocyclic compounds emanated from 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide.

Several infectious diseases are transmitted and spread by mosquitoes, and millions of people die annually from them. The mosquito, Culex pipiens is a responsible for the emergence of various Virus in Egypt. So, we devote our work to evaluate the larvicidal efficacy against C. pipiens of some new heterocyclic compounds containing chlorine motifs. The implementation was emanated from using 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (3) as scaffold to synthesize some new heterocyclic compounds. The structures of the synthesized compounds were interpreted scrupulously by spectroscopic and elemental analyses. Thereafter, the larvicidal activity against C. pipiens of thirteen synthesized compounds was estimated. Noteworthy, cyanoacetohydrazide derivative 3 and 3-iminobenzochromene derivative 12 showed a fabulous potent efficacy with LC50 equal to 3.2 and 3.5 ppm against C. pipiens, respectively, and are worth being further evaluated in the field of pest control.

Inhibition of Cxcr4 Disrupts Mouse Embryonic Palatal Mesenchymal Cell Migration and Induces Cleft Palate Occurrence.

Many processes take place during embryogenesis, and the development of the palate mainly involves proliferation, migration, osteogenesis, and epithelial-mesenchymal transition. Abnormalities in any of these processes can be the cause of cleft palate (CP). There have been few reports on whether C-X-C motif chemokine receptor 4 (CXCR4), which is involved in embryonic development, participates in these processes. In our study, the knockdown of Cxcr4 inhibited the migration of mouse embryonic palatal mesenchymal (MEPM) cells similarly to the use of its inhibitor plerixafor, and the inhibition of cell migration in the Cxcr4 knockdown group was partially reversed by supplementation with C-X-C motif chemokine ligand 12 (CXCL12). In combination with low-dose retinoic acid (RA), plerixafor increased the incidence of cleft palates in mice by decreasing the expression of Cxcr4 and its downstream migration-regulating gene Rac family small GTPase 1 (RAC1) mediating actin cytoskeleton to affect lamellipodia formation and focal complex assembly and ras homolog family member A (RHOA) regulating the actin cytoskeleton to affect stress fiber formation and focal complex maturation into focal adhesions. Our results indicate that the disruption of cell migration and impaired normal palatal development by inhibition of Cxcr4 expression might be mediated through Rac1 with RhoA. The combination of retinoic acid and plerixafor might increase the incidence of cleft palate, which also provided a rationale to guide the use of the drug during conception.

Copper-Curcumin-Bipyridine Dicarboxylate Complexes as Anticancer Candidates.

In this study, copper complexes with Curcumin (Cur) and 2,2'-bipyridine-5,5'-dicarboxylic acid (BPYD) were synthesized and their cytotoxicity on the MDA-MB-231 cell lines was evaluated. The resulting complex was characterized using FTIR, UV/VIS, CHNS, TGA, ICP-MS, and Mass spectroscopy techniques. The in-vitro cytotoxicity was studied on the MDA-MB-231 as a cancerous cell line and the HUVEC as a normal cell line. Reactive oxygen species (ROS) production was measured using the 2',7'-dichlorofluorescein diacetate (DCFDA) test in the MDA-MB-231 cancer cell lines. The in-vitro assays revealed that all synthesized copper complexes exhibited a higher cytotoxicity effect than carboplatin as a positive control on the MDA-MB-231 cells. While the synthesized complexes exhibited cytotoxic effects on cancerous cell lines, they are practically safe on normal cells. The Cu-Cur-BPYD complexes (a5 & b5) exhibited higher cytotoxicity on MDA-MB-231 cells with IC50 s around 4.9 and 2.3 mM, respectively. It can be concluded that the synthesized Cu-Cur-BPYD complexes (a5 & b5) could be considered effective anticancer candidates in complementary studies.

The Effect of Dual Bioactive Compounds Artemisinin and Metformin Co-loaded in PLGA-PEG Nano-particles on Breast Cancer Cell lines: Potential Apoptotic and Anti-proliferative Action.

The most prevalent malignancy among women is breast cancer. Phytochemicals and their derivatives are rapidly being recognized as possible cancer complementary therapies because they can modify signaling pathways that lead to cell cycle control or directly alter cell cycle regulatory molecules. The phytochemicals' poor bioavailability and short half-life make them unsuitable as anticancer drugs. Applying PLGA-PEG NPs improves their solubility and tolerance while also reducing drug adverse effects. According to the findings, combining anti-tumor phytochemicals can be more effective in regulating several signaling pathways linked to tumor cell development. The point of the study was to compare the anti-proliferative impacts of combined artemisinin and metformin on cell cycle arrest and expression of cyclin D1 and apoptotic genes (bcl-2, Bax, survivin, caspase-7, and caspase-3), and also hTERT genes in breast cancer cells. T-47D breast cancer cells were treated with different concentrations of metformin (MET) and artemisinin (ART) co-loaded in PLGA-PEG NPs and free form. The MTT test was applied to assess drug cytotoxicity in T47D cells. The cell cycle distribution was investigated using flow cytometry and the expression levels of cyclin D1, hTERT, Bax, bcl-2, caspase-3, and caspase-7, and survivin genes were then determined using real-time PCR. The findings of the MTT test and flow cytometry revealed that each state was cytotoxic to T47D cells in a time and dose-dependent pattern. Compared to various state of drugs (free and nano state, pure and combination state) Met-Art-PLGA/PEG NPs demonstrated the strongest anti-proliferative impact and considerably inhibited the development of T-47D cells; also, treatment with nano-formulated forms of Met-Art combination resulted in substantial downregulation of hTERT, Bcl-2, cyclin D1, survivin, and upregulation of caspase-3, caspase-7, and Bax, in the cells, as compared to the free forms, as indicated by real-time PCR findings. The findings suggested that combining an ART/MET-loaded PLGA-PEG NP-based therapy for breast cancer could significantly improve treatment effectiveness.

Limitations of bacterial culture, viral PCR, and tulathromycin susceptibility from upper respiratory tract samples in predicting clinical outcome of tulathromycin control or treatment of bovine respiratory disease in high-risk feeder heifers.

A cross-sectional prospective cohort study including 1026 heifers administered tulathromycin due to high risk of clinical signs of bovine respiratory disease (BRD), measured poor association between BRD clinical outcomes and results of bacterial culture and tulathromycin susceptibility from BRD isolates of deep nasopharyngeal swabs (DNS) and adequate association with viral polymerase chain reaction (PCR) results from nasal swabs. Isolation rates from DNS collected on day-0 and at 1st BRD-treatment respectively were: Mannheimia haemolytica (10.9% & 34.1%); Pasteurella multocida (10.4% & 7.4%); Mycoplasma bovis (1.0% & 36.6%); and Histophilus somni (0.7% & 6.3%). Prevalence of BRD viral nucleic acid on nasal swabs collected exclusively at 1st BRD-treatment were: bovine parainfluenza virus type-3 (bPIV-3) 34.1%; bovine viral diarrhea virus (BVDV) 26.3%; bovine herpes virus type-1 (BHV-1) 10.8%; and bovine respiratory syncytial virus (BRSV) 54.1%. Increased relative risk, at 95% confidence intervals, of 1st BRD-treatment failure was associated with positive viral PCR results: BVDV 1.39 (1.17-1.66), bPIV-3 1.26 (1.06-1.51), BHV-1 1.52 (1.25-1.83), and BRSV 1.35 (1.11-1.63) from nasal swabs collected at 1st BRD-treatment and culture of M. haemolytica 1.23 (1.00-1.51) from DNS collected at day-0. However, in this population of high-risk feeder heifers, the predictive values of susceptible and resistant isolates had inadequate association with BRD clinical outcome. These results indicate, that using tulathromycin susceptibility testing of isolates of M. haemolytica or P. multocida from DNS collected on arrival or at 1st BRD-treatment to evaluate tulathromycin clinical efficacy, is unreliable.

Discovery of potent antiproliferative agents from selected oxygen heterocycles as EGFR tyrosine kinase inhibitors from the U.S. National Cancer Institute database by in silico screening and bioactivity evaluation.

A similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structures related to 1,5-dihydroxy-9H-xanthen-9-one, a previously established EGFR-TK inhibitor. Compounds were virtually screened and selected for bioactivity testing revealed 5 candidates, mostly displayed stronger antiproliferative activities than erlotinib with IC50 values between 0.95 and 17.71 µM against overexpressed EGFR-TK cancer cell lines: A431 and HeLa. NSC107228 displayed the strongest antiproliferative effects with IC50 values of 2.84 and 0.95 µM against A431 and HeLa cancer cell lines, respectively. Three compounds, NSC81111, NSC381467 and NSC114126 inhibited EGFR-TK with IC50 values between 0.15 and 30.18 nM. NSC81111 was the best inhibitor with IC50 = 0.15 nM. Molecular docking analysis of the 3 compounds predicted hydrogen bonding and hydrophobic interactions with key residues were important for the bioactivities observed. Furthermore, calculations of the physicochemical properties suggest the compounds are drug-like and are potentially active orally.

Investigation of chalcogen bioisosteric replacement in a series of heterocyclic inhibitors of tryptophan 2,3-dioxygenase.

Selenium is an underexplored element that can be used for bioisosteric replacement of lower molecular weight chalcogens such as oxygen and sulfur. More studies regarding the impact of selenium substitution in different chemical scaffolds are needed to fully grasp this element's potential. Herein, we decided to evaluate the impact of selenium incorporation in a series of tryptophan 2,3-dioxygenase (TDO2) inhibitors, a target of interest in cancer immunotherapy. First, we synthesized the different chalcogen isosteres through Suzuki-Miyaura type coupling. Next, we evaluated the isosteres' affinity and selectivity for TDO2, as well as their lipophilicity, microsomal stability and cellular toxicity on TDO2-expressing cell lines. Overall, chalcogen isosteric replacements did not disturb the on-target activity but allowed for a modulation of the compounds' lipophilicity, toxicity and stability profiles. The present work contributes to our understanding of oxygen/sulfur/selenium isostery towards increasing structural options in medicinal chemistry for the development of novel and distinctive drug candidates.

The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological illness that causes dementia mainly in the elderly. The challenging obstacles related to AD has freaked global healthcare system to encourage scientists in developing novel therapeutic startegies to overcome with the fatal disease. The current treatment therapy of AD provides only symptomatic relief and to some extent disease-modifying effects. The current approach for AD treatment involves designing of cholinergic inhibitors, Aß disaggregation inducing agents, tau inhibitors and several antioxidants. Hence, extensive research on AD therapy urgently requires a deep understanding of its pathophysiology and exploration of various chemical scaffolds to design and develop a potential drug candidate for the treatment. Various issues linked between disease and therapy need to be considered such as BBB penetration capability, clinical failure and multifaceted pathophisiology requires a proper attention to develop a lead candidate. This review article covers all probable mechanisms including one of the recent areas for investigation i.e., lipid dyshomeostasis, pathogenic involvement of P. gingivalis and neurovascular dysfunction, recently reported molecules and drugs under clinical investigations and approved by FDA for AD treatment. Our summarized information on AD will attract the researchers to understand and explore current status and structural modifications of the recently reported heterocyclic derivatives in drug development for AD therapy.

Green synthesis of selenium based N-heterocyclic carbene compounds; structural, in-vitro anticancer and molecular docking studies.

Benzimidazolium salts (3-6) were synthesized as stable N-Heterocyclic Carbene (NHC) precursors and their selenium-NHC compounds/Selenones (7-10) were prepared using water as a solvent. Characterization of each of the synthesized compounds was carried out by various analytical and spectroscopic (FT-IR, 1H-, 13C NMR) methods. X-ray crystallographic analyses of single crystals obtained for salts 3 and 5 were carried out. Synthesized salts and their Se-NHCs were tested in-vitro for their anticancer potential against Cervical Cancer Cell line from Henrietta Lacks (HeLa), Breast cancer cell line (MDA-MB-231), Adenocarcinoma cell line (A549) and human normal endothelial cell line (EA.hy926). MTT assay was used for analysis and compared with standard drug 5-flourouracil. Benzimidazolium salts (3-6) and their selenium counter parts (7-10) were found potent anticancer agents. Salt 3-5 were found to be potent anticancer against HeLa with IC50 values 0.072, 0.017 and 0.241 µM, respectively, which are less than standard drug (4.9 µM). The Se-NHCs (7-10) had also shown significant anticancer potential against HeLa with IC50 values less than standard drug. Salts 3, 4 against EA.hy926, compounds 3,5,6, and 10 against MDA-MB-321, and compounds 4, 10 against A-549 cell line were found more potent anticancer agents with IC50 values less than standard drug. Molecular docking for (7-10) showed their good anti-angiogenic potential having low binding energy and significant inhibition constant values with VEGFA (vascular endothelial growth factor), EGF (human epidermal growth factor), COX1 (cyclooxygenase-1) and HIF (hypoxia inducible factor).

Chemical profile and potential mechanisms of Huo-Tan-Chu-Shi decoction in the treatment of coronary heart disease by UHPLC-Q/TOF-MS in combination with network pharmacology analysis and experimental verification.

Huo-Tan-Chu-Shi Decoction (HTCSD), a traditional Chinese medicine (TCM) prescription within Guangdong Provincial TCM Hospital (the largest TCM hospital in China), is used for effective clinical treatment of coronary heart disease (CHD) caused by phlegm-dampness syndrome with high incidence in the hot and humid climate of Lingnan region. However, its chemical components responsible for the therapeutic effects remain unclear, which restricts its application and further development. Hence, a detailed workflow, combing with UHPLC-Q/TOF-MS, network pharmacology analysis and experimental verification, was proposed and applied to characterize the chemical profile and potential mechanism of HTCSD against CHD. As a result, a total of 130 components from all six composed herbal medicines were characterized in a rapid and sensitive manner through UHPLC-Q/TOF-MS, of which 33 compounds were unambiguously confirmed with reference standards. Consequently, based on the integrated pharmacology network of "herbs-chemicals-targets-pathways-therapeutic effects", four chemicals (magnoflorine, menisperine, 13-hydroxyberberine, luteolin) with four CHD related targets (SRC, MAPK1, EGFR and AKT1) were considered as the key components and targets of HTCSD in the treatment of CHD. Furthermore, the effect of HTCSD was confirmed in animal experiments by enhancing the phosphorylation of MAPK, and the published literature and molecular binding results suggested that magnoflorine and luteolin tended to be the critical compounds involved in the process. Taken together, the characterization of chemical profile combined with network pharmacology analysis and experimental verification not only provided an efficient insight into the overall chemical profile of HTCSD but also revealed the potential pharmacological components and mechanisms of HTCSD against CHD, which laid a necessary chemical and biological basis for the discovery of in vivo bioactive components and the further revelation of functionary mechanism.

Magnetic nanocatalysts as multifunctional platforms in cancer therapy through the synthesis of anticancer drugs and facilitated Fenton reaction.

Background: Heterocyclic compounds have always been used as a core portion in the development of anticancer drugs. However, there is a pressing need for developing inexpensive and simple alternatives to high-cost and complex chemical agents-based catalysts for large-scale production of heterocyclic compounds. Also, development of some smart platforms for cancer treatment based on nanoparticles (NPs) which facilitate Fenton reaction have been widely explored by different scientists. Magnetic NPs not only can serve as catalysts in the synthesis of heterocyclic compounds with potential anticancer properties, but also are widely used as smart agents in targeting cancer cells and inducing Fenton reactions. Aim of Review: Therefore, in this review we aim to present an updated summary of the reports related to the main clinical or basic application and research progress of magnetic NPs in cancer as well as their application in the synthesis of heterocyclic compounds as potential anticancer drugs. Afterwards, specific tumor microenvironment (TME)-responsive magnetic nanocatalysts for cancer treatment through triggering Fenton-like reactions were surveyed. Finally, some ignored factors in the design of magnetic nanocatalysts- triggered Fenton-like reaction, challenges and future perspective of magnetic nanocatalysts-assisted synthesis of heterocyclic compounds and selective cancer therapy were discussed.Key Scientific Concepts of Review:This review may pave the way for well-organized translation of magnetic nanocatalysts in cancer therapy from the bench to the bedside.

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of -6.7 kcal/mol compared with the -6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.

The potency of heterocyclic curcumin analogues: An evidence-based review.

Curcumin, a potent phytochemical, has been a significant lead compound and has been extensively investigated for its multiple bioactivities. Owing to its natural origin, non-toxic, safe, and pleiotropic behavior, it has been extensively explored. However, several limitations such as its poor stability, bioavailability, and fast metabolism prove to be a constraint to achieve its full therapeutic potential. Many approaches have been adopted to improve its profile, amongst which, structural modifications have indicated promising results. Its symmetric structure and simple chemistry have prompted organic and medicinal chemists to manipulate its arrangement and study its implications on the corresponding activity. One such recurring and favorable modification is at the diketo moiety with the aim to achieve isoxazole and pyrazole analogues of curcumin. A modification at this site is not only simple to achieve, but also has indicated a superior activity consistently. This review is a comprehensive and wide-ranged report of the different methods adopted to achieve several cyclized curcumin analogues along with the improvement in the efficacy of the corresponding activities observed.

Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M.

One compound sometimes shows two biological functions, becoming important aspect of recent drug discovery. This study began with an attempt to confirm the previously reported molecular mechanism of the anti-human immunodeficiency virus (HIV) heterocyclic compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], i.e., induction of abnormal uncoating of the viral core at the post-entry step. Our mechanistic study gave results consistent with this mechanism. We further attempted to find out the molecular target of BMMP by a pulldown approach using previously synthesized biotinylated BMMP (Biotin-BMMP) and successfully identified heterogenous nuclear ribonucleoprotein M (hnRNP M) as a BMMP-binding protein. This protein was found not to be accountable for the anti-HIV activity of BMMP. As hnRNP M has been reported to promote cancer metastasis, we tested this mechanism and found that BMMP suppressed migration of the human lung carcinoma cell line A549 stimulated with transforming growth factor-ß (TGF-ß). Mechanistic study showed that BMMP suppressed the expression of CD44 mRNA via the regulation of hnRNP M. Furthermore, six new derivatives of BMMP were synthesized, and the patterns of their activities against HIV-1 and cell migration were not uniform, suggesting that the anti-HIV mechanism and the anti-cell migration mechanism of BMMP are independent. Taken together, the anti-cell migration activity of the anti-HIV heterocyclic compound BMMP was newly discovered by identification of its binding protein hnRNP M using a chemical biology approach.

Antimutagenic effect of an Asclepias subulata extract against heterocyclic aromatic amines commonly found in cooked meat and its heat stability.

The antimutagenicity of an extract from the medicinal plant Asclepias subulata (ASE) against heterocyclic aromatic amines (HAAs) commonly found in cooked meat, as well as its stability to heat treatment (HT), was evaluated. HT (180 °C/3 min) had no effect on the content in ASE of the bioactive compound corotoxigenin-3-O-glucopyranoside; conversely, calotropin significantly decreased by 72%. ASE exerted antimutagenicity against PhIP, MelQ, and MelQx in TA98 and TA100 Salmonella strains, and this activity was not affected by heat, with the exception of MelQ (p < 0.05). Since HAAs can induce colorectal cancer, the thermal stability of ASE's antiproliferative effect against colorectal cancer cells was also evaluated. HT decreased (p < 0.05) the antiproliferative activity of ASE; however, the remaining activity was still strong with an IC50 of 16.8 ± 2.03 µg/mL. Therefore, ASE can be used as a food ingredient to reduce the carcinogenic potential of thermally induced HAAs.

Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build-up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated with poor relapse-free and overall survival. The CXCR4 ligand, CXCL12 (SDF-1), is expressed by multiple cells types in the BM, facilitating the adhesion and survival of the malignant clone. Blocking the CXCL12/CXCR4 axis is an attractive therapeutic strategy providing a 'multi-hit' therapy that both prevents essential survival signals and releases the AML cells from the BM into the circulation. Once out of the protective niche of the BM they would be more susceptible to destruction by conventional chemotherapeutic drugs. In this review, we disentangle the diverse roles of the CXCL12/CXCR4 axis in AML. We then describe multiple CXCR4 inhibitors, including small molecules, peptides, or monoclonal antibodies, which have been developed to date and their progress in pre-clinical and clinical trials. Finally, the review leads us to the conclusion that there is a need for further investigation into the development of a 'multi-hit' therapy that targets several signalling pathways related to AML cell adhesion and maintenance in the BM.

In-vitro Anti-cancer assay and apoptotic cell pathway of newly synthesized benzoxazole-N-heterocyclic hybrids as potent tyrosine kinase inhibitors.

A series of benzoxazole-N-heterocyclic hybrids have been synthesized by a one-pot strategy. Molecular docking study revealed that such compounds have the ability to inhibit enzyme protein tyrosine kinase. The findings of this work have been the successful synthesis of benzoxazole scaffolds, featuring hybrids of benzoxazole with quinoline and quinoxaline respectively. The molecular docking studies have showed these compounds to be inhibitors of tyrosine kinase enzyme which triggers growth of cancer cells. The cytotoxicity study of compounds 4a-f showed better potency against breast cancer cell lines MCF-7 and MDA-MB-231 in contrast to oral and lung cancer cell lines KB and A549. The tyrosine kinase activity was measured using Universal Tyrosine Kinase Assay kit using horseradish peroxide (HRP)-conjugated anti-phosphotyrosine kinase solution as a substrate. The compounds 4c exhibited maximum inhibition in the activity of enzyme tyrosine kinase with IC50 value 0.10 ±â€¯0.16 µM, than other compounds which were studied and thus proved to be inhibitors of enzyme tyrosine kinase. The selective index of all four compounds was found out to be greater than two, indicating the non-toxic behaviour, i.e. good anti-cancer activity. Further, fluorescence microscopic study helped to characterize the mode of cell death, which was found to be late apoptosis as indicated by the orange fluorescence. The SAR analysis has also been carried out.

Effects of treatment with enrofloxacin or tulathromycin on fecal microbiota composition and genetic function of dairy calves.

The increasing concerns with antimicrobial resistance highlights the need for studies evaluating the impacts of antimicrobial use in livestock on antimicrobial resistance using new sequencing technologies. Through shotgun sequencing, we investigated the changes in the fecal microbiome composition and function, with a focus on functions related to antimicrobial resistance, of dairy calves. Heifers 2 to 3 weeks old, which were not treated with antibiotics by the farm before enrollment, were randomly allocated to one of three study groups: control (no treatment), a single treatment of enrofloxacin, or a single treatment of tulathromycin. Fecal samples were collected at days 4, 14, 56 and 112 days after enrollment, and DNA extraction and sequencing was conducted. The effect of antibiotic treatment on each taxon and genetic functional level by time (including Day 0 as a covariate) revealed few changes in the microbiota. At the genus level, enrofloxacin group had higher relative abundance of Blautia, Coprococcus and Desulfovibrio and lower abundance of Bacteroides when compared to other study groups. The SEED database was used for genetic functional analyses, which showed that calves in the enrofloxacin group started with a higher relative abundance of "Resistance to antibiotics and toxic compounds" function on Day 0, however an increase in antibiotic resistance genes after treatment with enrofloxacin was not observed. "Resistance to Fluoroquinolones" and "Erythromycin resistance", of relevance given the study groups, were not statistically different in relative abundance between study groups. "Resistance to fluoroquinolones" increased during the study period regardless of study group. Despite small differences over the first weeks between study groups, at Day 112 the microbiota composition and genetic functional profile was similar among all study groups. In our study, enrofloxacin or tulathromycin had minimal impacts on the microbial composition and genetic functional microbiota of calves over the study period.

[Effect of triptolide in improving platelet activation in patients with ankylosing spondylitis by regulating VEGFA,SDF-1,CXCR4 pathway].

The effect of triptolide( TP) on VEGFA,SDF-1,CXCR4 pathway were investigated in vitro to explore the mechanism in improving platelet activation in patients with ankylosing spondylitis( AS). Peripheral blood mononuclear cells( PBMC) were used for the experiment and divided into 4 groups: normal group( NC),model group( MC),triptolide group( TP),and AMD3100 group. The optimal concentration of TP was measured by the MTT method. The expressions of TNF-α,IL-1ß,IL-4,IL-10,VEGFA and VEGFR were detected by ELISA. The expressions of SDF-1,CXCR4 and VEGFA were detected by real-time quantitative PCR( RT-qPCR).The expressions of SDF-1,CXCR4,VEGFA and VEGFR were detected by Western blot. The expression levels of CD62 p,CD40 L and PDGFA were detected by immunofluorescence. MTT results showed that medium-dose TP had the strongest inhibitory effect on cells at24 h. The results of ELISA and PCR showed that TP inhibited mRNA expressions of IL-1ß,TNF-α,VEGFA,VEGFR and SDF-1,CXCR4 and VEGFA. The results of Western blot indicated that TP inhibited SDF-1,CXCR4 and VEGFA,VEGFR protein expressions; immunofluorescence results indicate that TP can inhibit the expressions of CD62 p,CD40 L,PDGFA. TP may regulate platelet activation by down-regulating SDF-1,CXCR4,VEGFA and VEGFR mRNA expressions,thereby down-regulating IL-1ß and TNF-αexpressions,and up-regulating the expressions of IL-4 and IL-10 cytokines.