Discovery of Simple Diacylhydrazine-Functionalized Cinnamic Acid Derivatives as Potential Microtubule Stabilizers.

To develop novel microtubule-binding agents for cancer therapy, an array of N-cinnamoyl-N'-(substituted)acryloyl hydrazide derivatives were facilely synthesized through a two-step process. Initially, the antiproliferative activity of these title compounds was explored against A549, 98 PC-3 and HepG2 cancer cell lines. Notably, compound I23 exhibited the best antiproliferative activity against three cancer lines with IC50 values ranging from 3.36 to 5.99 µM and concurrently afforded a lower cytotoxicity towards the NRK-52E cells. Anticancer mechanism investigations suggested that the highly bioactive compound I23 could potentially promote the protofilament assembly of tubulin, thus eventually leading to the stagnation of the G2/M phase cell cycle of HepG2 cells. Moreover, compound I23 also disrupted cancer cell migration and significantly induced HepG2 cells apoptosis in a dosage-dependent manner. Additionally, the in silico analysis indicated that compound I23 exhibited an acceptable pharmacokinetic profile. Overall, these easily prepared N-cinnamoyl-N'-(substituted)acryloyl hydrazide derivatives could serve as potential microtubule-interacting agents, probably as novel microtubule-stabilizers.

1,2,4-Trimethoxybenzene selectively inhibits NLRP3 inflammasome activation and attenuates experimental autoimmune encephalomyelitis.

NOD-like receptor (NLR) family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in inflammation-associated diseases such as multiple sclerosis, Parkinson's disease, and stroke. Targeting the NLRP3 inflammasome is beneficial to these diseases, but few NLRP3 inflammasome-selective inhibitors are identified to date. Essential oils (EOs) are liquid mixtures of volatile and low molecular-weight organic compounds extracted from aromatic plants, which show various pharmacological activities, including antibacterial, antifungal, antiviral, antioxidant, and anti-inflammatory properties. In this study we screened active ingredients from essential oils, and identified 1,2,4-trimethoxybenzene (1,2,4-TTB) as a selective NLRP3 inflammasome inhibitor. We showed that 1,2,4-TTB (1 mM) markedly suppressed nigericin- or ATP-induced NLRP3 inflammasome activation, thus decreased caspase-1 activation and IL-1ß secretion in immortalized murine bone marrow-derived macrophages (iBMDMs) and in primary mouse microglia. Moreover, 1,2,4-TTB specifically inhibited the activation of NLRP3 inflammasome without affecting absent in melanoma 2 (AIM2) inflammasome activation. We further demonstrated that 1,2,4-TTB inhibited oligomerization of the apoptosis-associated speck-like protein containing a CARD (ASC) and protein-protein interaction between NLRP3 and ASC, thus blocking NLRP3 inflammasome assembly in iBMDMs and in primary mouse macrophages. In mice with experimental autoimmune encephalomyelitis (EAE), administration of 1,2,4-TTB (200 mg · kg-1 · d-1, i.g. for 17 days) significantly ameliorated EAE progression and demyelination. In conclusion, our results demonstrate that 1,2,4-TTB is an NLRP3 inflammasome inhibitor and attenuates the clinical symptom and inflammation of EAE, suggesting that 1,2,4-TTB is a potential candidate compound for treating NLRP3 inflammasome-driven diseases, such as multiple sclerosis.

[Research progress of TRPV4 and cerebral ischemic reperfusion injury].

Transient receptor potential vanilloid 4 (TRPV4) channel is a member of transient receptor potential superfamily. TRPV4 is selectively permeable to calcium. Activation of the TRPV4 channel induces an increase in intracellular calcium concentration and plays an important role under physiological and pathological conditions. Especially, there is evidence showing that TRPV4 is involved in cerebral ischemic reperfusion injury. The present paper reviewed some research progress about the role of TRPV4 in cerebral ischemic reperfusion injury.

Discovery of tryptanthrin analogues bearing F and piperazine moieties as novel phytopathogenic antibacterial and antiviral agents.

BACKGROUND: Plant bacterial infections and plant viruses seriously affect the yield and quality of crops. Based on the various activities of tryptanthrin, a series of tryptanthrin analogues bearing F and piperazine moieties were designed, synthesized, and evaluated for their biological activities against three plant bacteria and tobacco mosaic virus (TMV). RESULTS: Bioassay results indicated that compounds 6a-6l displayed excellent antibacterial activities in vitro and 6a-6c and 6g exhibited better antiviral activities against TMV than commercial ribavirin. In particular, 6b showed the most effect on Xanthomonas oryzae pv. oryzae (Xoo) with a half-maximal effective concentration (EC50 ) of 1.26 µg mL-1 , compared with the commercial pesticide bismerthiazol (BT; EC50 = 34.3 µg mL-1 ) and thiodiazole copper (TC; EC50 = 73.3 µg mL-1 ). Meanwhile, 6a also had the best antiviral activity at 500 µg mL-1 for curative, protection, and inactivation purposes, compared with ribavirin in vivo. CONCLUSION: Compound 6b could cause changes in bacterial morphology, induce the accumulation of reactive oxygen species, promote apoptosis of bacterial cells, inhibit the formation of biofilm, and block the growth of Xoo cells. Proteomic analysis revealed major differences in the bacterial secretory system pathways T2SS and T6SS, which inhibited membrane transport. Molecular docking revealed that 6a and 6g could interact with TMV coat protein preventing virus assembly. These results suggest that tryptanthrin analogues bearing F and piperazine moieties could be promising candidate agents for antibacterial and antiviral use in agricultural production. © 2023 Society of Chemical Industry.

Design, synthesis, antibacterial evaluation of isopropylamine linked with different substituted phenol and piperazine novel derivatives.

BACKGROUND: Xanthomonas oryzae pv. oryzae (Xoo) is often considered one of the most destructive bacterial pathogens causing bacterial leaf blight (BLB), resulting in significant yield and cost losses in rice. In this study, a series of novel derivatives containing the isopropanolamine moiety linked to various substituted phenols and piperazines were designed, synthesized and screened. RESULTS: Antibacterial activity results showed that most compounds had good inhibitory effects on Xoo, among which compound W2 (EC50 = 2.74 µg mL-1) exhibited the most excellent inhibitory activity, and W2 also had a certain curative effect (35.89%) on rice compared to thiodiazole copper (TC) (21.57%). Scanning electron microscopy (SEM) results indicated that compound W2 could cause rupture of the Xoo cell membrane. Subsequently, proteomics and quantitative real-time polymerase chain reaction revealed that compound W2 affected the physiological processes of Xoo and may exert antibacterial activity by targeting the two-component system pathway. Interestingly, W2 upregulated Xoo's methyltransferase to impact on its pathogenicity. CONCLUSION: The present study offers a promising phenolic-piperazine-sopropanolamine compound as an innovative antibacterial strategy by specifically targeting the two-component system pathway and inducing upregulation of methyltransferase to effectively impact Xoo's pathogenicity. © 2024 Society of Chemical Industry.

Quantitative detection of relative expression levels of the whole genome of Southern rice black-streaked dwarf virus and its replication in different hosts.

BACKGROUND: In recent years, a disease caused by Southern rice black-streaked dwarf virus (SRBSDV) has resulted in significant loss in rice production in Southern China and has spread quickly throughout East and Southeast Asia. This virus is transmitted by an insect vector, white-backed planthopper (WBPH) Sogatella furcifera (Hemiptera: Delphacidae), in a persistent propagative manner. Aside from rice, SRBSDV can also infect numerous Poaceae plants. However, the molecular mechanism of interaction between SRBSDV and its plant or insect vector remains unclear. In order to address this, we investigated the whole viral genome relative mRNA expression level in distinct hosts and monitored their expression level in real-time in rice plants. METHODS: In this study, a reliable, rapid, and sensitive method for detecting viral gene expression transcripts is reported. A SYBR Green I based real-time polymerase chain reaction (PCR) method was adopted for the quantitative detection of SRBSDV gene expression in different hosts and real-time changes in gene expression in rice. RESULTS: Compared to the relative mRNA expression level of the whole genome of SRBSDV, P3, P7-1, and P9-2 were dominantly expressed in rice and WBPH. Similarly, these genes also exhibited high expression levels in corn, suggesting that they have more important functions than other viral genes in the interaction between SRBSDV and hosts, and that they could be used as molecular detection target genes of SRBSDV. In contrast, the levels of P6 and P10 were relative low. Western blotting analysis partially was also verified our qPCR results at the level of protein expression. Analysis of the real-time changes in SRBSDV-infected rice plants revealed four distinct temporal expression patterns of the thirteen genes. Moreover, expression levels of P1 and other genes were significantly down-regulated on days 14 and 20, respectively. CONCLUSION: SRBSDV genes showed similar expression patterns in distinct hosts (rice, corn, and WBPH), indicating that SRBSDV uses the same infection strategy in plant and insect hosts. P3, P7-1, and P9-2 were the dominantly expressed genes in the three tested hosts. Therefore, they are likely to be genes with the most crucial function and could be used as sensitive molecular detection targets for SRBSDV. Furthermore, real-time changes in SRBSDV genes provided a basis for understanding the mechanism of interaction between SRBSDV and its hosts.

Allicin-inspired disulfide derivatives containing quinazolin-4(3H)-one as a bacteriostat against Xanthomonas oryzae pv. oryzae.

BACKGROUND: Plant bacterial diseases have seriously affected the yield and quality of crops, among which rice bacterial leaf blight (BLB), caused by Xanthomonas oryzae pv. oryzae has seriously affected the yield of rice. As plant-pathogenic bacteria gradually become resistant to existing bactericides, it is necessary to find effective bactericides with novel structures. RESULTS: Herein, a series of compounds containing quinazolin-4(3H)-one and disulfide moieties were designed and synthesized using a facile synthetic method. The bioassay results revealed that most target compounds possessed noticeable antibacterial activity against Xanthomonas oryzae pv. oryzae. Particularly, compound 2-(butyldisulfanyl) quinazolin-4(3H)-one (1) exhibited remarkable antibacterial activity with the half effective concentration (EC50 ) of 0.52 µg mL-1 . Additionally, compound 1 was confirmed to inhibit the growth of the bacteria, change the bacterial morphology, and increase the level of reactive oxygen species. Proteomics, and RT-qPCR analysis results indicated that compound 1 could downregulate the expression of Pil-Chp histidine kinase chpA encoded by the pilL gene, and the potting experiments proved that compound 1 exhibits significant protective activity against BLB. CONCLUSIONS: Compound 1 may weaken the pathogenicity of Xanthomonas oryzae pv. oryzae by inhibiting the bacterial growth and blocking the pili-mediated twitching motility without inducing the bacterial apoptosis. This study indicates that such derivatives could be a promising scaffold to develop a bacteriostat to control BLB. © 2022 Society of Chemical Industry.

Highly Selective and Sensitive Detection of Biogenic Defense Phytohormone Salicylic Acid in Living Cells and Plants Using a Novel and Viable Rhodamine-Functionalized Fluorescent Probe.

Detecting plant-derived signal molecules using fluorescent probes is a key topic and a huge challenge for scientists. Salicylic acid (SA), a vital plant-derived defense hormone, can activate global transcriptional reprogramming to systemically express a network of prominent pathogenesis-related proteins against invasive microorganisms. This strategy is called systemic acquired resistance (SAR). Therefore, monitoring the dynamic fluctuations of SA in subcellular microenvironments can advance our understanding of different physiological and pathological functions during the SA-induced SAR mechanism, thus benefiting the discovery and development of novel immune activators that contribute to crop protection. Here, detection of signaling molecule SA in plant callus tissues was first reported and conducted by a simple non-fluorescent rhodamine-tagged architecture bearing a flexible 2-amino-N,N-dimethylacetamide pattern. This study can markedly advance and promote the usage of fluorescent SA probes for distinguishing SA in the plant kingdom.

Development of proteomic technology of shotgun and label free combined with multiple reaction monitoring to simultaneously detect southern rice black-streaked dwarf virus and rice ragged stunt virus.

The co-infection of rice caused by southern rice black-streaked dwarf virus (SRBSDV) and rice ragged stunt virus (RRSV) was widely found at many regions, such as Yunnan Province, China, and North and Central Vietnam. These rice viral diseases lead to seriously yield loss of rice. In this study, the proteomics technology of shotgun and label free combined with multiple reaction monitoring (MRM) was developed to detect rice sample of a single or/and co-infection. The shotgun assay indicated that some proteins coded by SRBSDV and RRSV were detected via the mode of in-gel digestion, except for P5-2, P7-2 and P9-2 of SRBSDV and P4b, P5, P6, P8a and P8b of RRSV. The technology of label free combined with MRM indicated that P2, P5-1, P4, P8, P7-1, P6, P9-1 and P10 of SRBSDV and P1, P3 and P9 of RRSV were higher abundance in rice plant, and P5-2, P7-2 and P9-2 of SRBSDV and P4b and P5 of RRSV were lower abundance in viruliferous-rice plant. So SRBSDV P9-1 and RRSV P3 was selected as marker molecule to be used in detection technology, and the label free combined with MRM technology was established to detect two kinds of rice virus.